Good morning, everyone, thank you all for joining us today to discuss the potential of our lead neuroscience program, BXCL501, which is our proprietary sublingual thin film formulation of dexmedetomidine. This is the last time I'm going to say "dexmedetomidine." I'm doing it for a certain person in this room. I know he knows it. We'll call it dex from this point on. Dexmedetomidine, dex. We'll call it dex. Which is being developed for acute treatment of agitation across neuropsychiatric diseases. Today, we look forward to discussing the global clinical development plans, the market opportunity, preliminary data results from our phase I study, commercialization strategy, as well as our indication expansion plans for BXCL501.
With us today is an outstanding panel of key opinion leaders that will contribute to the acute agitation overview with respect to each of the proposed neuropsychiatric indications. For now, let me turn the podium over to our Chief Executive Officer, Dr. Vimal Mehta, to provide an overview of our strategy and vision for BXCL501. Vimal.
Thank you, Frank. Good morning, everyone. Thank you for joining us today here and everyone who is joining us via webcast. I'm so excited and thrilled to be here to give you the overview of BioXcel Therapeutics. Just to give you a quick history of BioXcel Therapeutics, BioXcel Therapeutics went public in March of 2018. We are here today. We are moving our 501 program into the phase II, we expect those results to come out in Q3 of this year, we'll be in a position to move this program into the registration trial. We are very excited. I'm Vimal Mehta. I'm CEO and co-founder of BioXcel Therapeutics. Before I begin, I like to remind everyone of the safe harbor statement that as we will be making forward-looking statements. Frank already went through the agenda.
This is a quick recap what we will be covering for today. Starting with the strategy and vision that I will cover, we'll go into the program, with the key opinion leaders, clinical program, we have a Q&A for the KOL panel. In terms of the BXCL strategy and vision, where we are today, we feel very excited that there is a very broad potential to go into multiple neuropsychiatric disorder from where the agitation results. Our product is a proprietary sublingual thin film. This film was developed and this film has immediate release film with mucoadhesion. It's a proprietary technology, how we put in the dex on the film. It delivers broad range of doses, and it's flexible for combination dosing and therapy. You can see the film is green in color.
It's little minty in taste, and it's the right kind of a size to put it under the sublingual portion of the patients, basically. We have recently transitioned our process to an automated process because initially we made film to do our phase I study. We are ready to initiate our phase II studies with the film. We needed a lot of samples of the film for our phase III as well as getting ready for the commercial readiness. Now our process has been transitioned to an automated process, and we feel very comfortable that the timelines we have projected that we will initiate our phase III trials this year will be ready with the materials. In terms of our development plan for this product, we are at this stage, phase II, initiating in schizophrenia.
As I mentioned on Monday, we announced the results from the phase I study where we covered the PK exposure levels as well as the safety for the product. This study, we will get the data readout in Q3 of this year. It's a short study. Rob will go in detail about the design of the study and how many sites and how many patients we are planning to enroll for this study. That will help us power our phase III study, which will be one in schizophrenia patients and other one in bipolar. Phase II is only in schizophrenia. This data will be sufficient to initiate registration trial using one in schizophrenia, one in bipolar disorder. With a potential filing of the NDA in second half of 2020. We anticipate the commercial launch will be in 2021.
Those are the timelines for our first indication, schizophrenia and bipolar. In addition, we have done human proof of concept using the IV dex, a current form of the drug in all these indications like dementia, in opioid withdrawal and delirium work was published by the investigators. We have good human proof of concept using the current form of the drug. Clinical plans are under development for all these three indications, and we anticipate that we will roll out the clinical plans, specifically the way we have done it for schizophrenia and bipolar in 2019. Let me just flip to the right slide. Just one more. Okay, now it's working. In terms of the commercial opportunity, when we did the analysis of these four indications that we are discussing here, we looked at how many patients are at risk.
This is done by our pre-commercialization team. They looked at about 18 million patients are at risk. About 8 million patients experience agitation. Agitation is a spectrum, which is mild, moderate, and very aggressive. We believe, and what we have put in here is a moderate agitation where the film will be amenable, the patient that are going to be cooperative. There are cooperative patients who are in mild to moderate, and there are uncooperative patients. That's where we are targeting the patient pool. We do believe that it's not only the moderate. There are some patients who are going to be mild to moderate. They will be able to use the film because they cannot be de-escalated using the verbal de-escalation, what normally physicians do.
There are going to be patients who are going to be moderate to aggressive, but they still may be able to take the film. Best way Rob tells is the patient who will use this film will be who is willing to take the film or who can take the film. That's kind of our target patient population. Moderate, we call as a core population. These patients experience multiple episodes per year. We know schizophrenia and bipolar patients have multiple episodes. They end up in the emergency room. Dementia patients, it can vary depending on where the state of dementia is. I know our key opinion leaders are going to talk about it, I will skip that. Opioid withdrawal in detoxification, it could be a 5-7-day period.
Similarly, delirium, Dr. Maurizio Fava will talk about it, what the needs of these patients is. We see this as a pretty large opportunity, our development is a 505(b)(2) development pathway. It's a very rapid development pathway, what I showed you in the previous slide. Today, I'm joined by my team, Frank D. Yocca, who is Chief Scientific Officer. He's here. Vince O'Neill, he's Chief Medical Officer. Chetan Lathia, who is Head of Clinical Pharmacology and Regulatory Affairs. Robert Risinger, he's VP of Clinical Development. David Hanley, VP of Global Pharmaceutical Development and Operations. He developed the film. Pascal recently joined us, he's doing all the pre-commercial strategy for 501. He's VP of Commercial Development Medical Affairs. Finally, Dr. Peter Mueller, who doesn't need any introduction. He's the Chairman of the Board, he has joined us.
All of you know him from Boehringer Ingelheim, as well as the Vortex days, that he has very excellent track record in bringing multiple drugs to the NDA, getting them approved, we are very happy that we have the oversight of Dr. Mueller to help us build BioXcel Therapeutics. In terms of the vision of the company, we want to bring one NDA every 2 to 3 years. That's the vision of the company. How can we achieve that? We have an AI platform that we use to identify 501, which is our lead neuroscience product. Then we have immuno-oncology asset, which is for working on the innate immunity activator. Those are the two lead assets. 501 is our example of executing on our vision of the BioXcel Therapeutics.
Then we have two ongoing trials on 701, one more trial will be started very soon for our lead immuno-oncology asset. With that, I will stop, I will pass it on back to Frank.
Thank you. What we're going to do is, I'll talk a little bit about the concept and what we were trying to achieve in actually developing 501. Our goal here was we were looking at agitation as a problem that was going to grow. It was going to become even bigger. Why? Because in the neuroscience field, you not only have problems with agitation coming from the psychiatric side of the neuroscience limb, but you also have problems now growing problems in the geriatric side of things. With these diseases not being able to be treated, this is going to be a real problem, and not just for the patient, but for caregivers and for families. The idea was: Can we now turn our attention to these behavioral issues? The one big behavioral issue is agitation.
When we looked at the drugs and we looked at the problems that physicians and clinicians were facing with the current drugs, we said, "Can we make this better?" Can we come up with a 21st century type drug that fits all of the needs, both psychiatric as well as geriatric? Basically, there have been a number of consensus opinion groups that have been put together that have talked about this problem, that have been made up of psychiatrists, emergency room physicians, and these are the different characteristics that they came up with. They want something that's non-invasive. They want something that will calm the patient, not just sedate the patient. It has to be easy to administer. It has to have a rapid onset, non-traumatic.
What we mean by non-traumatic is that introducing a syringe into an agitated situation is not good for the patient, and it's not good for the caregiver either. Could we come up with something that's a non-injectable? Has to have a good safety profile, a favorable tolerability, and then would be something that once a patient uses it, that they would have a preference to actually go back to that. Because a lot of these patients, particularly the psychiatric patients, know when they're heading down this path, and the idea is that can they use something that they feel comfortable with and abort the situation. This is where BXCL501 came in. It has the properties that fit a lot of that criteria that we have listed here.
What we thought we would do today is have key experts in the areas that we think BXCL501 could play a role. What I mean by that is that in different indications where agitation is a problem. What we're talking about is psychiatry, schizophrenia, and bipolar, which is really our first approach that we're doing. Dementia, which is also becoming a huge problem. Opioid withdrawal, where these patients who are withdrawing from opioids and are in that withdrawal system suffer severe agitation. Not only that, it seems to be a locus coeruleus event where BXCL501 does its work. Then finally, delirium, where you have these anesthetized geriatric patients who come out of surgery, and they're delirious. A lot of times, these patients never come out. The question is: could BXCL501 in a different format than an IV play a role?
With that in mind, we have our four KOLs that I'll introduce to you. One at a time, they'll come up and speak to these problems that agitation causes in their areas. With that in mind, our first guest this morning is Dr. Sheldon Preskorn, who will discuss acute agitation in schizophrenia and bipolar disease. Dr. Preskorn is President and Chief Executive Officer of Worldwide Psychopharmacology Consultants and Professor of Psychiatry at the University of Kansas School of Medicine-Wichita. He's one of the world's leading experts in psychiatric drug development. Over the last 25 years, Dr. Preskorn has been a principal investigator on numerous antidepressant and antipsychotic medications marketed in the U.S. He served on the U.S. Food and Drug Psychopharmacologic Drugs Advisory Committee and presented 12 new drug applications to eight different FDA advisory committees.
What Dr. Preskorn will do is talk for about 10 minutes. What I'd like you to do is to hold your questions until we have the panel come up so that they can go through their presentations. With that in mind, Sheldon.
Thank you very much, Frank. You've got the remote. Okay.
Of course.
Yeah. Very good. It's a pleasure for me to be here with you today. One, I'm sure you've all seen agitated individuals. You possibly passed some in the street today on the way here. I certainly have, over four years of academic medicine. One stands out, in particular. It was after hours. Everybody had gone. My desk was set back away from the door by several feet. I could smell the bourbon when the person entered the room. He came over to my desk, sat down, and explained that he wanted to have a serious conversation with me. To emphasize the point, he pulled out his 9mm automatic pistol and his clip, which was loaded. He chambered a round, and for the next hour, we had a meaningful conversation. That is one example of agitation, of which there are many.
I wished I'd had dexmedetomidine on my desk and could've offered it to him, but that wasn't possible at that moment. Okay. Psychomotor agitation is an unmet medical need in terms of being able to give medicines that are well-tolerated and do not actually worsen the condition early on. Benzodiazepines, which you're probably familiar with. Unfortunately, at the early phase of benzodiazepines getting into your system, that'd be drugs like Valium, Ativan, Xanax, actually disinhibit you. Therefore, make it more likely, until you get to sedation, that you may act on your agitation. It's characterized by motor restlessness and irritability. That patient, by the way, was agitated, that I just described to you. To aggression and violence. We've already gone through the statistics. 10%-31% of all patients with schizophrenia or related psychotic disorders exhibit aggressive or violent behavior.
You encounter them, as I say, on the streets. You encounter them in the emergency room. You encounter them on the floors. You encounter them in the outpatient clinic. Acute episodes of psychomotor agitation represent a serious number, a substantial number of emergency room department visits, because they're often brought in because they're agitated. Agitation has medical costs. First of all, it can cause death. It can cause injury, and longer hospital stays, increased medication consumption, higher readmission rates, and increased numbers of violent incidences against staff and others. One can calculate the cost of this and compare that against the cost of the medication. The treatment algorithm, a need for pharmacologic intervention. If the answer is yes, as it would've been in that case I gave you, cause of agitation, a psychiatric disorder. In this case, there was an underlying psychiatric disorder fueled a bit by bourbon.
Is the patient cooperative? He may have actually taken Dex if I had been able to offer it to him. If the patient is cooperative, the current options are inhaled antipsychotics. There's a formulation of that. Sublingual antipsychotics, an oral antipsychotic, or oral benzodiazepines. I've already given you one of the limitations of benzodiazepines. They intoxicate you, and the first thing that happens is you lose your cortical inhibitions for your subcortical drives. With antipsychotics, the problems are numerous and quite varied depending upon the nature of the antipsychotic. I won't go into all of those for you, except if you want to ask questions during the Q&A sessions. Over on the right-hand side, we have the characteristics of an ideal drug for the treatment of psychomotor agitation. Calm without sedation, which Frank has already emphasized. Directly targets the hyperarousal system, as a pathophysiological mechanism underlying the agitation.
Non-traumatic and non-invasive. We've discussed that particularly as it relates to intramuscular administration of drugs, which generally you only do when you have the individual in four-point restraints. Rapid onset of action, unlikely to cause respiratory depression, which benzodiazepines can do, particularly if you push the dose rapidly, and unlikely adverse cardiovascular or motor events. By the way, atypical antipsychotics, if you're dealing with high-potency D2 blockers, one of the problems they can cause is a condition we call akathisia. akathisia is motor restlessness, and motor restlessness can look a lot like agitation. It's also extremely uncomfortable for the patient. I actually had a patient come in and say, "If I had to continue this way, I would shoot myself." It literally is a significant problem.
The prediction, you can see the checkboxes for yes and no, but the prediction is Dex on sublingual film will exhibit a superior profile compared to these currently used drugs for the acute treatment of agitation in a wide variety of patients, not just schizophrenia and bipolar disorder. If I were you, I probably would wonder, well, how can one drug do all of this? How is that possible? To understand that, this is the brain, and right here, this green dot is the locus coeruleus. The locus coeruleus is your sympathetic ganglion in your brain. It is there to arouse you, to control your respiratory drive, and your cardiovascular output. It is like the fire alarm system in your brain. When it detects that you are getting acidotic, it fires off, and that's a panic attack. In the morning, it awakes you.
It's part of the arousal system for your awakening. The downward projections drive your cardiovascular system to increase cardiac output, to vasoconstrict you, and it drives your respiratory system to be inhaling more, and you can hyperventilate. The upward projections alerts your brain. This is a key component to agitation. How does Dex work? Dex works by binding to the alpha-2 adrenergic system. This system has a feedback loop. It has an auto control to not get overly active, but sometimes that doesn't work. You have norepinephrine, what we call alpha-2 receptors on the cell bodies. When your norepinephrine gets too high, you decrease the firing rate of these neurons. Dex works to decrease the firing rate of these neurons. It's central to the whole concept of overarousal and agitation. That's how it can work in so many different conditions.
It's a sublingual film intended for patients from mild to moderate agitation. Treats the underlying cause, which is this hyperarousal system, which your brain has in it for perfectly good reasons, but it can get overactive. Goals of therapy, increase cooperation of the mildly agitated patient, prevent escalation to more severe. We can look at how we grade patients. A patient may be mild, meaning they have nervousness, they're tense, they're grumpy, they're anxious. There's a continuum between anxiety and severe agitation, all driven by the system I just described to you. Moderate, they may be insulting. They may be unable to respect interpersonal space. They may be frightened, and in danger. At this point, in both of these conditions, they may actually want treatment to calm themselves down. I'm too irritable. I'm too on edge. I need to sort of feel more calm.
You get into the severe cases where you have violent aggression, confused, desperate, and where they can cause harm to themselves and harm to others. This simply shows you that, as Vimal mentioned, we've looked at this in individuals with agitation and schizophrenia. We've looked at it in agitation in individuals with senile dementia of the Alzheimer's type, and in opioid withdrawal. This is from the schizophrenia study. This here is a reduction in the score of agitation. It's reflected in what's called the PEC score, which is simply a subscale of the positive and negative symptoms of schizophrenia. That's how you get PANSS, positive and negative symptoms of schizophrenia. It is the excitatory component. So P stands for PANSS, E stands for excitatory, and C stands for the component subscale. The reduction in this represents onset of therapeutic action. Over here is arousal.
The key thing here is that the drug has an anti-agitation effect, as reflected by these drops, with very few patients actually having a decrease in their arousal. Here is where you end up starting to have the arousal go up. The bars represent arousal. The dashed line represents a reduction in agitation. You nicely see the anti-agitation effect occurring in most individuals well before they have an impact. By the way, a RASS of -1 means you're drowsy. Not obtunded. You're simply more likely to fall asleep if you're not stimulated, but you're not somebody who needs. A RASS of -2 would be, I would have to call your name vigorously to wake you up, and as soon as I stopped, you would drop back to sleep. This is simple drowsiness. All right. I think I've finished.
Yes.
Probably on time. Even with a vignette. Thank you so much.
You are always on time. Sheldon, thank you so much. Never quite had the sympathetic system described to me in such an elegant way. Let's turn our attention now to dementia, and Dr. George Grossberg, who is our second KOL, who will discuss the area of acute agitation in dementia. Dr. Grossberg is a professor and director of geriatric psychiatry at Saint Louis University School of Medicine. Dr. Grossberg has served as a consultant for central nervous system disorders to companies such as Abbott, AstraZeneca, Bayer, Forest, Janssen, Lilly, Novartis, Organon, Synthélabo. His area of clinical expertise includes later life depression, delirium, psychiatry in the nursing home setting, and geriatric psychopharmacology. His research interests include behavioral symptoms in Alzheimer's disease and new treatments for neurocognitive disorders. In addition, he is also president of the American Association for Geriatric Psychiatry and the International Psychogeriatric Association. With that, George.
Thank you very much. Nice to be here. Thank you for inviting me. Important topic. Before I start, being that Sheldon started with a vignette, I just thought of an interesting vignette. I saw a family recently who brought their mom to me for a more definitive diagnosis. She was in her early 80s. They had been to their primary care physician, and what they basically told me was, there was good news and bad news. The good news was that they were told it was not Alzheimer's disease, but the bad news was that Mom had dementia. I knew right away that she had a totally unthorough, non-appropriate evaluation because the reality is that over three-quarters of all dementias, which is kind of a wastebasket diagnosis, indeed are secondary to Alzheimer's disease. My presentation today. Assuming I can advance my slides. Okay. Let's go back.
Is going to be on Alzheimer's disease/dementia, because we're not just looking at Alzheimer's disease, although that's the big target. We're also looking at things like Lewy body dementia. Many of you have heard about that. It's been in the news because some famous people at autopsy were diagnosed with that. We're also looking at what's called vascular dementia or neurocognitive disorder, small strokes or larger strokes causing cognitive impairment in an older adult. All of these, and there are Parkinson's dementia, there are many other, frontotemporal dementia, many other dementias. Again, think Alzheimer's disease, because that's really the big one. I would venture to say that there probably isn't a single person in this room that hasn't been personally touched by Alzheimer's disease. You know someone that has it, you maybe have a family member who has it.
It's very different than other diseases that receive a lot of attention and a lot of federal funding, like AIDS, for example, which is a horrible disease. We've made great progress, but most of us may not personally have been impacted. With Alzheimer's disease and dementias, it's very, very different. Just before, while we were having breakfast, I was talking with one of you about a family member with Alzheimer's disease or with dementia, who gets agitated whenever the caregivers try to give her a shower or a bath or to get her bathed in the morning. We call that agitation with hands-on care. It's extremely common, both at home when the family is taking care of a loved one, in the memory care setting, in the assisted living setting, in the nursing home environment. We have three teaching nursing homes in Saint Louis.
I'm going to come and visit some of those. Probably 80%-90% of all the residents in those nursing homes have some type of dementia. When I take third-year medical students with me, and we do teaching rounds in the nursing home, and one of the nursing homes has a special dementia unit, they assume that everybody with dementia is only on that 20-bed unit of a 240-bed nursing home. I tell them, "No, those are the more severe patients." 90% of everyone is cognitively impaired. It's the number one reason now for winding up in assisted living memory care or in the spectrum of long-term care, including nursing homes. These are my disclosures. You've heard about some of those. I work with small and large companies to help them to develop new compounds, primarily for Alzheimer's disease. Whoops. Now we skipped that slide.
Sorry about the technical issues. Is this supposed to be working or what? You didn't have any trouble with it, Sheldon. Let's go back to the one before. Trying to go backwards, but there we go. All right. The scope of the problem, and again, I don't need to belabor this, but I do want to emphasize that this is not merely a U.S. problem, the problem of Alzheimer's disease. It's really been called a worldwide epidemic. I would point to, in particular, look at the dramatic growth in numbers in Asia. In emerging countries, I consult to a number of institutions in India. I go a couple times a year. I started a program at King George's Medical University, looking at, in Lucknow, looking at late-life mental disorders and advising the Indian government about the growing problem of Alzheimer's disease and dementia.
There, too, and in China and other emerging countries, people are living longer and longer, and they've not really addressed the growing problem of Alzheimer's disease and dementia in their elders. We, too, in the U.S. are not quite ready for it. The big problem is what we're going to be talking about in just a moment is trying to control the behavioral manifestations. We don't have a cure. We don't have a way to halt the disease. We don't have a way to undo the damage that's already been done. What we can do is make it easier for caregivers, for families, professional caregivers, to take care of their loved ones, take care of our elders with this growing population of Alzheimer's disease or dementia. Just some kind of quick facts. This is from the U.S.
Alzheimer's Association, and I'm on the board of our Alzheimer's Association in Saint Louis, and I've been very involved with them. I would advise many of you who are interested specifically in dementia or Alzheimer's disease to go to the annual Alzheimer's Association International Conference. It's always held in July. This coming July, it will be in Los Angeles. Sometimes it's held in Europe, but most of the time in the U.S., particularly in Chicago, where the association's based. You can, by going to that four-day meeting, get a feel for the broad spectrum of disorders that we're talking about and what kind of research is happening all over the world. Especially interesting are the posters. The business media is very heavily represented, and you guys are getting close to at least beginning to present maybe some data in this population at that meeting.
Sixth leading cause of death in the United States. A very, very expensive disease. One of the costs that's often not included in the overall cost of Alzheimer's disease is all the unpaid caregiver time. I can tell you that I have people that come to me, an adult daughter or a son who has to take off from work to bring their mom for a routine follow-up or for medication management, or take off for work to get a second opinion or to get them diagnosed or worked up or evaluated. Some are living with family, and the family is putting in tons of time, which is not cheap, to take care of their loved one.
What we've also seen, as you see in the third bullet, is that over the last decade or little more than the last decade or two, heart disease, we're making a lot of progress in healthcare. So less and less people are dying of heart disease, heart attacks, and strokes, but unfortunately, more and more deaths from Alzheimer's disease, at least over the past couple of decades. One in three seniors who lives long enough dies of Alzheimer's disease, which is more than a couple of common cancers, breast and prostate, combined. Huge cost. This is 2019 cost, $290 billion. It's something that happens literally every minute. It's a huge disorder. This is a study, I'll walk you through this award-winning study. We actually got a lot of kudos for this that we did a number of years ago.
What was unique about this study is we took 100 autopsy-confirmed Alzheimer's patients. We knew that at autopsy, at death, they definitively had Alzheimer's disease, and nothing else was responsible for the brain disease. We put these 100 people under a microscope. This is called a timeline diagram. What we're looking at here are months before the diagnosis. This is the time of diagnosis of Alzheimer's disease. Keep in mind that even today, this is a study that was done in 1996, but even today, patients are not diagnosed early. By the time families bring their mom or dad or grandma or grandpa to me, and we eventually diagnose dementia or Alzheimer's disease, it's been going on for two or three years or longer.
You wonder, well, why did you We ask them, "Well, how long has it been since you've been concerned about Mom's memory?" "Oh, it's been going on for at least two or three years." Another daughter might say, "Gee, I remember four years ago, I came home for Christmas, and I was noticing that Mom wasn't quite right. We figured, what the heck, she's 85. You're going to be a little forgetful when you get to be 85." People don't get diagnosed early. In this study, we look at the time of diagnosis, which is the vertical line here. These are months before and months after, and we're looking at the frequency of different behavioral symptoms in Alzheimer's disease. Again, you want to focus on a couple things. You want to focus on, this is low-level agitation or irritability. This is higher level.
This is more moderate agitation, 80%. This has been confirmed by other studies, not just our autopsy study, and about 40%, in the later stages, more overtly aggressive behaviors. This is a behavioral problem that is going to impact pretty much every patient with dementia, with Alzheimer's disease, whether they're at home, whether they're in the nursing home, or somewhere in between in assisted living or memory care, which I'm sure you're all seeing. I can tell you in Saint Louis, in our part of the Midwest, it's everywhere. More and more memory care, assisted living units are popping up to take care of this patient population that the family can no longer take care of. Why can the family no longer take care of them? Because of behavioral problems.
Behavioral problems, particularly two stand out, agitation and psychosis, are really the two most common behavioral symptoms that result in placement, either in assisted living or memory care or in nursing homes throughout the United States. The loving family that's taking care of mom or grandma or the individual taking care of their aging spouse, their husband or their wife, usually their wife, women are more commonly seen, they're able to deal with all kinds of things. In the old days, the leading cause of institutionalization, believe it or not, was incontinence. Urinary incontinence, particularly bowel incontinence. Now we have really good products to deal with those things. People can get a little bit of help, hygiene help. That is no longer a leading reason for institutionalization. The leading reason, the number one reason is behavioral problems, particularly agitation and psychosis.
Whatever we can do to help with those behaviors enables the family to keep their mom or dad or their spouse at home longer, which obviously is a great benefit to our healthcare economy. The other, by the way, huge reason for institutionalization, I don't want to not mention this, is falls.
You have to point to the back.
Oh, I have to point to the back. Oh, not toward the. That makes sense because the projector's back there. Thank you. All right. Well, all right. Let's move on. What do we do currently? I think Sheldon showed you what happens currently with patients with schizophrenia, patients with bipolar disorder. What do healthcare providers recommend for agitation in Alzheimer's disease or in the broad spectrum of dementias, which would include all the other dementias that we talked about earlier? Number one, nothing is FDA approved. That's important to keep in mind. Everything that physicians and healthcare providers are recommending is basically off-label for agitation and any of the symptoms of Alzheimer's disease or dementia.
Similar to what you mentioned, Sheldon, is happening with the schizophrenia and bipolar patients, the same two categories of medications are being utilized, both acutely, whether it's in the emergency room, acutely in the nursing home or memory care, acutely at home. There are two categories of drugs. The big difference in this population versus the population that Dr. Preskorn talked about is here we're looking at frail older people who have multiple comorbidities. They're not just on one or two medications. On average, they're on five or seven or more medications, which they need. They have their blood pressure medicine. They have their arthritis medicine. They have their diabetes medicine. They have their hyperlipidemia, their cholesterol-lowering medicine.
Sometimes they're on too many medications, and we begin de-prescribing, which often helps. This is a frail population that doesn't do well with the two options that are currently being utilized. For example, I gave you some names of the antipsychotics. These are the newer antipsychotics, so-called atypical. We still see the use of older drugs that are even more dangerous in this patient population, like Haldol, you know, haloperidol. There is a specific black box warning on the labeling of all of these so-called atypical or newer antipsychotics, specifically in this patient population. It's relative specifically to dementia patients, that there's increased risk of mortality. It's one thing we don't want to mess with, is mortality. We don't want to kill people, God forbid. Again, there's an increased risk of mortality, usually due to cardiovascular events that these drugs can precipitate. Heart attacks and strokes.
That's obviously a major problem. Another major problem, and I think, Sheldon, you pointed this out, even in the older patient, is these drugs take time to work, take time to kick in. They don't work immediately, and if you have someone that's very agitated, you might want something that works more quickly. The other group you also heard about are the benzodiazepines. In the old days, these were the Valium and Librium drugs. The new versions of Valium and Librium are basically Xanax and Ativan and Klonopin or clonazepam. These drugs not only take time to kick in, but they can be particularly dangerous in an 85-year-old because they make confusion worse. Then the really big risk is they impair balance and increase the risk of falls.
You remember just in the previous slide that I told you that falls are a huge reason why people get institutionalized. Why families finally decide to move mom from her independent living, from the assisted living to the nursing home, because they now can no longer guarantee her safety. Safety is a huge thing. Number one reason overall for ending up in a nursing home is in fact falls. Again, they take time to kick in. What about this new agent?
If the profile is, as Sheldon, as you pointed out, we have a drug that doesn't have the liabilities of the current therapies, which are, again, off-label, the antipsychotics and the benzodiazepines, and may indeed have benefits in this vulnerable population by not sedating, which also increases the risk of falls, by not making the person more confused, not affecting balance and confusion and so on, but having a positive calming effect. With that, I'm going to finish, and thank you all for your attention. I'll be happy to have questions later. Thank you. Many of you know that BioXcel Therapeutics is a company that exists in Connecticut and specifically in New Haven, Connecticut.
That location has been very beneficial to us, specifically because we get to tap into the knowledge base and the resources of Yale University, and in particular, Yale University Psychiatry, with John Krystal and his entire group. Ismene Petrakis is one of those people who works actually in the VA under the auspices of Yale. Let me introduce Ismene, who's going to provide an overview of acute agitation as it relates to opioid withdrawal symptoms. Dr. Petrakis is a professor of psychiatry at Yale University School of Medicine and director of the mental health service line at the VA Connecticut Healthcare System. Dr. Petrakis is also the director of the addiction psychiatry residency at Yale. Her research interests are predominantly twofold. One, finding appropriate treatments for the dually diagnosed individual, and two, understanding neurobiological mechanisms underlying alcohol dependency. With that, I'll introduce Dr. Petrakis.
Okay. Can you all hear me? Yeah. Okay. Great. I'm going to change gears a little bit here, and we're going to talk about opioid withdrawal and the opioid epidemic, and that's where I'm actually going to start. As you all know, if you've read the paper at all in the last few years, we're in the middle of an opioid epidemic here in the U.S. This is an opioid crisis that's a public health crisis that's affected our country for several years, and it's really all over the news. Just to give you some facts, to put it in perspective, it's estimated that 12 million Americans use prescription opioids non-medically. In other words, they're abusing them, they're addicted, or in one of those categories. 1.9 million people are addicted to prescription opioids, and another 600,000 are addicted to heroin.
It's a huge economic burden on the U.S., where the CDC estimates that it's a $79 billion a year problem. I think the reason that it really has captured the attention is because of the dramatic and tragic deaths that have occurred in response to the opioid epidemic. What happens often is it's a young, otherwise healthy person who either accidentally or whatever, overdoses on opioids, and it's just devastating to the family, obviously. It's been estimated, I missed a zero here, 700,000 Americans have died of opioid overdoses from 1999 to 2017. That's 12 times the number of Americans who have died in the Vietnam War. It's estimated that 130 Americans die every day of an opioid overdose. It's not just the overdose and those consequences. There have been medical consequences as well.
There's been an uptick in new incidence of HIV and Hepatitis C, and that also got some news attention. There was recently an outbreak in, I think it was in Indiana. Circumscribed, but still, this is an incidence of new episodes that occur above what you would expect from what happens in the normal population. There are also some interesting and tragic social consequences. When you have young-ish adults die suddenly, what it has done is left some children without parents. There was an article recently about the number of children in foster care due to the opioid epidemic. This has social, medical, and other consequences. Yeah. A little louder. I'm not loud enough, yeah. Can you hear me now? Can you hear me better now? Yeah. Okay. Sorry.
This is just a visual representation, and if you think about what happened with the opioid epidemic, this is opioid deaths, but it does highlight something that I wanted to mention here. First, there were prescription opioids, and you probably have all heard that there was an over-prescribing of prescription opioids, and so they got out into the general population, and you saw an increase in accidental deaths. As people became aware of that and did things, physician education, decreasing the number of prescriptions that could be given, the deaths plateaued, but in its stead, you see this uptick in deaths from heroin. If you talk to patients, sometimes they will tell you that they couldn't get their prescription opioids. They actually turned to the street. They got heroin, which unfortunately, at the same time as all this was happening, became very available and cheap.
That was an uptick. Now, that has plateaued, but unfortunately, that's been overtaken by the most recent problem, which is an increase in synthetic opioids like fentanyl. Again, you hear about this in the news as well, and they are very powerful. If you look at it, I saw an interesting slide that showed how much heroin you need to overdose and how much fentanyl you need to overdose, and it's very different quantity, and if you're not sure what you're doing, you don't know what's in it's very easy to accidentally overdose, and you see this huge uptick in deaths. There's a spectrum. People are prescribed opioids for legitimate pain issues. Sometimes they misuse them. They can become physiologically dependent. Then some people end up having what we call an opioid use disorder, which is an addictive disorder.
This is the definition based on the Diagnostic and Statistical Manual, which is what we psychiatrists use to diagnose and to communicate with each other. This is a behavioral disorder. It's not just a physiologic dependence. This is a disorder where people are using opioids despite the medical, psychological, and social consequences of use. In order to be diagnosed with this, you need several of these symptoms or events. Here, people are taking more than they intended. They try to cut back, and they can't. They spend a lot of time obtaining, using, or recovering from opioids. They fail to fulfill their obligations. They give up activities because of opioids. They continue to use despite medical consequences, physical hazards, psychological problems. Tolerance and withdrawal are things that happen with opioids.
If you start taking, if you're prescribed an opioid, you take it regularly, eventually, it's not going to work at the same dose. You need to increase the dose. This is a physiologic phenomenon and can happen to people who are prescribed them legitimately and taking them the way they're supposed to. It's not necessarily a symptom of addiction, especially when you're talking about prescribed opioids. In order to meet criteria to have an addiction, you need these other things to be present before you actually make that diagnosis. There's this continuum, as I mentioned. People are prescribed opioids legitimately. They may misuse them, they may abuse them, and then some of them become dependent and have an opiate use disorder. There are treatments to treat opiate use disorder, and I just want to mention what they are.
It's sort of the context of treatment here. The first is to use methadone, and methadone is a full-on opioid, but it is limited in how it can be prescribed. You cannot just get this at your doctor's office for addiction. You could only be treated with methadone for an addiction if you're in a federally licensed facility. It is not available to patients uniformly across the U.S. There are some places that have these programs and some that do not. The next is buprenorphine or SUBOXONE, and some of you may have heard of that, and there's a lot of emphasis on the use of SUBOXONE. This has properties that are opioid-like, but they're limited, and at higher doses, it's more like an opioid antagonist or blocker.
It can be safely prescribed, and there's emphasis on getting this out to people through regular physician offices. Now, not just anybody can prescribe it. You do need to have this added training, it's an eight-hour course, and to have a special DEA license to prescribe. You don't need to be in some kind of a federally regulated facility like methadone. The final is naltrexone, which is an opioid antagonist which blocks the effect of opioids, and that's available either orally or with an injection. Orally, it really has not been found to be very effective for opiate use disorder, except in very certain circumstances because people don't take it. VIVITROL or the long-acting injectable naltrexone is, and there was a recent two studies that showed some equivalence between buprenorphine and naltrexone for opiate use disorder. Moving on to opiate withdrawal.
Opiate withdrawal occurs when somebody's been taking opioids regularly and discontinues them abruptly. If someone's been taking opioids regularly and you give them an opioid-blocking medication, then you precipitate withdrawal. Withdrawal is these symptoms, essentially. It's a very well-documented phenomenon. You can do it to animals, you can see it in humans, and these are the symptoms that people have: nausea, vomiting, you get dilated pupils, sweating, goose flesh, muscle aches, runny nose, diarrhea, fever, yawning, and insomnia. I think what I want to really emphasize is this intense state of unease or distress. It really makes people feel terrible. They complain about it, and it makes them agitated and upset.
Patients will say, even patients that want to get off their opioid medication, they will say, "I just don't want to stop this because I just never want to feel like that again." It can also dissuade people from seeking treatment for opioid use disorder. It's a serious problem, and sometimes it's the first foray of someone who's trying to get off their medications into some kind of treatment. How do you manage opioid withdrawal? There's several, this is theoretical, several ways to do it. You can slow taper whatever medications people are taking. You can do that for any addictive medication. You just slowly decrease it. But it takes time, and there's no guarantee that people won't have some symptoms. You can substitute a longer-acting medication and taper.
The two that are most commonly used are methadone and buprenorphine, but these also take time, and again, no guarantee that there aren't going to be symptoms. The last is to treat the underlying neurobiology, and I'm actually glad my colleague mentioned the locus coeruleus and gave you an anatomy lesson there, I'm not going to do it. Basically, just like in the disorders he describes, people who are opioid-dependent, who stop their opioid use, have an increase in noradrenergic function, and here in the locus coeruleus, you see overactivity that happens there. This has led to treatments for opioid withdrawal, that if you know that this is what's happening, if you dampen that down, you can then treat opioid withdrawal. Again, that is the mainstay of treatment for opioid withdrawal are the alpha-2 adrenergic agonists.
This has been for years, and the one that's most classically used is clonidine. Clonidine is an antihypertensive or a blood pressure medication. It decreases blood pressure, and it's been used in opioid withdrawal. It is not FDA-approved, however. It's been used off-label for many years. One of the biggest problems with clonidine is the hypotension or blood pressure drop that occurs when you're using it because it is a blood pressure medication. There is also another medication, lofexidine, which was just recently approved by the FDA in 2018. It is also an alpha-2 adrenergic agonist like clonidine. The data comparing the two suggests that they have similar efficacy. They work equally well, but clonidine causes more hypotension or decreased blood pressure, which is not really something you want in this case. The way you do opioid withdrawal is one of two ways.
You either just wait until someone's taking their opioids or heroin or whatever they're on, they stop, they develop these symptoms, and you treat them. Another way to do it, though, is to add an opioid antagonist like naltrexone, which blocks opioids. That precipitates withdrawal, you treat that. Why would you do that? It shortens the time that someone is in opioid withdrawal, but it can make patients feel crummy because you are actually precipitating the opioid withdrawal. The clonidine or these agents don't treat all the symptoms, often you do use some adjunctive medications like sleep aids or something for the muscle pains or for nausea. At times when patients are going through opioid withdrawal, you do need to treat with multiple medications.
I just wanted to put it all together and say, when are you going to treat opiate withdrawal? There are cases where you may not treat it. I'll just put those, and we can dispense with those. Patients who are coming in who have an opiate use disorder and are going to go on to either methadone or buprenorphine may not need to go through withdrawal. You may be able to treat them, and they go for their maintenance treatment, and that's it. There are times when you do want to treat opiate withdrawal, and I just wanted to be clear when those are.
First of all, for people who do not have opiate use disorder but have a pain, but are addicted, perhaps physiologically addicted for pain or other reasons, they may be getting off because the opioids might actually be exacerbating their pain. There's this phenomenon called hyperalgesia, which is being studied more now, where people who are on chronic opioids for a long time, it might actually make their pain worse. They become more sensitive to pain is one way to think about it. For those patients, they may really need to get off their pain medication, and find alternatives for treatment. There are people who cannot tolerate the side effects, for example, of the pain medications, or there may be patients who have an episode of pain, become physiologically addicted, but now it's time to get them off.
For them, you may need to treat their opioid withdrawal. People have an opiate use disorder, there are instances when you do want to treat them, and you need to treat their opiate withdrawal. One is patient choice. Even if you think they should be on buprenorphine or methadone, they want to be drug-free, they are going to choose to get off their opiates. That's something that you might need to do. There are patients who are court-ordered to be off opiates, or perhaps they're going to jail and there is no opiate substitution there, so they need to be off their opiates. There are also otherwise mandated treatments. Healthcare professionals like physicians who become addicted to opioids, and it does happen. If they get off of them, they are not going to be going on methadone or buprenorphine.
They're going to be going on naltrexone or be drug-free and being monitored. For those patients, there's also emergency management. When people overdose on opiates and they're brought to the emergency room, the way you reverse the opioid overdose is to give them an opiate blocker like naloxone. They come in, they're obtunded. You give them the shot, they wake up. It reverses the opioid overdose, that's great, but they're often very agitated and upset because now they're in full-blown withdrawal. For these patients, they need to also be treated. Again, remember, this may be their introduction to treatment, and you don't want that to be a terrible experience because you're hoping to engage them in treatment and not have them just turn around and go back and use opiates.
This is a big issue here, treating with IM naltrexone, which is one of the three medications that is recommended in the treatment of opiate use disorder. You can't get on naltrexone if you're still taking the opiates. You have to be completely detoxed before you can start this. There's a lot of interest in figuring out how to do this smoothly, how to do this perhaps on an outpatient basis, so you don't have to be admitted to the hospital. You have to really be off the opiates completely before you can start naltrexone. This is also another big area that's just being examined now. What about all these patients that we put on buprenorphine or methadone? Many of them don't want to stay on this medication for their whole life. When do they come off? How do they get off?
Do they transition to VIVITROL? That is something that is just currently being really explored. There's several studies that are being funded by NIDA to evaluate this, because the guidelines now for people who are on buprenorphine or methadone are really unclear about how long somebody should stay. This is a new sort of area that I think is very important. That's it, except for that I did have a few, if anybody's interested in more readings. These are some really nice reviews, especially this one about opiate withdrawal.
Thank you.
Thanks.
Our last KOL, Dr. Maurizio Fava, who will be presenting on hyperactive delirium and its relation to acute agitation. Dr. Fava serves as the Director of the Division of Clinical Research, Executive Vice Chair of the Department of Psychiatry, and Executive Director of Massachusetts General Hospital Clinical Trials Network and Institute, the CTNI, at the MGH Research Institute. He founded and served as the director of the hospital's Depression Clinical and Research Program, the DCRP, one of the most highly regarded depression programs in the country. Dr. Fava is a world leader in the field of depression. He served as a principal or co-principal investigator in numerous studies, most notably the co-principal and the investigator of STAR*D, the largest research study ever conducted in the area of depression. Maurizio.
Thank you. Good morning. It's a pleasure for me to be here today. In terms of disclosures, I am a consultant to BioXcel. However, I do all my consulting through the hospital, so I don't receive personally, directly or indirectly, any honorarium, and I decline any transfer of value. That's why I brought my own snacks and water because I don't want to receive anything from the companies I consult on behalf of MGH. In terms of delirium, this is an area that is kind of very important from my perspective. Delirium is a kind of a condition in which there's an acute and reversible disorder of attention and cognition. The patients look disoriented, disorganized, and you have a clear disruption on the sleep-wake cycle. We typically characterize delirium in kind of three ways.
You have the hyperactive and agitated delirium, where the patient gets kind of restless and agitated, and they get violent or they pull the IVs. You can have a more lethargic or hypoactive patient with delirium that is confused, but basically doing very little. Then there are patients who have kind of a combination of a mixed state of hyperactivity and lethargy. Delirium in the ICU, in intensive care units, is very important because if you develop it, you have an increased morbidity and mortality. You have a prolonged stay in the ICU. The study that was conducted in Australia on 185 patients, it was a multicenter study in six ICUs. They screened patients for delirium, and they found that almost 45% of the patients developed it during the ICU. I've seen this over and over.
The situation of intensive care, sensory kind of deprivation, many people become delirious in those settings. Another common cause for delirium is post-operatively. A very sobering fact is that 40% of inpatient surgeries in the U.S. are performed in people 65 years and older. Postoperative delirium is the most common complication of major surgery in older patients. A study that was actually published a couple of years ago by Moskowitz and colleagues looked at 172 patients who underwent elective operations with admissions and found, once again, 44% rate of delirium. You have to realize that in the same study, when they did the follow-up, the mortality was 59% in those with delirium versus 13% in those without. Developing delirium, either postoperative in the ICU, is really a cause for increased morbidity and mortality.
You're going to say, "Well, we shouldn't worry about delirium because we got all these tools, antipsychotic drugs." A great study in the "New England Journal of Medicine" last year kind of at least made us feel foolish because, as you know, Mass General, we've always used IV haloperidol, been big proponents. It turns out in this study that was published, as I mentioned, in the December issue of the "New England Journal of Medicine," they compared ziprasidone, an atypical antipsychotic, or Geodon, with haloperidol or Haldol, kind of an old typical antipsychotic or placebo. When you look at the days alive without a delirium or coma, there is pretty much no difference. If you look at days with delirium versus placebo, haloperidol and ziprasidone, no difference.
It was a discouraging study, but in some ways it suggests that we need to do better if we want to prevent and treat delirium in our patients. Interestingly, we have very robust data. In fact, we at Mass General, we do a fair amount of use of dex for delirium, IV dex. Based on a very important study from The Lancet 2016 that showed this is placebo, and these are rates of delirium, and this is dex. You can see that after surgery, you have a marked reduction, significant reduction of delirium from day one to day three using dex. In another study that was published by Kim and colleagues this year, last month, they looked at the Riker Sedation-Agitation Scale after extubation, looking at dex added to an anesthetic, sevoflurane.
Sevo alone had a shift towards more agitation than when it was used with dex. In my mind, we have compelling evidence that dex can treat delirium, can potentially prevent agitation or delirium postoperative or post-extubation. The interesting thing, last year there was a terrific paper in Nature that showed that dex has a protective effect against traumatic brain injury and the damages of anoxia and so forth. A few years ago, a study looked at in laparoscopic cholecystectomy patients, if you were given placebo or dex, you had fewer cognitive impairment following the surgery, which was laparoscopic, if you got dex than if you got placebo. For all these reasons, this is a very recent meta-analysis by Ng and colleagues of dex in intensive care patients.
You can see that the bottom line is that you have an odds ratio of 0.36 with dex versus placebo, which is really, really robust. In my mind, it's kind of the potential use of dex as a prevention of delirium or treatment of delirium with the neuroprotective effects of dex, which may reduce the negative impact of surgeries and anesthesia on the brain, seems like a low-hanging fruit. Thank you.
Thank you, Maurizio, and thanks to all the KOLs for their insights on agitation as it relates to each of their neuropsychiatric specialties. They'll return in a few minutes during the KOL panel where you can ask questions, and they'll address them. I'd like to introduce Dr. Robert Risinger. He's our VP of clinical development and is the development lead for BXCL501, who will discuss the summary of our clinical results and provide overview of where we're going in our registration trial. Rob?
Thank you. All right. Thank you for being here and participating in this. I have some very exciting results to describe. We announced this in a press release earlier this week on Monday. This is our first human study with the sublingual film, BXCL501. We conducted this study in healthy volunteers. The study was a double-blind, placebo-controlled, single ascending dose trial. We were testing three doses of dexmedetomidine, 10, 20, and 40 micrograms. It was done at a single site. We studied healthy volunteers in the range of 18 to 65. In fact, we had almost a 50% distribution of females to males. It was quite representative. Total number of patients, 42 patients. Each dose group was randomized two to one, active to placebo. Our primary objective was to determine the PK, safety, bioavailability, and of course, tolerability. All right, it's working.
Let me describe the pharmacokinetic results. The BXCL501 film rapidly delivered to the targeted exposures, which were consistent with therapeutic responses we saw in agitated patients with schizophrenia when they were exposed to IV dexmedetomidine. I'll review that data in a moment. You've already seen a slide presented by Dr. Preskorn. Note that this dotted line represents the lowest concentration which was effective in the agitated patients with schizophrenia who responded to IV dexmedetomidine. The range of BXCL501 doses produced exposures which were, in fact, overlapping with the range of exposures that we saw that resulted in a calming effect in the patient population, as measured by the PEC score. The exposures were rapidly achieved. You see on the left-hand side here. They were rapidly achieved by each of the doses, 10, 20, and 40 microgram dose strengths. The PK was, in fact, predictable.
It was dose proportionate. That enables us to select doses for future development. Further, the pharmacodynamic effects that we found lasted about four to six hours, and we believe this is an optimal treatment duration for agitation in particular. Next, let me describe the safety and tolerability findings from the first human study. We found that dosing with BXCL was safe and well-tolerated across the range of tested doses. There were no serious adverse events. The severity of adverse events was mild to moderate, meaning Grade 2 or below. All adverse events were transient. They required no intervention, and completely resolved. The most common adverse event reported was drowsiness. The rate of drowsiness in each treatment group was similar to that reported by placebo group. The cardiovascular changes were not clinically meaningful. Further, we saw no clear sedative effects in comparison with placebo.
A maximum tolerated dose was not achieved. The safety profile between the sublingual film and IV dexmedetomidine, when we were testing that in separate studies, is consistent. I'm going to review that in a moment. From these results and the PK observations, we're confidently advancing clinical development to dose agitation in patients with BXCL501. Before I describe the development plans. There we go. Let me share the context as to why we're so excited about these results. To develop rapid proof of concept in agitation, we generated IV exposures across four different diseases. We conducted studies in three diseases. The bottom left in green was an independently published study. In schizophrenia, we saw a 90% response rate in terms of reduction in agitation using the PEC, or PANSS excitatory component scores.
We saw this without excessive sedation as measured by the RASS, the Richmond Agitation and Sedation Scale. Recall that the PEC is an FDA agreed-upon registration endpoint for the indication of the treatment of agitation. In dementia, we saw a 70% response. In opioid withdrawal, we saw a 100% response. In a separate published study of agitated delirium, there was a 100% response. The pharmacokinetics and safety profile from these three studies in blue are remarkably consistent across the disease populations and with our sublingual film now that I just presented. Let me further detail the proof-of-concept study completed in agitated patients with schizophrenia. Dr. Preskorn presented some of this data. Let me present the exact same data now. In our IV proof-of-concept studies, agitated patients with schizophrenia demonstrated a clinically significant reduction in PEC scores.
They had exposures that were consistent with those that we observed in our film formulation. In the proof-of-concept study, the PEC scores were reduced before we saw evidence of rising levels of sedation. Let me just say that this degree of calming is robust. It is not just a few points on the scale, although it is. It is actually what clinicians think of as a therapeutic response. This is why it is a regulatory endpoint. When we were developing the film, we are targeting exposures that produce this robust reduction in agitation in patients with schizophrenia. The film achieves the exposures that equate with clinical PEC reduction in agitated schizophrenic patients, and that is why we are confident that the film can provide exposures that are potentially therapeutic in the populations of patients that we intend to test.
Most reassuringly, I think, the PK and safety profile has been consistent across schizophrenia, dementia, opiate withdrawal. Let me provide you with a little bit more context regarding the levels of exposure that were achieved with BXCL501 in relationship with the labeled use of Precedex as an IV sedative anesthetic. Precedex has a very impressive volume of safety data. It has been given and prescribed to more than 10 million patients. There have been more than 120 published studies, some of which are reviewed today. Early in development, we saw levels of exposure that were tenfold lower than the IV indicated use that resulted in calming effects without sedation in pre-clinical models. Since then, moving into the clinic, we have been systematically fleshing out clinical data to de-risk development and demonstrate a broad therapeutic index. There have been no surprises. We have been providing doses.
We have been testing this in 42 patients now in this lower exposure range, and we believe that the lower exposures provide a benefit risk ratio that improves. In proof-of-concept studies, IV dex in humans gave us exposures that were up to fourfold greater, and these were well-tolerated in agitated patients with schizophrenia. This data provides us with great confidence in advancing BXCL501 to test the safety and efficacy across a broad spectrum of illnesses. Let me describe now the path to our first registration. This is a development plan for acute agitation associated with schizophrenia and bipolar disorder. This is a broad, high-level overview. We have a phase II study and a total of about 200 agitated patients with schizophrenia, which we will initiate soon. It is a two-part study. The first half will dial in the doses, and the second half allows us to characterize efficacy.
Following this, we'll initiate two phase III trials for registration later this year for a total of about 700 agitated patients, one in schizophrenia, one in bipolar disorder. These trials use the same endpoints and designs as previously successful registration studies. We expect the registration trials to complete in the first half of 2020, and that enables an NDA filing in the second half of 2020. All right. Let me outline the phase II designs. This is designed to de-risk our registration trials. In this two-part study, the first half will dial in the doses, while the second half will allow us to characterize the efficacy in terms of calming as measured by the change from baseline in PEC total score to two hours. The first half confirms effective doses, the range of dosing, and the tolerability.
Stage 2 characterizes variability in terms of response to a specific dose, and that is critical to powering a phase III pivotal trial. At the conclusion of Stage 1, we expect to have at least two effective doses, which we label here as a lower and higher dose. The designs and endpoints are comparable to other agents which achieved regulatory success. We've considered multiple options and believe this plan robustly increases the potential probability of success in separating from placebo in the phase III in order to gain regulatory approval. We believe the phase II trial is the most capital-efficient manner to potentially de-risk development without impacting timelines. These are relatively rapid studies to enroll. Let me outline our phase III registration trial. I'm sorry, trials. We will have two registration trials for the same indication.
We will have one trial for the agitation associated with schizophrenia and another trial for agitation associated with bipolar disorder. These will be running concurrently in parallel. This is designed very similar to the Stage 2 of the phase II study. Patients are randomized 1 to 1 to 1, placebo, lower dose, higher dose. The inclusion criteria will be a PEC total score of greater than or equal to 14, and the primary endpoint will be a change from the baseline in the total score at two hours. The number of subjects per trial will be in the range of 3 to 350 patients. The design is quite similar to previously successful global trials and will be very similar to the Stage 2. Like the phase II trial, these trials are generally rapid to enroll.
These patients are found commonly, and that's why it's so easy and rapid to enroll. We expect to initiate these trials in the fourth quarter of 2019, and we mean to take advantage of operational efficiencies in conducting two trials in parallel. We expect the data readout in the first half of 2020. As you heard from our panel of experts, we have multiple potential therapeutic indications. Let me place these in the context of our plans for our first NDA for the indication of the treatment of acute agitation associated with schizophrenia or bipolar disorder. We will initiate the phase II trial in the first half of 2019. These are short trials to execute. We expect rapid enrollment, principally, again, because agitation is a commonly encountered condition. We expect to have data readout in the third quarter.
That enables us to initiate our phase III trial in the fourth quarter of 2019. This data enables filing our NDA in the second half of 2020. We believe a commercial launch would ensue in 2021. In parallel, we've staggered development plans in agitated dementia, opioid withdrawal, and delirium. These plans will be rolled out throughout 2019, all the way through 2020, as part of the planning process, we consult with our expert advisors to systematically examine, evaluate, and de-risk the development in order to achieve technical and regulatory success. Our development plan for agitation associated with dementia will be rolled out, likely first, in the later half of this year. All right. With that, let me turn this back over to Frank, who'll describe our agitation franchise.
Okay, Rob, thank you very much.
Thank you.
Good job. Just two other points that I want to make, then we can take a break before we have the KOL panel. We view dex as a significant opportunity, obviously, our first attempt really is to look at dex in the context of acute treatment of agitation. That's really for mild to moderate, there's a lot of other things that this drug could be potentially used for. The first two opportunities are what we're pursuing now, which is the mild to moderate in psychiatric disease and the effect of the drug in terms of acute treatment in these other indications. There's still the problem with severe agitation and the types of drugs that are used. We think that potentially dex could play a role in this area as well.
What we've been doing is we've been experimenting with some combination treatments with dex. In other words, trying to take advantage of a synergistic pharmacological effect where you can lower the actual dose of both to get a basically anti-agitation effect. This is one thing that we are pursuing right now, and when we have more information on that, we will show you what we have at the proper times. The other is the possibility, because the drug really seems to work well, we think will work well as an acute treatment. The possibility to tie this to some kind of digital integration. What do I mean by that? Well, what we're doing right now is we are now taking patients who are already agitated or on their way to being from mild to moderate to severe agitation and treating those patients.
The question is, by utilizing some digital software and digital hardware, can you come up with a process where you can determine whether these patients are on their way to becoming agitated? Because I think the beauty of dex is if it's well-tolerated, which we think it is, and particularly because it has the low-dose phenomena, there's a chance that we could, if this could be determined, that we could abort potential agitated events from occurring, not just treat. Okay? One of the things that we're pursuing here is to see, utilizing, understanding the pharmacology of the drug, the sympathetic nervous system, all of those things rolled in. Is there a way to actually determine this phenomenon with proprietary algorithms, utilizing our capabilities in AI, okay, to predict emergence and notify caregivers?
Just thinking about it, putting it in a simplistic way, thinking about a patient wearing something like this, particularly if you're thinking in the area of dementia. The caregiver has the phone, and they all of a sudden get an alert that this patient's on his way to becoming agitated. The idea is, could giving a drug like dexmedetomidine try to stop the more advanced issues that occur with an agitation attack? This is where we are right now. This is in the development stage. We're thinking. We believe that dex offers us a really unique opportunity to marry with this type of science, the digital integration. Okay? I'm going to stop there. I want to thank you for your attention so far this morning. What we're going to do is we're going to take a 10-minute break. The restrooms are down the hall.
Okay. You can mingle for a while, and then we'll come back with the KOL panel. Thank you.
Hello, everyone. We're going to start the next agenda item now. If you can kindly take a seat.
What we'll do now is, we are going to have our panel discussion. Just a note, Dr. Maurizio Fava has to get back to Boston. What we're going to do is ask you to potentially focus your questions on delirium or any other questions that you have for Dr. Maurizio Fava to do it early, because he has to leave in about 20 minutes. I also want to take the opportunity. This session is going to be moderated by Sumant Kulkarni, who is a biotech research analyst at Canaccord Genuity.
Thanks. Thank you everyone for being here and tuning into the webcast. We do have a mic going around, please feel free to raise your hands to ask a question. Don't be shy. Thank you also to the distinguished panelists here. I'm going to kick it off with one big picture question. We've heard a lot about why 501 or dex in its format that BioXcel Therapeutics is trying to commercialize eventually is good. Is there anything in Precedex as a molecule itself or this formulation that might want you to not use this product in the patient indication that you might be going after? We'll start.
The main issue with the Precedex or dex is that it can lower blood pressure and heart rate. This is really a surgical drug for affecting surgical precision, pinpoint precision. In comparison to all the other drugs which have targets, either targets that widely affect the brain, like benzodiazepines or multiple targets. This has one target. That target is the locus coeruleus. If you remember that the downward pathway controls blood pressure and respiratory drive, the upward is arousal. The key thing is to achieve a dose which decreases arousal without affecting blood pressure and heart rate. That was a key feature in the IV dexmedetomidine studies that were done. That was really aimed to determine the therapeutic index, where you would have wide separation between an anti-agitation effect and an effect on the cardiovascular system.
Yeah, maybe I can add to that. I referred a couple of times during my brief presentation to the 85-year-old
We've kind of redefined what geriatrics is these days. We feel that people in their 60s and 70s are in their middle years, and you really don't start thinking geriatric until people hit the age of 80, particularly 85 plus. We know that as you get into your ninth decade of life or beyond, the sensitivities as far as autonomic nervous system-related issues such as blood pressure and heart rate and so on, can also increase. One of the issues which will be very important will be to determine the optimal dose for that vulnerable, more frail 85-year-old who has Alzheimer's disease, who's agitated, and maybe won't allow the family or the caregivers to give them a bath or a shower or to dress them or to change their diaper, whatever, without affecting those same parameters.
It may be that the ideal dose may be lower for that population versus the young, robust, schizophrenic or bipolar patient.
If I could go on, I would say, that's also the logic behind the development plan in terms of starting first with schizophrenia and bipolar patients, gaining experience now through the phase II and III studies, and then looking at going into potentially more vulnerable populations. All of that is really accumulating data to drive the design and the dosing of the next studies.
The other issue is really the fact that you can see, for example, in delirium, whether you can use dex for the treatment of delirium, which may require probably higher doses, or for the prevention of delirium, which may require lower doses. That, to me, is a very, very appealing thing. If you think about it, the studies suggest that the elderly, 45% of people post-operatively may have delirium. If you can reduce the risk and recurrence, if you prevent delirium, you're saving lives. The dosages may be even lower when it's used for prevention because you're targeting the locus coeruleus, you're trying to diminish that hyperarousal, which can be so lethal in our patients.
Those patients are also largely geriatric patients.
Advanced age is probably the second, number 2 risk factor for delirium. Number 1 being preexisting cognitive impairment. You're looking at that same population. The other issue I wanted to add is the benefit of a compound that is not a knockout drug, that doesn't cause too much sedation. Sedation in my population, again, the 85-year-old, is a huge risk factor for falls. As you saw, falls, not being able to guarantee safety, are the number 1 risk factor for ending up in a long-term care facility.
Yeah. It's slightly different for opioid withdrawal because the medications that already exist have a similar mechanism of action. It's not that this has a completely different mechanism. I think what would be important for opioid withdrawal is if it offers a benefit. For example, if it's more effective than clonidine or causes less hypotension, those are all things that would be really important in terms of using it in opioid withdrawal.
I'll direct a couple questions here to Dr. Fava because he has to leave. You mentioned that a large percentage of patients already experience delirium when they're in the ICU. What prevents use of IV dexmedetomidine? It should be relatively simple to use in that setting. What would make a sublingual formulation advantageous?
No. In fact, in Mass General, we use significantly dex in the ICU and post-operatively. In general, we see these are the issues with implementation science even though dex has the most robust evidence in delirium. You still see hospitals continuing to use antipsychotics for delirium even though the New England Journal of Medicine showed that it's no better than placebo. Unfortunately, we tend to practice a little bit the same way we used to practice 20 years ago. There's no reason right now not to use it. The question in my mind is, because people say, "Well, why not use Precedex? Why do you need an oral formulation for delirium?" I think that the idea is that psychologically, the idea of an IV intervention for prevention is not appealing to doctors. They don't like the idea of giving something IV for prevention.
Oral, for whatever reason, psychologically, they say, "Oh, okay, I'll give it." I think that, particularly if we're using lower doses for prevention of delirium, this could be, in my mind, a breakthrough clinically.
Given you are so much in the know on use of dex, it doesn't take too much convincing for you, but what do you think needs to happen for wider practices to adopt dex?
Well, I think that we've seen that in all areas, you have to start educating. You have to start really elevating the practices and the quality of care. Unfortunately, in delirium, I think this has been a neglected area. I've seen over the years that whenever you have a new treatment and people get educated about the condition, how many hospitals really get very good education about treatments of delirium? We can really see a kind of a deployment of educational programs in this area to raise the standards.
This was something that I was planning to ask last, but given you have limited time, I'm going to ask it up front anyway. Payers and pricing are in the public eye, for better or worse. How do you think that might influence the use of dex in the ICU setting if there is a new branded product approved as the first one?
Sure. Well, I don't know how people will react, again, IV administration is more expensive than oral. The level of monitoring that it requires. I think that a cheaper IV versus a more expensive oral, at the end of the day, people may side with the more expensive oral because of the safety and the lesser need for a kind of vital signs monitoring.
Yeah, certainly in our situation, it requires an anesthesiologist to be present when you use IV dexmedetomidine. The trade-off would be a reduction in professional fees versus the cost of the medication. I think one could probably actually do an economic analysis of that. I certainly think that adoption is not going to be problematic because there are many of these drugs that are available. They haven't been developed for this reason. We talked about clonidine. The issue is having it in the right dose form, and having it in a rapidly absorbable and predictable absorbable way. That's the difference. I think doctors will not be particularly surprised or require a great deal of education about the mechanism and that these are useful, but rather understanding why this formulation, the science behind the delivery of the right dose, will be the critical issue.
Yeah, let me just add to that. We've been focusing on delirium in the ICU. The reality is that there's more delirium outside of the ICU in older adults. We see it in the nursing home. We see it in the outpatient setting. We see it in the hospital on various wards where we get asked to consult on usually an older adult who's now acutely confused. Maybe they don't have an IV, and obviously in the nursing home and outpatient settings, going to an IV preparation is not desirable. Having something oral is obviously much preferred, even if it's at a greater cost. Much better tolerance. In my agitated dementia type patients who also are at risk for delirium, they're going to pull the IV out. You may have to strap it down. It's very complicated and just not practical.
The oral form, I think, has great potential. Where I really see a lot of potential, and I haven't been aware of it until today as you brought it up, is the prevention concept. We already know what the risk factors, who is at greatest risk for developing delirium. We know those factors. If we can identify those people and treat them and prevent, wow. That would be amazing given the huge cost to our healthcare economy, quality of life for patients and caregivers of undiagnosed, untreated delirium.
Yeah.
Wow.
Yeah, that's a great point. The studies are focused on delirium post-operatively in the ICU because they have the highest rates of delirium, and it's easier to study them. Delirium happens throughout inpatients. People with urinary tract infections may become delirious, elderly. They don't have IVs.
They don't want IVs.
The access to an IV is not the same. That said, even where you have the IV in and you could say, "Well, isn't it easier just to do it?" I still think that the use for prevention will be much more acceptable in oral formulation.
If you have any questions for Dr. Fava, please raise your hands. I'll ask a general question now. I'll start with Dr. Petrakis because we've seen dex. We've seen the label for IV dexmedetomidine. Now granted, that could be a very different situation. How do you see the potential for dex to have any kind of drug-drug interactions, especially given that patients in either the opioid use withdrawal indication or the others are already on various other quote unquote drugs?
I don't know, are you saying specifically about the IV formulation or just in general?
No, in general, a formulation like this, how would that help or hurt practice given that might interact with some of the drugs that are already being used?
Right. A lot of times opiate withdrawal is actually occurring in people who are relatively younger and healthier. I think these are less issues than it might be in the geriatric population, for example. Most of these patients, if they're on other medications, it may be adjunctive to treat the withdrawal, just to treat some of the symptoms. In reality, they don't necessarily have to be on a number of other medications. They may be relatively healthy. They're taking opiates. They stop their opiates. They go through withdrawal. I don't see the treatment as being particularly problematic in that setting.
For Dr. Preskorn, you mentioned the vignettes there which involved a little bourbon. How about alcohol interactions and things like that? Any special studies that might need to be done there with this formulation?
On alcohol, yeah.
Certainly, if you're dealing with alcoholism, and you're dealing with delirium treatments, a physician's going to need to be cognizant of the fact that they may have volume depletion. They are in sympathetic overdrive. Again, one would be cautious with regards to dosing and dose appropriately and look at vital signs, et cetera, when you do that. That's nothing different than what happens today.
Question from the audience.
When you're treating delirium patients and agitation patients who are generally uncooperative, what is their willingness to take an oral medication? Is that something that you plan for or have procedures and techniques to do?
Well, again, once the patient is completely delirious and aggressive, it may be very hard at that point to have an oral administration. As I mentioned, if you have a 50% risk of delirium post-operatively, you can give this drug to everybody after surgery. You have the cognitive protection that has been suggested by a number of studies, and you're reducing the incidence of delirium. To me, you don't have to wait until the patient gets really hyperactively and aggressively delirious. You give it preemptively, and you're preventing it. That's why, to a certain extent, we're probably going to see in the hyperactive, really agitated, delirious patients, we'll see a combination of IV and oral. There'll be some IM, whatever, parenteral, when they're really agitated and delirious, because they won't be cooperative enough to take something orally.
I would say for prevention, that's going to be very easy.
Let me just add to that. I agree with everything you said. For acute treatment, whether you have irritability, agitation, mild to moderate overtly aggressive behavior, whether it's due to delirium, whether it's in the context of the dementing disorders like Alzheimer's disease. The degree of the agitation, aggressivity, and the acuity of it is going to determine whether you're able to get the patient to take something by mouth. Probably 80% or more of the patients will have mild to moderate either irritability or agitation and won't be overtly aggressive to the point where, as you pointed out, you may have to even give something intramuscularly, like an injection. They may not even stand still for an IV. That will be the relative minority, at least in the delirium/dementia category that we would run into.
Yes.
I think the whole point is to catch this early. As we sort of indicated in the slides, you start out grumpy, anxious, on edge, a little irritable. Frequently at that point, you actually want treatment. The issue is having a treatment that is well-tolerated and safe and doesn't cause side effects and does not behaviorally disinhibit the patient. I'm impressed by the fact that markets don't define drugs. Drugs define markets. Until you have a novel treatment, a treatment that does something existing treatments don't do, you don't really understand the size of the potential market. I'll give you a simple example. With the introduction of Prozac and the subsequent SSRIs, the market of antidepressants went up an order of magnitude. That wasn't because the market didn't exist.
It's because with the old drugs, they were so dangerous that you only gave it when you absolutely had to. With the new drugs, the danger of the disorder vastly outweighed the drug.
I'll move on to a specific question on dementia here. This product 501 is going to be a rescue treatment for the most part. We are aware of other drugs in development for dementia-related psychosis or treating agitation. How do you think rescue treatment or the landscape for rescue treatment might change if other drugs are approved more as chronic treatments?
I was thinking of actually presenting a slide for you to show you what's in the pipeline as far as treatment of agitation in dementia or in Alzheimer's disease. The drug that is closest to approval is an antipsychotic, and it's in phase III trials right now. It does have, unfortunately, the same liabilities that all of the antipsychotics have, including the black box warning, which for many clinicians is a major deterrent for prescribing. Their phase II data looks promising and looks positive. They're in the middle of a large multicenter phase III trial. There have been a couple of other drugs in the pipeline that are not antipsychotics that unfortunately have failed recently.
There's another very interesting compound that's also kind of number 2 behind the antipsychotic, which is a unique compound, but again, very different than this one, has much more of a sedating kind of posture. There are things that are really much farther back where there's no guarantees that they're going to pan out. I think from a structural standpoint, a side effect or tolerability standpoint, the profile of this compound is different than anything that's in the pipeline, and I think meshes pretty well with what we get concerned about relative to our older dementia patients with agitation. This is not an antipsychotic, so I think we want to keep that in mind. That's a plus, because the antipsychotics have a lot of heavy duty baggage in this population.
I'm going to ask almost a pure investor type question to make our lives easier here from a modeling perspective. If you go at each of these indications and you look at the patient profiles here, how many times do you think an average patient might need to use this film in, let's say, the schizophrenia, bipolar disorder setting, or dementia, or in opioid use withdrawal in a given year? Any averages or medians you might care to throw out there?
I would say that it's quite variable, but I think that, again, it depends upon the efficacy and the safety and the tolerability of the drug. For example, if you looked at a patient with Alzheimer's disease, I'm going a little off target, but what frequently leads to them not being able to stay at home is sundowning and agitation. If you could administer this drug to aid the patient in not getting up and wandering, not get up and being frustrated, and irritable, then you prevent that person having to go into a nursing home. In the nursing home, again, they can be pacing. They can be, in other ways, agitated, et cetera. When they reach a level that the nursing home isn't able to manage them, then they go into a geropsych unit. Each one of these is an increase in cost.
You could imagine a patient potentially needing a medication like this on a nightly basis. Again, this will vary depending upon the stage of the illness they're at.
Yeah. I can try to give you a partial answer because I think it's a great question. I don't think we really have all the data to fully answer that question. It may be that this could be used as a PRN or a as needed drug when the occasion arises, whether at home or in the long-term care environment. It may be that we're going to learn from our studies that patients do better who maybe have more chronic administration, their quality of functioning improves, and they're much more manageable. I think that's an important issue. We still need more answers on that.
I think the answer that it's variable is true. I think unlike the other disorders, an opioid use disorder, what you would hope is that you detox someone once, and then they go into treatment, and that would be the end of it. Of course, that's the ideal and very infrequently happens because opioid use disorder is a chronic relapsing disorder. Even for people who are, say, taking methadone or buprenorphine, the number of people who stay on the treatment in a year is less than 50%. That means that they're out but using again, and they're going to go through withdrawal again. In a year, I don't know how often it's going to be.
The other thing that's happened now is that there's a big emphasis on prescribing NARCAN, which reverses opioid overdose, which people take in the field. That can precipitate withdrawal acutely out there. You don't really know how often that's happening because there's not good data on that. People are doing it at home. They're doing it with their friends, their family members. It is common that people will experience opioid withdrawal several times over the course of a year.
Yeah. I would say the other thing is, the company has data that the drug has preventive actions. This comes from preclinical rat data, using an intruder mouse experiment in which you dose the animal knowing they will typically attack the intruder, and actually demonstrate that pretreatment decreases the percentage of attacks. That's difficult to do in humans. You're going to start with acute symptoms, but then as you get comfortable with the drug, it's conceivable that you could look at a prevention treatment.
Dr. Preskorn, you brought up an interesting point. You said potential nightly use. If we look at, again, the intravenous label that's out there for the approved Precedex, there is, I think they use the word tolerance to dexmedetomidine. Is there any potential to develop a tolerance for this drug if used in a different formulation?
You can develop tolerance to alpha-2 drugs. With chronic administration, with clonidine, for example, you can get rebound hypertension. I think the concept here is the drug would be used for a short period of time at night. The drug is relatively rapidly cleared, so you wouldn't be looking for sustained effects of the drug. A tolerance typically occurs when there is chronic blood levels of the drug resulting in a reregulation of receptors. I think with the pulsatile effect, that will diminish that possibility.
Moving on to the setting of use. For the most part, again, this is probably going to be used where a care provider is present. What about the potential for a film of dex to be allowed for at home use, and how do you see that evolving? Are there any roadblocks that you might see in getting that in the homes?
I think that'll be a function, again, of having adequate safety data in sizable percentages of patients. It probably is not much different than taking a drug over the counter, where you develop enough history with the drug that you are able to then use it in less restrictive environments. Certainly I think right now the plan is to look at it in carefully defined populations with acute levels of symptoms for the obvious reason that this is the initial entry into the market. Then if you look at the effects of the drug and its safety profile, that will dictate the comfort level that the FDA would have with moving it to a less restrictive environment.
I was going to say, in the patients that I deal with and working with them and their families and professional caregivers, they're used to giving patches. They're used to giving sublingual nitroglycerin, for example. This is not something that's different. Again, if we have the safety and tolerability profile, something that actually could be advantageous in my population, a lot of whom dementia patients often have difficulty swallowing pills. They get stuck, they spit them out, various other things. Having a film that instantly kind of dissolves under the tongue, patient can swallow it, they're getting the medication, and it's easier to administer. I think in many ways it could be attractive.
On the opioid withdrawal side, clearly this is not a new mechanism of action, as you mentioned. What might you consider might be the biggest hook for the use of a film in that setting?
First of all, it's the action of the medication, if it causes less hypotension, for example, like than clonidine and more effective, that would all be a big sell. A film is quite appealing in this population. The SUBOXONE or buprenorphine, that's the way it's given. It's in a film preparation. If people feel nauseous and aren't going to swallow pills, like you mentioned with the geriatric patients, that might be a plus. IV is unlikely to be used in these settings. First of all, most people, they may not need it. Second of all, if you're talking about an IV drug user, they may have limited access to this vein. A medication that can be administered in another route is a real plus.
dex is a very well-characterized molecule, given it's been out there for so long. Now, there's definitely not going to be an advisory committee meeting here, but Dr. Preskorn, you've been part of many. If you had to look at what the FDA might do, assuming all the trials work as they're intended to, and the drug is safe, efficacious, and things like that, if you had to nitpick, what do you think the FDA might pick on to not want to approve a product like this, if any?
To not approve it?
Yes. Is there anything that you see that the agency might raise its eyebrows on?
I'm speaking having actually served on the Psychopharmacologic Drugs Advisory Committee. My comments on over-the-counter, I have actually served as an expert testifying to the over-the-counter committee, so that I have some idea of what they look for. All of drug approval is a balance of the efficacy of the drug in a given condition versus its safety and tolerability. That's the bottom line. The reason why you have indications is to show that the drug has A, effect size, A, therapeutic benefit in a given population, and then you weigh that against the safety and tolerability of the drug. That's what they're going to look for with this compound.
I should maybe add that in dementia patients and Alzheimer's patients, the FDA has been relatively liberal in generalizing dementia as a whole rather than being specifically focused on one subtype of dementia, like Alzheimer's versus vascular versus Lewy body. There are a whole range of different compounds that are in the pipeline that they've now approved the studies for. The bottom line will always be in a vulnerable population where these patients often can't even give informed consent, you have to have the family and the legal representative give informed consent. It's going to be safety and tolerability. As long as you can show safety and tolerability, and the drug is efficacious, I don't think there'll be any problem from the FDA.
For opioid withdrawal, I don't know if this is an FDA issue or a marketing issue, it would seem that if you distinguish it somehow from sufentanil, that would be an important point to at least be thinking about.
If you look at sufentanil, you have very serious adverse events, percentage-wise. The other thing that the FDA looks at is what's the severity of the untreated illness. The touting is the efficacy of the drug in the illness, the seriousness of the illness, and then the safety and tolerability. I think you can readily see that in the sufentanil package insert, and where one considers the problem of the opioid epidemic.
So-called risk-benefit ratio.
We have a good sense of what the competitive landscape is on the withdrawal symptom side. If you look at agitation as such, there aren't really a whole lot of treatments out there. Dr. Grossberg, you mentioned you might have had a pipeline slide. Are you aware of any other products that might go head to head versus a BXCL501 film on the agitation side that might be making it to the market around the same time or a little after?
That's hard to predict, because I was recently on a safety and efficacy monitoring committee for a compound that was already in phase III, where the interim analysis showed that it failed. It didn't work. You just never know. I think you have a compound here where we know that at least in certain populations, it does seem to work. We do have some relatively reassuring safety data, particularly if we can figure out the optimal dosing for the given population. Again, I can't be a soothsayer and tell you that there's anything that's quite like it. There is a compound which will probably get approved, but who knows, it could fail, which is a combination of dextromethorphan and quinidine, which has some similarities. One of its liabilities may be sedation. It is a real sedating compound, which does have anti-agitant effects.
It's hard to predict. I think this is, again, different and unique, and it could potentially have a role. We'll see.
Delving a little bit into the data that BioXcel has on the product so far. We're heading into a phase II here in the schizophrenia and bipolar disorder indication. Given what you've seen so far, what would you say would be the most impressive or not characteristics of the data that are out there that have been generated by the company on the BXCL501 film specifically or in the bridging studies?
I've been involved in all the IV studies, and what's truly remarkable, this is going to be presented at the American Society of Clinical Psychopharmacology next week, is how reproducible the data is from one population to another. The drug is very well behaved in terms of its predictability. I think that, to me, is what's truly striking.
There's a question in the audience.
Scott Puckhaber from Barclays. Just wondering if you could give us a breakdown of your current mild to moderate patients that are on antipsychotics or benzos or others, and what % you would switch to the 501 asset if it was approved. Maybe which patients would be least likely to switch. Maybe as a follow-up, what the potential abuse potential is for patients and caregivers for this asset.
I think probably you're not necessarily looking at switching. There are plenty of people who are on antipsychotic medications to treat their psychosis. Your situation is when they start to get agitated, when they start to get restless, some of which may be reducing the dose of those medicines. I would say rather than necessarily switching, it is really using the drug as a PRN as needed basis for specific symptoms. I'm sorry, I didn't catch the last portion of your comment.
Thinking about the abuse potential, the asset of, you say you probably give it as needed, is there a scenario where patients are taking it more frequently or the caregivers are giving it to more frequently to avoid that agitation? Just how you think about that as well.
Yeah. I don't know of any evidence for abuse potential of the drug that I'm aware of. It's not particularly rewarding. On the other hand, humans are remarkably susceptible. I remember people injecting peanut butter. It actually was a fad because it hits your valves and it makes your heart flutter. There's always the possibility.
I guess we have a formulation question on peanut butter film.
I don't think it was chunky style.
Clearly, each of you has experience in a wide variety of indications, not just the ones that you were speaking on today. If you had to look at other indications that a film like this might be useful for in a neuropsychiatric setting, what might those be?
Yes. I'm just thinking about this as you're asking. I think it's a really good question. We've already discussed a broad array of potential indications. I think if the company would be very fortunate to have those indications approved by the FDA, you're going to be one of the larger pharma. Again, there may be other areas, potentially, depending on whether the compound has, let's say, anti-anxiety effects. Maybe at particularly low doses, it might be able to be used for either acute treatment of anxiety or even longer-term chronic treatments. We've only peripherally touched on alcohol, and one of the things, I just wrote a piece in a national magazine that's gotten a lot of attention, where I commented about the opioid epidemic and how, as horrible of a problem as it is, nobody, because of that, is talking about alcoholism anymore.
Which is by far and away magnitudes greater problem for our society in every way, financial cost, emotional cost, families broken, suicide, you name it, than the opioid epidemic is. We're no longer talking about it. If there's potential in the alcohol abuse area, again, I don't know, that would be another huge opportunity.
One other area is clonidine was looked at a little bit in post-traumatic stress disorder, which is another disorder that has a lot of hyperactivity in the noradrenergic system. The medications to treat PTSD are pretty lousy, that's a huge issue.
It's a growing population, right?
Hi. Nina with Out There Media. To circle back to an earlier point that was made, how are you thinking about the clinical setting which BXCL501 will be administered specifically to agitated dementia patients? Is it reasonable to conclude that at least the initial site of treatment is going to be predominantly in the emergency room?
For dementia patients?
I'm sorry, emergencies you're talking about?
Yes.
Yeah, I think it can be used. We touched on this earlier, that this may potentially be a PRN drug, which can be used in acute situations. Where it may not be appropriate, because of the sublingual film component, would be the out-of-control aggressive patient, where whom, as Dr. Fava mentioned, you may even have to give an intramuscular preparation, perhaps in the emergency room or wherever, to get them to a point where they may be able to use a film like this. I think it does have potential as an as-needed drug for mild to moderate agitation in the dementia population. Some subsets of that, the overtly out-of-control patient, at that point in time may not be a candidate.
As a follow-up, how should we think about how ER doctors will slot BXCL501 into their treatment paradigm relative to nurses in an at-home setting? What are the differences and nuances there?
Among nurses and?
An ER doctor.
As far as how they would use this?
Right.
Versus what's already available off-label?
The way that those two caretakers or clinicians will think about applying it to a treatment paradigm, the way that they're going to approach using it, similar or different? How do you see any nuances there?
Okay. I'm not sure I fully understand that question, but let's think about where the drug would be used. It can be used in the outpatient setting, where a family member might administer it under guidance from a physician, similar to many other medications that they currently use. It might be used in an outpatient clinic setting. It may be used in the emergency room in all but the totally out-of-control patient. It may be used in the assisted living memory care scenario, where these patients periodically with dementia do have these problems, always under the prescribing of a physician, but may be administered by the nurse on the unit, and the same thing in the nursing home. Advanced practice nurses, PAs, would be able to prescribe this.
This would not be, as far as I know, a controlled substance. They should be able to freely prescribe it without restriction. Reimbursement, we haven't talked about that. Dr. Preskorn and I were talking earlier that there are some physicians, for example, and prescribers who are reluctant to prescribe anything that's not FDA approved. They're reluctant to prescribe off-label. Insurance companies, I've been told by our legal people, have a legal right not to reimburse things that are also off-label. Dr. Preskorn said, "Well, sometimes they don't want to reimburse even things that are on-label." That's true, but you have a much better case when something is on-label, and you can justify that that's the best medication for that patient in the office or in the nursing home.
It's the safest, where basically the risk-benefit ratio is the highest. I think it's going to be widely prescribed by a range of healthcare providers. There should be no impediments.
I think all of these things are really driven by the phase III data. What's the therapeutic index? The wider that therapeutic index, the more you can see at-home prescribing. You can see use at home, in nursing homes, et cetera. I think physicians may-- I always say you're using an approved drug for an off-label indication. We sometimes use clonidine in folks who have trouble falling asleep. That's not common, but we do. This drug produces a sleep architecture rather comparable to normal sleep architecture. One of the things that the locus coeruleus does sometimes is to, when it intrudes, when you should be going to sleep, it keeps you awake. I'm always leery about going too far afield from what are the planned indications, because I think you have to do first things first. That's certainly defining that therapeutic index.
Hi. Edward , H.C. Wainwright. Following up on that alcohol use disorder, I'm wondering if this could be used for something like cocaine or methamphetamine, or whether that mechanism is a little bit too different.
There is a huge graveyard of medications that have been tried for cocaine and methamphetamine. They've tried a lot of different agents. I suppose you could try. Years and years of trying to find something that helps with those disorders has been pretty frustrating, to say the least. That doesn't mean that it couldn't possibly be tried, and I don't remember the literature on if clonidine's been tried in this area. It may be. I'd have to go dig it. I haven't been. I don't know. I'd have to dig that out. Because it's been an area of frustration.
The issue is that when you go into withdrawal, frequently, you activate the locus coeruleus. It's a component of the agitation and sympathetic overdrive that you get with substance withdrawal, a variety of kinds. You have really three phases of addiction. One is the binge intoxication, two is the adaptation and withdrawal phenomena, and three is anticipatory. During that withdrawal, which actually is what drives principally addiction, part of the symptomatology arises from locus coeruleus overactivity. That doesn't mean the drugs will treat the addiction. It means they treat the symptoms from the withdrawal phenomenon.
Just on a broader level, I'm wondering what APIs might be used most synergistically with 501. You talked about it being used individually in acute settings, is there any sort of medications that a patient might be on for a more chronic level, that would either not be used very well with 501 or would be most beneficial to be used with 501?
I think you'd be careful about antihypertensive medications. For example, drugs that block alpha-1 receptors cause orthostatic hypotension. That's working on a different adrenergic receptor, the alpha-1. I think, again, this would be where you begin accumulating data. Does that pose a problem? I would think certainly in terms of things such as blood pressure medications, which ones are problematic, if any.
I can add to that. Obviously, blood pressure management is particularly important in older adults. A lot of times, their fluid intake isn't very good. They might have a tendency of dehydration. Even without antihypertensive blood pressure medications, they tend to have a lower baseline blood pressure, especially if they're not getting enough liquids. Anything that could potentially exacerbate that would be considered problematic and may affect dosing and utilization. There are some common off-label drugs that are used in this population, in my population, for mild to moderate, but more mild irritability. One that comes to mind that's used very commonly is an antidepressant called trazodone. Trazodone at high doses, which older people can't tolerate, is a good antidepressant. It's way too sedating and drops blood pressure.
Even at low doses, again, it can mildly lower blood pressure, and if it's combined with an agent like this, we'd have to be particularly cautious. It may be that you don't want to use that combination together. A lot will depend on what the patient's already on and what the profile of that compound is.
We're almost out of time here. I'll squeeze in a question. We touched upon reimbursement a bit. For a product like 501, especially if it's used in a care setting, do you think it would be reimbursed as a pharmacy benefit or a procedure benefit? Would that make any difference in potential for use?
I would think it'd be more of a pharmacy benefit. That's not particularly my area of expertise. I don't know if you guys want to comment.
I would guess pharmacy benefit.
Yeah.
Okay. With that, I'll turn it back over to Vimal.
Thank you. First of all, I want to thank our distinguished panel for making the effort and answering all the questions about the program and outlining the opportunity and unmet medical needs related to these four diseases. As everybody heard that there is a big potential for 501 to go in different directions. I will remind everybody one statement that Peter always say is, "Our company strategy is to land and expand." We want to land, and we want to get to the NDA as fast as possible with one indication so that we can get this drug approved. That's the path we have chosen with schizophrenia and bipolar, the plan that Rob described today. That we feel that's the fastest path to get there because there is a regulatory precedent in terms of the clinical endpoint, which is reduction in fact.
At two hours, FDA has already approved such drugs. That helps, as well as the drug has been reimbursed by the reimbursement agencies. We have some baseline there that you can get this kind of drug approved for acute treatment of agitation resulting from schizophrenia and bipolar. There are very minimum unknowns, as we say, for this indication. As we go, market are big. Dementia market is a very big market. As we all know, there are a lot of chronic treatments being developed to treat these patients. What we get to hear all the time is that you need optimal treatment whenever there is a breakout of their agitation for the dementia patients when they are in the nursing home or they end up in the ER.
A TRN use could be very valuable, as you heard today from our experts, and particularly from Dr. George Grossberg, there is a huge need for this population. We continue to build our plan, and we'll roll it out that one as a second plan after schizophrenia and bipolar. Opiate withdrawal, it's very clear this mechanism FDA like. They approved a drug last year, Lucemyra. That's a very fast path for us to get to the NDA because these trials are very short, and they can be conducted, and endpoints are well-defined. It's called COWS, and with our IV dexmedetomidine, we have seen that 100% reduction in COWS score. We have a good proof of concept there to move the drug in that direction. We continue to work with Dr. Maurizio Fava and other experts to see what is the opportunity for us in that area.
I think initially, company has chosen to focus on these four because we have a human proof of concept in all of them. In addition, alcohol withdrawal as well as PTSD are the other thing that in future can be explored. We are, as a company, super excited that we have a product that is going into the phase II, and we will have the data coming out in few months, by Q3, on the schizophrenia and bipolar. Some of the question that were asked was the profile of the drug is. It will allow us to power our phase II trial effectively so that we can get to the registration and file the NDA, our first NDA at the end of 2021. Basically, that's a kind of a very high-level summary of the plan for 501.
Company as BioXcel Therapeutics, we work in immunology area also, and we have a product, 701. Which where we have 2 INDs approved already and third already filed. We are targeting neuroendocrine prostate cancer, which is a very big high unmet medical need. Pancreatic cancer as a triple combination with our partners, NKTR-214, as well as with Pfizer and Merck's avelumab. That trial will start. I think our company is very excited, and as a company who became public company in last 12 months and where we are, we are very pleased the direction we are heading, and both programs are moving forward. In addition, Frank presented our symbol says, Nasdaq symbol, BTAI. AI is in our DNA. We try to use AI at every stage in discovering of the drug, in our translational work, as well as in the clinical work.
You heard today that we are looking at digital markers to see how we can expand the patient populations for agitated patients. We'll continue our quest for that, utilizing the technology as much we can in 3 states of discovery, translation research, as well as in the clinic in terms of the patient selection or identifying the patient. With that, I will stop, and I want to give you an opportunity, if you have any commercial questions. We do have Pascal here, who's just joined us as VP of Commercial, and they've been conducting lot of key opinion leader interviews. [Dasha], who is our partner, and she's also here, and they will be happy to share with you some initial things in their market research they've been finding, and they have gotten some answers what was discussed here.
I think bottom line is we are trying to define the profile of the product so we know what questions to ask in the future.