BioXcel Therapeutics, Inc. (BTAI) Earnings Call Transcript & Summary

Greetings, and welcome to the BioXcel Therapeutics KOL Virtual Roundtable Day. It is now my pleasure to introduce Vimal Mehta, CEO. Thank you. You may begin.

I'd like to start by welcoming our participants. We are thankful for your leadership and expertise in the Alzheimer's agitation space, particularly as we focus on the significant and underaddressed challenge of acute agitation episodes in Alzheimer's dementia. Next, I would like to thank our moderator, Anjalee Khemlani, an award-winning journalist who moderated our last panel in December. We are thankful to have her experienced voice be the guide for today's conversation among our distinguished KOLs. There are currently no FDA approved treatments specifically for acute episodes leaving a critical gap for patients, caregivers and clinicians managing these episodes. The need for a treatment specific to acute agitation episodes remain urgent. At BioXcel Therapeutics, we are steadfast in our commitment to advance meaningful innovation in areas of unmet need such as this one. Our mission is to advance BXCL501 to reach patients and caregivers who currently face limited treatment options. In the previously announced results from a Phase III pivotal study of BXCL501 for the acute treatment of agitation in Alzheimer's dementia BXCL501 was well tolerated and met its primary efficacy endpoint. Anjalee, I will turn it over to you for the panel.

Thank you so much, Vimal. Hello to everyone. And let me take a minute to introduce this wonderful panel. We've got Dr. George Grossberg, Dr. Anton Porsteinsson and Dr. Angela Sanford, I'm going to give you all a minute to quickly introduce yourselves. Let's start off with Dr. Sanford.

Hi. My name is Dr. Angela Sanford. I'm a Professor of Geriatric Medicine at Saint Louis University, and I'm also serving as the Interim Division Director of the Division of Geriatric Medicine. Thank you for having me today.

Of course, welcome aboard. Dr. Porsteinsson.

Yes. Good afternoon, good morning, depending on where you are. Anton Porsteinsson, by training, a geriatric neuro psychiatrist that I specifically focus on the current study of older individuals with dementia, such as Alzheimer's disease. And I'm a professor at the University of Rochester School of Medicine. Pleasure to be here.

Welcome. And then finally, last but not least, Dr. Grossberg.

Thank you. George Grossberg, I'm an academic geriatric psychiatrist at Saint Louis University School of Medicine, and I have a new endowed Professor ship, which is the Dr. Henry and Amelia Nasrallah Professorship. But I've been in this space Alzheimer's disease and specifically developing new treatments for neuropsychiatric symptoms of Alzheimer's disease, like Dr. Porsteinsson for a number of years. I am speaking to you now from one of our teaching nursing homes which is an environment where obviously new treatments for particularly acute behaviors are sorely needed. Happy to be here.

And my goodness, you talk about being on the ground level to understand this very important subject. Well, thank you all for joining us. And I want to start out with getting our hands wrapped around the acute agitation issue. So as we understand it, episodes in Alzheimer's dementia remain significantly under addressed. It is an issue that affects so many millions of people and their caregivers and to your point, Dr. Grossberg as well in care facility. So this is an issue that is really something that we need to look at. It's something that has no real solution other than basically sedating patients as far as they understand. And so I'd love to start off with Dr. Grossberg, we're going to kind of get our handle around why this conversation is important. What do we need to understand about acute agitation and it's sort of a debilitating impact on care and caregiving.

Yes. No. I think that's a great question. I think most of us, when we think about agitation in disorders like Alzheimer's disease, think of it as kind of a chronic persistent problem. And currently the only FDA-approved medication for agitation in Alzheimer's disease as well as almost every other drug in the pipeline, except for the one we're going to be talking about today, focuses on more persistent or chronic agitation. In fact, the International Psychogeriatric Association, the IPA, who have developed the diagnostic criteria for agitation. Those criteria call for pretty much persistent day-to-day agitated behaviors that are impacting quality of life for at least 2 weeks or longer. So they don't really address acute agitation which can occur intermittently, which can occur even during the course of more persistent kind of chronic agitation. And of course, when it happens in the nursing home like where I'm at right now, often it's a reason why patients are sent to the hospital to the emergency room. If it happens at home or the family is taking care of someone who has an acute aggressive or agitated behavior, Often, they're also rushing off to the emergency room. So it's a reason for heavy utilization of health care resources and we do not have anything currently that's FDA approved for the acute agitated episodes.

Maybe if you can tell us a little bit about what is currently out there? Why it's looked at in terms of a chronic management situation and how we can think about what defines chronic versus acute?

There are not many FDA-approved medications, really only the one that I know of for even chronic agitation. And acutely, we will try anything in the acute setting, not anything, but we have not very good medications, medications that aren't very safe to use in older adults, but we use as last resorts. And that's sort of what we're stuck with in the acute settings. Like Dr. Grossberg, I work in the nursing home. And yesterday, I had a patient that was acutely agitated and the nurse was saying, I don't know what to do. What can we give her? This is not going to work out today for us to deal with this. So it's a very chronic problem with acute flares and it can really impact quality of life for patients and caregivers.

Portion maybe explain to us what -- how it presents in the acute form and then how it presents maybe more in the product form?

Absolutely. So I want to make sure we understand that episodic agitation or acute agitation, those are the 2 terms that we use pretty interchangeably, it can happen in any setting, it that can happen in long-term care. So a skilled nursing facility. It can happen in an assisted living facility, and it certainly happens at home in the community. So you heard George talk about the diagnostic criteria for agitation according to the IPA criteria. And there, you require at least 2 weeks of relatively frequent occurrence of agitation, and you also want a certain intensity of that agitation. And agitation is one of the most distressing behavioral disruption in Alzheimer's disease as well as other dementias. The episodic agitation is, on the other hand, it happens sporadically. It happens episodically. It can happen in someone who doesn't have chronic agitation but it can also happen for someone who has chronic agitation. But now whether you use nonpharmacological interventions or medicines like the one that is approved for that brexpiprazole, you still can have these kind of breakthrough episodic agitated behaviors. They often are associated with the patient not understanding what's going on, getting overwhelmed and just kind of boiling over, becoming restless, there can also be verbal aggressiveness, even physical aggressiveness. It can be because someone is uncomfortable. They've got pain, they cannot communicate what's going on. It can be very simply that someone wants to be left alone all the time. And you can't do that. You have to provide care. You have to provide attention. It can be personal hygiene. It can be attending to urinary or bowel needs, et cetera, and it creates this blow up. And I can give you another example. One of my patients lived with her husband, their kids, grandkids, lived one city over 45-minute drive. Every time that they thought about visiting the grandkids, the family, just the right over, she would get so agitated, so restless. Yet whenever he was there, she was happy. It gave her husband reprieve, allowed them to connect with family. But that -- those are the types of situations where we can have this bubble up. And what often will happen is that you stop going out, you stop socializing. You stop seeing family, you stop seeing friends. You don't get the care that you need or should be entitled to because people, be it family caregivers, professional caregivers have to deal with the intensity of these behaviors.

Yes. It seems like it could be really disruptive to daily life. And so having a solution and one that would be easy for caregivers in addition to be able to use is really necessary. I also have started thinking a lot more about how we're sort of in a phase of having more care needed for an increasingly elderly population. And so not only are these treatments needed because of the ongoing need, but also because volume-wise, there is an opportunity there. So let's break that down a little bit, right? In terms of looking at the population and understanding who benefits the most, what does a treatment like BXCL501 have what opportunity does it have to help the market help caregivers help in facilities, but also to help maybe bring down the cost of emergency care as well. Maybe Dr. Grossberg, you can start there. Dr. Grossberg?

I didn't know you were calling on me. I'm sorry. Yes. So I alluded to some of the issues that you brought up a whole lot of different things. But obviously, we know the demographic imperative that the population is aging and that the most rapidly growing segment of our population are older adults. We know that the Alzheimer's population is expected to double or more in the next couple of decades. We have already over 7 million individuals. And I think Anton, as you pointed out, these people are living with Alzheimer's disease in different locations. They may be living at home with family. They may be in memory care, assisted living, they may be in skilled nursing or long-term care retirement communities. And as the numbers of Alzheimer's patients increases, obviously, we're seeing more and more of the neuropsychiatric or behavioral problems and the most disturbing and common behavioral problem is what I call the spectrum of agitated behaviors. Everything from irritability to anxiety to more overtly agitated behavior to even more overtly aggressive behaviors. And when you see the most overt behaviors, including aggressive kind of behaviors, no matter what setting one is in, then you need to take that patient usually to the hospital to find out what's going on. And once they get to the hospital, we use off-label treatments that can make things worse. We use antipsychotic medications, like quetiapine and drugs like olanzapine and so on, which can sedate the patient, increase the risk of falls, making it really hard to figure out what's going on. I think Anton, you pointed out so many of the good triggers of agitation, whether it's pain or infections or environmental changes. There are quite a few things that we need to look at. But first, you need to get the patient under control, and you need something that's going to not make them a zombie. It's not going to sedate them, it's not going to make them more confused. It's not going to increase their risk of falls. And that's where a compound like dexmedetomidine, a BXCL501. That's where it comes in, where it can get the patient under control relatively quickly. Unlike some of the things in the pipeline and the currently approved drug, which you need 2 weeks to even titrate an effective dose, it gets them under control in minutes rather than days or weeks. And that's what you need, especially in acute agitation situations, whether in the hospital, the emergency room, whether in long-term care, whether at home, whether in memory care, it can be useful in all of those arenas.

To emphasize that point from earlier, this is the acute episodes can happen in those who do experience chronic agitation, but also in those that don't, correct if I'm understanding that correctly. And so the idea that this could help a very large percentage of the population is imperative how often do you see breakthrough agitation episodes in patients? That's a question coming from the audience. And by the way, audience, you are allowed to send in questions, I will be reading them, periodically, continue.

I don't know if it's for any of us, but I'm not sure that we have really good data on -- relative to that question. I can tell you from an experiential standpoint and all of us are coming from a little different kind of arena, as we can all comment about that is that it's not rare. It's actually quite common. Whether it's occurring in isolation in someone who hasn't had the chronic agitated behavior, or whether it's episodic, like you pointed out, Anton, it is very common and even individuals who may be already on treatment for more chronic, we'll call it, or persistent agitation. There can be this breakthrough kind of agitated or aggressive, whether physical or a verbal episode that makes it very hard for the staff or for the family to take care of the individual, and that's when they go to the hospital or reach out for help.

I think one of the difficulties is the unpredictability. And we shared examples of that. Sometimes maybe that patient on the car ride would do okay. And once she got to the family's house was okay. But sometimes it just was very difficult, and you never know the family members and the caregivers and the patients never know sort of when it's going to come on. And so I think the unpredictability makes it so difficult for quality of life.

And let me give an example and kind of put it more into maybe the results that we see in clinical trials. So for chronic agitation, if we see about a 30% improvement in frequency and intensity of behaviors. We often say that that's a responder. 50%, we're very happy. So that tells you that there remain about 50% to 70% of the symptoms that are kind of boiling underneath. This can take chronic agitation from being unmanageable to manageable. But the medications that we're looking at 4 chronic agitation. None of them by the way they work, none of them, it doesn't help to give another pill. Okay. He's having a bad day today. How about if I give another pill? It doesn't work. That's not the way that the currently available medication works or the ones that are currently in development. So therefore, we have to have other options. A lot of the medications that are used in the community right now are sedatives. And they may have hours worth of sedation associated with them. Many of them are specifically kind of advised against in terms of don't overuse these medications for this population. So finding something that works predictably with a relatively rapid onset of action that doesn't kind of -- that more makes people tranquil and somnolence, sleepy, sedated. That's appealing. That's appealing to clinicians.

The other thing I'll just say, Anton. The other thing that's appealing is not having the box warning. Because this is not an antipsychotic, and it's not -- doesn't have the box warning relative to increased mortality. And one of the things I find, for example, in the nursing home I'm at right now, the primary care doctors who admit here and follow patients here often don't want to deal with antipsychotics. They want to prescribe them because of the box warning, they'll refer those people immediately to us. So having a potential treatment that doesn't have that liability, in addition to all the pluses you mentioned, Anton, I think, is a good thing.

It's important, too, when compared to what's on the market because we do have that concern of overmedicating of not being able to treat people correctly. And to your point, Dr. Grossberg, about the quality of life, I think that's a key part of this conversation, right? We haven't able to, at a point in time where there are so many folks that are entering the space we have been able to find a solution that is going to help maintain some kind of independent living, quality of life. It really does hamper individuals in their ability and puts extra burden on caregivers who aren't able to then put their lives in active mode. They have to constantly be watching out for episodes to your point, even hiding and staying away. So is it -- the first part of the question is this eases the burden for caregivers and caretakers and clinicians. Is there any possibility in this situation for self-administration -- or is it not an option because individuals who are going through the episodes can't really -- don't really realize they're in the middle of it?

Let me just kind of give a quick perspective from my end. So clearly, we're using oral medications in most of these situations. There are occasionally in the hospital or even possibly in the nursing home that we may have behaviors that are so intense. That you need to -- and people are so unwilling to or unable to kind of help with taking medication, et cetera. that you might need to use an IM or a melt away or something like that. But in most situations, people aren't distressed, they're upset, but they often seek some sort of solution to this as well. This is not just distressing to family caregivers or professional caregivers. These are behaviors and actions that are very distressing to the patients. And they seek some sort of a solution, some sort of a solace. But you do need to kind of work with people if you have someone who has moderate or more advanced dementia, how do you take a thin film. So it's a medication where the active compound is kind of built into this thin film that you put on the mucosa in the mouth. And with that, you have a pretty quick and reliable absorption. So that is an issue. Clearly, there's not going to be 100% success rate with that. But targeting people in the earlier clinical trials, there was a pretty good success rate even with patients that had moderate to advanced the dementia living and skilled nursing facilities. So it's doable. It's absolutely doable. And so I still see it as a viable delivery system.

I interpreted your question differently. I interpreted your question as asking about whether this population could self-medicate. And generally, the answer is no. It's really almost unheard of that I would have an Alzheimer's patient come to me when they come to clinic or in the nursing home saying, Doc, I need help with my agitation, what do you recommend? So we're almost always depending on the family, on the professional caregivers, in the long-term care environment to really tune us into what the problem is and that there is a problem. And we're making a decision for the patient about what's best. Yes, I agree, Anton that it's easier when you have a film, you could put it anywhere in the mouth. A lot of these patients might spit out a pill if you put a pill in their mouth, if you don't have that rapid absorption. But generally, the format that this drug is available in, I think, would have pretty high adherence.

That's good to know because one of the incoming questions is thinking about safety. We mentioned or we were discussing earlier that it's not going to be like other medications where you have maybe an overdosing problem or not overutilizing. Does this also have that concern? Or how do you think about that in terms of an at-home setting, the use of in at-home setting?

Well, I think there are plans to do an at-home study, and I think that will be useful and very important I think in some data that the company that I've seen has previously, it seems like the compound can be administered, maybe 3 or more times even during the day, spaced out over time without additional deleterious side effects. But I think we need probably more information about specifically about -- we know about the half-life, but how often it can be given within a 24-hour or any given kind of time frame. I think that's going to be very important, particularly in the home where a nonprofessional person who is making the judgment about when to give and how often to give.

Yes. Do you think that there is any concern about general dosing safety considering what we see with sedatives and the like. Is this the type of medication because it's an episodic situation, do you think that there needs to be or based on any of the data that you've already seen that there's any discussion that needs to be had around what -- if there is potential of overdosing?

So if you look at the data for dexmedetomidine, I think it is important to understand that this is a medicine that has been used particularly in ICU settings and for multiple years. Then it's given via injection. So this is a way to use the same medication that doctors in those settings are actually quite comfortable with using without injecting someone. So if we look at the side effects in the TRANQUILITY II study, then basically, slight somnolence, so in the kind of mild to moderate range was the most common in about 15% of participants. Lethargy was extremely rare. So you had kind of some somnolence, but the highest state of that, which we would refer to as lethargy, that was very rare. That was in kind of the low single digits. You kind of be thoughtful about anything that kind of sedates people. And if you think about how this drug works, it then does that by kind of tuning down the norepinephrine system. And with that, there are going to be some people that might have a slight drop in their blood pressure. But that was also kind of seen at about 15% and also usually in the mild range of severity. So we're not seeing in the clinical trials, a lot of incidents where someone had to be attended to or taken to the hospital or something like that because they had a significant reaction to a single dose.

I agree with that. I think the example you cited, Anton, of this drug having been used and being used even currently, in its intravenous form in the ICU in older people with multiple major cardiovascular and other serious medical problems. And having confidence in this drug that it's not going to snow the patient, it's not going to exacerbate other acute serious medical problems that are serious enough to have them wind up in intensive care gives you a great deal of comfort. It gives us a great deal of comfort. And it's not a new drug. It's something that we know, albeit in a little bit of a different form.

The administration of this. Is it something that would be needed just as needed? I know we mentioned there's a difference in the patient population between those that already have chronic and those that don't in the chronic population, is it seen as sort of in tandem? You can give a patient who's on chronic meds also this? Or will that need additional studies?

It's used that way in the intensive care unit in its intravenous form. But I do think that we might need additional data, let's say, for example, someone is on brexpiprazole which is the FDA-approved drug for chronic agitation, and they have breakthrough anxiety. I wouldn't have any hesitation in recommending the oral film version of this drug for those acute episodes because there's no indication there would be any adverse interaction or significant side effects when both are on board, although that hasn't been specifically studied as far as I know.

What do you see as sort of the biggest challenge in addressing this population in being able to identify the right moments to administer and the like. How do -- how should we be thinking about how to think about this drug once it reaches commercialization and is on the market? Anyone, any takers? We can skip over that one.

Go ahead, Anton.

Sorry, George, you take that one.

Maybe you can put your question in more of a nutshell. I mean I hear you asking about, let's say, this drug does get FDA approval and becomes commercialized how it's going to be utilized? Is that what you're asking?

How it's going to be utilized and are there any challenges you're foreseeing?

Well, I mean, cost is always a challenge, any new medication and trying to get insurance reimbursement. But otherwise, I think with its really good profile, ease of administration, not having to worry about the patient kind of spitting pills up and so on. I think it would be relatively easy to use and would have high adherence. So I don't see any particular problems.

So a few of the things for me would be basically it's novel. It's different. So anything that's different is has a little bit of you have to kind of explain to people, okay, this medication doesn't come in a pill. It comes in this film. You have to explain to people why the film can be appealing. You have actually basically placebo films that you can work with teaching people to use. So they get a sense of comfort. I saw one of the questions in the list of questions sent in. How quickly does this bring about the benefit. And I think that it's important to understand that you see behavior start to kind of drop in 30 minutes and 60 minutes, it's considerably lower and a split between drug and placebo. The big issue is that events where we have someone go completely off the rocker. Those happen, but they're relatively rare. And when you have something that is that intense, be it at home or in a skilled nursing facility or assisted living. Those are in the situations where someone appropriately might need to go to the emergency room if they can't be safely managed at all. But there are so many kind of incidents that are somewhere kind of in the middle. You can't just work with them nonpharmacologically, distract them, offer them ice cream, whatever you do. It's not enough. And that's -- those kind of rightsized events are pretty common. They are often situational. Like I said, you can kind of have a sense when they are more likely to happen. Around personal care, around you needing to go to the doctor or maybe a right to visit family. So you work around that. And I saw another question. What about if someone is so angry, so agitated would you stick a finger in their mouth? I mean there are going to be situations where you hopefully will use good judgment. But it is remarkable what we ask of professional and family caregivers and what they can manage. These are not wallflowers. They handle situations that I would not want to be in on a day-to-day basis. And here, we offer them an additional tool that may help with kind of keeping someone out of the most intense settings. It's really hard to take someone to the emergency room to urgent care. It's disruptive for everyone involved. The professional setting as well as the home setting. We want to avoid that. nobody benefits really from going to the emergency room. That's really just a safety issue or a last resort because you can't handle it better.

In terms of the sublingual administration, I also worry about when staff members have to use an injection. When the person is acutely agitated and you're coming at someone with the needle, that doesn't seem very safe. So I almost would prefer the sublingual route than here, take a needle and go inject this in this person who's filing about. I think we're asking a lot when we ask people to do that.

It's a really good point. It does help with the safety.

And there's other -- we have other products that have been on the market for a long time that are commonly utilized. We have olanzapine comes in an oral film, where risperidone comes in an oral film and those have often been used.

I was going to ask how does it compare delivering this oral route versus some of the other drugs that are on the market, to your point of having to teach individuals that this is a film. It seems like that is a fairly novel but not hard to do necessarily at all. Dr. Grossberg, do you ready to this?

It's an easy sell we talk -- I use -- one of the medications I use for this indication is a transdermal patch and I think that's a lot more complicated than this as to where it goes, where it shouldn't go, how you change it, make sure there isn't too much air underneath it. That's much more complicated. And people are okay with that. I think this is a really easy sell.

Or dealing with -- the skin irritation from the topical patches and then how much you need to kind of teach people to wipe off any adhesive residue, et cetera, et cetera. So we work with this.

It seems like this is going to be able to answer a lot of questions and save a lot of folks' time. You've also clearly defined kind of who this potential market is I'll give it back to you guys to kind of share any final thoughts on sort of what you see as the potential market, the sort of benefit of this drug in its form and its oral form, and we'll just go a round-robin, Dr. Sanford, we can start with you.

I work across the geriatric care continuum. So in the outpatient setting in my clinic setting, I see it as a way for caregivers to keep people in the home longer before institutionalization and I also work in assisted living and memory care, the same with that care setting. Everyone's dreaded thing in life is going to the nursing home. No one wants to go to the nursing home. And so I see this as a way to be able to help people live independently with their caregivers in the less restrictive care settings for as long as possible.

So for me, I think the big issue is that the medications that I'm kind of forced to use currently. Those could be the atypical antipsychotics, the more sedating ones or benzodiazepines. They often have an impact of -- it could be short to 6 hours, but it could be a 12-hour tranquilization, a pretty high side effect burden. And I'd like something that is less likely to cause a problem where the kind of onset of action is, fairly well prescribed. The absorption is reliable and the duration of effect is reasonable. So for the situations that I mentioned before, where there are episodic agitated events that you can't deal with otherwise. This is going to be helpful. That's where I want to use this for, for example, the rights, the flights, the oppositional behaviors around personal care. That doesn't necessarily have to happen every day, but you also can't do that every 2 weeks. I mean you will need to kind of make sure that you're meeting the needs of the patients. And ultimately, that's going to reduce caregiver burden. And I think Angela put it very well, reduce the need to kind of push up to a higher level of care.

Yes. So it occurred to me that there are other arenas where a drug such as this in its current format may be useful. And just this past week, I got a call from one of our residents who was seeing patients on the consult service of our big teaching hospital. It was an older woman in her 80s, who was on internal medicine, who was clearly delirious. Delirium is an acute confusional episode. I think she maybe had some baseline dementia, but I'm not sure. But now she was very confused, very disoriented and very agitated and they needed to find out what the cause of this acute confusion and disorientation, which was triggering the physical agitation and aggressive behaviors was all about and they wanted to give her something that wasn't going to knock out, wasn't going to be heavily sedating, was not going to even further maybe impair her cognition and so on. So BXCL501 or dexmedetomidine becomes a really good choice because it can give you relatively quickly, not in hours or days or weeks but usually within, let's say, 60 minutes or 90 minutes, pretty good control of the patient without really contaminating things with sedation or other impacts on the cardiovascular system without making them more foggy or more confused cognitively, giving us an opportunity to evaluate them and see what the trigger might be for this delirium the acute confusion and disorientation. So I think it has a major role there, it might be used off-label, but that's okay as long as we know that it's safe and well tolerated.

Yes, that's a really good point. Well, thank you so much for your insights really helpful in sort of explaining what we're dealing with here and the market potential for this. Thank you so much for your thoughts.

Thank you.

So back to you, Vimal.

Thank you, Anjalee, for guiding today's discussion, and thank you to Dr. Sanford, Dr. Grossberg and Dr. Porsteinsson for sharing your expertise and perspective. We are also grateful to everyone who joined us and contributed their attention to this important topic. Today's conversation confirm the importance of acute agitation in Alzheimer's dementia and the clear gap that persists in treating these sudden episodic events. Patients, caregivers and clinicians are still without an FDA-approved option, specifically designed for acute episodes. Advancing solution that is specific for these episodes remain an essential priority for us at BioXcel Therapeutics. We appreciate your participation and look forward to continued progress in addressing this critical area of need. Thank you again.

Thank you.