Study Result

Jan 5, 2021

Press Release

Hello, and welcome to the BioXcel Therapeutics Conference Call. At this time, all participants are in a listen only mode. A question and answer session will follow the formal presentation. As a reminder, this conference is being recorded. I will now turn the call over to BioXcel's CEO, Vamil Mehta. Thank you, sir. Please go ahead. Thank you, operator. Good morning, everyone, and thank you for joining our conference call today to discuss our positive top line results from the Phase Ibtwo Tranquility trial for the acute treatment of agitation in dementia, including Alzheimer's disease. This is an exciting day for Biotech Therapeutics and a hopeful day for dementia patients and their caregivers. And you can imagine from the press release we issued this morning, we are delighted by the findings of the TRANQUILITY study showing that BXCL501 was well tolerated and demonstrated rapid and durable reductions in agitation in patients with dementia. A copy of the press release is available on BioXcel Therapeutics website. As a reminder, we will be making forward looking statements regarding our financial outlook in addition to statements regarding the advancement and development of BXCL501. Such forward looking statements are based on current expectations and assumptions that are subject to risks and uncertainties and actual results may differ materially from those expressed today and due to a variety of factors. Additional information concerning these risk factors is contained in our filings with the SEC and available on the Investors section of our website, www.bioexceltherapeutics.com. Joining me on today's call to provide further insight to the exciting Phase 1btwo data are Doctor. Rayna Venabu, Chief Development Officer and Doctor. Ross Wissinger, Senior Vice President of Development. Zena will start the presentation by providing a summary of the positive clinical data we are reporting today from the TANQUILITY trial. Rob will walk us through the details of the data before turning the call back to me, so I can discuss what is in store for our dementia program and conclude the presentation. The presentation will be followed by a Q and A session and after we will display short video highlighting the unmet medical needs for this significant patient population. And with that, I would now like to hand over the call to Dana. Dana? Thank you, Vimal. Agitation is a common and difficult to manage symptom associated with multiple neuro psychiatric conditions such as dementia. Dementia, which includes Alzheimer's disease has a large global and national prevalence with over 50,000,000 patients worldwide and of that 6,000,000 patients living in the U. S. Of this population, up to 70% experience agitation, undergoing approximately 100,000,000 agitation episodes per year. Agitation in this patient population causes much distress and if untreated can result in endangerment to the patient and their caregivers, also caregiver burnout, early institutionalization and frequent hospital visits. Unfortunately, there are no effective therapies that directly treat agitation episodes and off label therapies that are being currently used have black box warnings for the elderly, resulting in an extremely high unmedical need. We do believe the XCL501 has the potential to be the 1st product designed to address this large gap in treatment options, providing and durable therapy to struggling patients and caregivers. We're pleased to announce BXCL501 was well tolerated among this elderly patient population with no severe or serious adverse events across all treatment groups. Very importantly, there were no cases of syncope or false in any of the patient studies. On top of meeting the primary safety and tolerability endpoints, the trial also demonstrated a statistically significant reductions in agitation with a 60 microgram dose cohort as measured by all 3 secondary endpoint scales. The PANSS Excitatory Component or PAC, the Pittsburgh Agitation Scale or PAS and the modified coenmansteal agitation inventory or modified CMIA. We reported that there was numerical separation from placebo in the PEC total score as early as 30 minutes with highly statistically significant calming observed at 60 minutes in both PAC and PAC total scores. In addition to our rapid onset of action, we are also excited to showcase BXCL501's durability with a statistically significant calming effects lasting 8 hours after treatment. The 30 microgram dose cohort also showed numerical separation from placebo at all three measures. Our exploratory endpoints demonstrated highly statistically significant reductions in agitation within the 60 microgram dose cohort, which further confirms BXCL501's rapid and durable response. It is important to note that higher exposure levels of BXCL501 were seen in this elderly patient population compared to patients in earlier trials, resulting in the investigation of lower doses. Tranquility was designed to identify a tolerable and effective dose of BXCL501 and we're extremely encouraged by this data set as these strong results set the stage for our planned dementia program and provide a clear path towards initiating a pivotal program with BXCL501 for the acute treatment of agitation and dementia. With that, we do look forward to consulting with the FDA on this data. Now, I would like to hand the call over to Rob, who will walk you through these exciting results in greater detail. Rob? Thank you, Rayna. I'm pleased to report the results of our top line analysis from the TRANQUILITY trial of BXCL501, our proprietary orally dissolving thin film formulation of dexmedetomidine. TRANQUILITY was a randomized double blind placebo controlled ascending dose Phase 1btwo trial designed to evaluate the efficacy, pharmacokinetics, safety and tolerability of BXCL501 in adults aged 65 years and agitation associated with all forms of dementia, including Alzheimer's disease. After screening, patients were randomized to ascending cohorts of BXCL501 at either 30, 60 or 90 micrograms or matching placebo. Once dosed, the patients were closely monitored for 24 hour evaluation period with an additional safety and efficacy evaluations on day 7. Following the completion of each dose cohort, a safety and tolerability review was performed to determine the next tested dose. The primary endpoint focused on characterizing the safety and tolerability of BXCL501 at each dose level. The secondary endpoint was to demonstrate the onset and magnitude of calming effects for these different doses of BXCL501 using the Pittsburgh Agitation Scale or PAS, the PANSS excitatory component or PEC and the modified Cohen Mansfield Agitation Inventory or MOD CMAI. We chose to explore efficacy with 3 different agitation scales as currently there's no registration endpoints for acute agitation. In line with our discussions with the FDA, our inclusion criteria was broad and included all forms of elderly dementia patients who had a history of acute agitation that impaired their daily living. In addition to having a total score of 8 or greater on the four items that make up the path at screening as well as at baseline before dosing. We excluded patients that had agitation that was due to acute intoxication and disallowed the use of sedatives or antipsychotics 4 hours before the study medication, as well as use of other alpha-one noradrenergic blockers or alpha adrenergic antagonists within 8 hours prior to dosing to avoid potential confounding factors and pharmacodynamic interactions. Now to review Tranquility's compelling top line safety, tolerability and efficacy results. Here on Slide 11, a total of 54 patients were enrolled in the trial. And as you can see, the treatment arms were balanced with no meaningful differences. Consistent with the known epidemiology, Alzheimer's disease was the most prevalent type of dementia in this patient population. The mean PET and Pittsburgh agitation scale scores demonstrate a moderate to severe state of agitation at baseline prior to dosing. Lastly, there were no discontinuations. All patients completed this trial. Next slide. The study's primary safety and tolerability endpoints were met. There were no severe or serious adverse events reported. The most common adverse event was somnolence. This was described as intermittent drowsiness or sleepiness. 95% of the cases were characterized as mild, with only one moderate case. All subjects were able to interact and respond appropriately. None were stuporous, for example. Other adverse events in the trial included hypotension and orthostatic hypotension, which were about 5% for each dose. Notably, there were no syncope events, no falls reported in all study cohorts. All adverse events resolved spontaneously and without requiring any medical intervention. None were of concern such that additional monitoring was indicated. In addition and consistent with our previous trial, all patients were able to self administer the film. This slide depicts the overall robust efficacy results with rapid and durable effects observed by PEC in the 60 microgram dose cohort. The PEC scale used to quantify the severity of a patient's acute agitation by evaluating 5 elements associated with agitation: poor impulse control, tension, hostility, uncooperativeness and excitement, each of them rated from 1 to 7. This dose clearly demonstrated statistically significant reductions in agitation at 2 hours post dosing. Starting with numerical separation from placebo as early as 30 minutes and statistically significant separation from placebo at 60 minutes. This lasted through 8 hours. Also remarkable was the PEC's response rate at the bottom table. The proportion of patients who achieved a greater than 40% PEC reduction from baseline was 70% at 2 hours post dose in the 60 microgram cohort. Consistent with this pet scale, we see concordance in the overall onset and durability of efficacy results with the Pittsburgh agitation scale. This scale was developed to monitor the severity of agitation associated with dementia patients by measuring 4 behavioral groups: aberrant vocalization, motor agitation, aggressiveness and resisting care. Each of these are rated 0 to 4 from absent to extreme. As you clearly see, again, BXCL501 at 60 micrograms showed a statistically significant separation from placebo starting at 60 minutes and also lasting through 8 hours post dosing. Additional confirmation of BXCL501's effect on agitation at 2 hours post dosing was achieved with our 3rd efficacy endpoint, the modified Cohen Mansfield agitation inventory. The modified Cohen Mansfield agitation index is an inventory consisting of 29 behaviors observed in dementia patients, each rated on a 7 point scale relative to the frequency of that behavior. Only the behaviors manifest by the subject at baseline were assessed throughout the study. If a new behavior emerged, that too was rated. The modified CMAI was assessed at 2 hours post dosing and at the end of the study on day 7. In the 60 microgram cohort, a highly significant separation from placebo was observed 120 minutes post dosing. Efficacy was further evaluated using 2 additional measures of agitation, the Agitation and Calmness Evaluation Scale, or ACES, and the clinical global impression of improvement scale or CGI I. This slide demonstrates significant improvements observed with ACES, providing additional evidence of BXCL501's calming effect with the 60 microgram dose. The ACEs consists of a single item that rates the overall agitation through calming. Additionally, some highly statistically significant separation from placebo was observed at 2 hours post dosing. According to the ACES ratings, a baseline I'm sorry, at baseline, patients went from a score of 2, which is a moderate state of agitation, and they were calmed by a total of 2.6 points on average, which represents a return to normal behavior or mild calmness, with no patients rated as being in deep sleep or excessively sedated to the point of unarousable sleep. This calming profile shown by these patients is in line with the known physiology of both agitation and calming effects and is supported by the ACES data in this trial. The second additional measure of agitation, the CGI eye, showcases the clinically meaningful improvement observed with a responder rate of 90% at 2 hours post dosing in the 60 microgram dose cohort. The CGI scale for improvement is a 7 point scale, ratings of very much or much improved were considered responders. It was assessed at various time points after dosing and is used to document how much the patient improved with dosing. The 60 microgram dose cohort showed consistent statistically significant proportion of responders compared to placebo. This started at 1 hour after treatment and lasted through 8 hours. The 30 microgram dose cohort showed numerically greater rate of clinical response versus placebo and became significant at 8 hours. I'll now turn the call back to Vimal to wrap up. Thanks, Ross. We are very excited by the results announced today. As you just heard, the TANCLITY trial achieved the objective we set for ourselves as we identified a tolerable and effective dose to advance into a pivotal program. As previously discussed, the 60 microgram dose of BXCL501 was well tolerated and achieved all efficacy endpoints showcasing this candidate's quick onset and durable response. In addition, we are very encouraged by the 30 microgram dose demonstrating noteworthy numerical improvement from placebo for all efficacy endpoints. These results bring us one step closer to providing the first treatment to address acute agitation related to dementia where there are no current FDA approved treatment. Additionally, the data supports our belief that BXCL501's mechanism appears to be independent from the disease state as acute agitation in dementia is our 3rd indication to demonstrate this candidate success. Moreover, all patients in the trial which took place in the assisted living centers facilities were able to successfully self administer our film, which will be key benefits for caregivers and for patients. Individuals with dementia often have trouble with swelling and BXCL501's novel film formulation offers an optimal solution that has a more rapid onset of action and durable responses. These results provide a clear path to a pivotal program for BXCL501 in acute agitation and we look forward to discussing the data with the FDA shortly. Of note, BXCL501 has already been given Fast Track designation for the from the FDA for the treatment of acute agitation associated with dementia, which validate the urgent need to find a therapeutic option for this elderly population. We look forward to providing you with further updates on our clinical plans with our dementia program this year. Tranquility is the foundational study in our dementia program and these results are the first step to demonstrating BXCL501's ability to address the full agitation spectrum in dementia. These results provide us with the necessary information for dose selection, for late stage clinical trials, investigating patients with acute agitation and give us insight needed to explore 501 as a chronic treatment administered at treatment centers or at homes. Before we conclude our presentation, I would like to remind you of the commercial opportunity in dementia. Dementia is a highly prevalent disease throughout the world impacting more than 50,000,000 people, U. S, Europe and Japan are 3 markets that are key to our focus for BXCL501 commercialization plan and account for approximately 40% of global prevalence. Alzheimer's disease represents up to 80% of patients with dementia and the incidence of Alzheimer's disease is expected to increase significantly over the coming decade. In this, U. S. Specifically, the Alzheimer's Association estimate that the number of people with this condition will double between now and 2,040 with agitation occurring in up to 70% of patients and approximately 100,000,000 agitation episodes per year in the U. S, we estimate that the treatable patient population will increase rapidly from approximately 4,000,000 patients today to 8,000,000 by 2,040. Given the significant unmet needs high interest in new treatment to help manage agitation, BXCL501 could be a welcome intervention. With that, I would like to conclude our call. Up next, we will open the call for questions. Operator? Thank you. Ladies and gentlemen, the floor is now open for Our first question is coming from Geoff Meacham of Bank of America. Please go ahead. Hey, guys. Thanks for the question and congrats on the data. Just had a couple of quick ones. The first one is Rob, I know the longest you measured out was 8 hours, but if you put this into real world context, how long do you think the benefit could last? Is it more than 12 hours and what could that do to the adoption? And then the second question is Vimal or Rob, just talking about next steps, what are you guys thinking about in terms of the size of the safety database needed for this indication? I know you still have to talk to FDA, but if you put some bookends on the size and scope of the registration program, that'd be great. Thank you. Sure. So let me take those in sequence. How long might the effect last? Well, it lasts at least 8 hours. It may last 12 hours. And frankly, patients with humans, I say, have diurnal rhythms and circadian rhythms. And at 12 hours, you're starting to run into sleep and normal sleep hours. And many of these patients, obviously, although they're agitated, they will become exhausted and sleep. So the duration of effect beyond 8 hours is almost icing on the cake in the sense that if you can keep a patient calm for the entire length of the day and enable them to fall asleep, that's really a benefit that I see would help with adoption. Now there's a lot of evidence in the literature as well that dexmedetomidine improves glial removal of toxic metabolites, improves slow wave sleep and improves the quality of sleep, it may well be that this drug has long term effects, even with a single dose on subsequent sleep. So again, related to adoption, I guess I'd have to ask Will about how this may benefit the uptake of the drug. So I'll let Will answer that in a moment. Let me take your last question. The size of a safety database, I honestly don't think it would necessarily have to be bigger than our serenity trials. Certainly, I'll just anticipate a question maybe. The efficacy is quite robust. So if you translate that to effect size, we don't need a huge number of patients to demonstrate that this will have efficacy. So we will have that discussion with the FDA and they will weigh in on how large the trial has to be, but it certainly doesn't have to be bigger than what we've done with Serenity 12. Thanks, Rob. I'll just comment on potential adoption. I mean the data clearly indicate a rapid onset and a durable response. The data at 8 hours is persistent. So there's a consistency to it, which I think will be important. So I think we have a profile at least at this stage that does enable the 2 things that matter most to clinicians and caregivers, which is rapid onset and the ability to sustain that calming effect for hours. Okay. Thanks guys. Thank you. Our next question is coming from Craig Sinojupia of Goldman Sachs. Please go ahead. Hi, team and congratulations. This is Anna on for Greg. Just a few questions from us. Just wanted to know if there's a way you can characterize the dementia, the agitation in dementia versus like schizophrenia and bipolar and what that could look like? Are these more mild patients? And also, if you could please just comment on any color on your first and primary focus on assisted living setting and how we can size the opportunity and any color there? And I have a quick follow-up after that. Thanks. Rob, do you want to take the first question? Yes, I'll take the first question. If you compare the baseline PEC scores, if you want to do apples to apples comparison of these dementia patients with what we've tested in the Serenity trials in bipolar patients and patients with schizophrenia, the PEC scores in fact were greater in some cases for these dementia agitated patients. Now the behaviors may be slightly different. Elderly don't tend to be what maybe quite as paranoid. They tend to bite and kick, however. And certainly patients with schizophrenia and bipolar don't tend to do that per se. But in terms of agitation, there's a lot of similarities. And the PEC scale captures these dimensions nicely. Obviously, the Pittsburgh scale as well was designed to capture agitation in dementia. So, I mean, these are truly significantly agitated patients and the demonstration here and across 5 different measures was absolutely robust and consistent. So we were able to calm these patients in both a rapid and robust and durable manner. So I'll let Will speak to the other part of your question. Sure. So I think assisted living facilities were a terrific setting for this initial Phase 1btwo trial. It is a nice pivot point because we'll establish as it has not only the safety and tolerability and the efficacy in this population, but it allows us to explore and pursue use of the drug not only in the institutional setting in emergency departments and nursing homes, but also as a bridge to the community setting, the at home setting. So obviously, the data are encouraging, given the consistency of efficacy and the TAE T T tolerability. So I think in that particular setting, it's a great starting point. There's obviously a sizable patient population living in assisted living facilities. And with the increase in Alzheimer's population over the next 2 decades and beyond, that will most likely increase. So sizable in and of itself, but it will contribute to a broader strategy with product. Okay, great. And just a quick follow-up. Any color you can give us on the non responders? And is there anything you could do to be able to stratify those in the Phase 3 study to enrich for the responders? Well, unfortunately, we didn't have many. And that makes it hard for me to characterize non responders. We had 90% or 70% response. So we'll do our best to see if there was a pattern of non response. But I think unlike most of neuroscience, we have a vast majority of patients who respond. And so it'll be much harder for us to characterize non responders when we have a 90% response rate. Okay, great. Thanks so much and congrats again. Thank you. Thank you. Our next question is coming from Robyn Karnauskas of Truist Securities. Please go ahead. Hi, guys. Congratulations and thank you for starting off my new year better than last year. So thank you. A few quick questions. You mentioned in the prepared remarks about how you excluded use of other drugs. And I assume some of these patients are going to be on other drugs at certain times. Maybe you help us understand your thoughts on whether there's any PKPD any I guess PK interactions and how you might address that in a Phase 3 trial for the FDA? Second question is sort of we've asked a lot about the next dose or the next type of trial that you do. You have a slide I think toward the end of going to more frequent dosing and going to potentially out of assisted living. Do you think you'll be able to incorporate any elements in the Phase 3 trial? I mean, given the color from the FDA and PTSD, is there any thing that you might be able to incorporate, maybe it be more than one dose after 24 hours for a same patient that might help with your label and your marketing uptake? So just two questions there. Thank you. So I'll take the first question, the drug drug interactions. It's a physical chemical property of the drug. Although it's metabolized through multiple mechanisms in the liver, it's principally cleared through transferase. And there is no known, for example, single nucleotide polymorphism. There's nothing like P450 system for UGT. And so there's very few drug drug interactions. And I think that's a real advantage to this API. In terms of adapting this to Phase 3, well, I'll point out that these patients were on a variety of other medications, although they weren't receiving doses within hours prior to the VXCL501, they were nonetheless many of them on antipsychotics, which are black box. So I don't know that we have to make adjustments for drug drug interactions in the Phase III trials. As for the next dose or a more frequent dosing, it's always possible in neuroscience to use lower doses and sort of titrate up. But we have right now a very clear efficacious dose. So it was in fact fairly safe and well tolerated to the point where I don't know that we have to split doses. So we'll probably consider how to look at repeat dosing or in this case, there really was little need for a repeat dose in this particular trial. So we'll adapt to that in the Phase III trials, perhaps like what we did in the Serenity trials. We did allow repeat dosing in the Serenity trials, not for the within the 2 hours to show efficacy, but for labeling purposes to give the FDA confidence and us confidence that in the label we can describe the proper use of this that is safe and effective for a physician treating an agitated elderly patient with dementia. Got it. And if I could have one follow-up, thank you for the color. So what might be the timing of your interactions with the FDA? So how much more work do you have to do to request a meeting with the FDA? When would you expect that to happen? And then on the heels of that, when do you think we'll get the clarity on Phase 3 design? Do you have any sense of timing over the course of the year? Ravin, this is Vimal. We expect that we will get the meeting with the FDA in first half of twenty twenty one and that's where we will discuss the design endpoints. Now we have 5 endpoints that are concordance. So we will discuss those endpoints, get their recommend and initiate the trial. So we will keep you updated post meeting with the FDA what our plan is, how to move this drug into the pivotal program. Great. Thanks so much. Congrats. Thank you. Our next question is coming from Yatin Suneja of Guggenheim Partners. Please go ahead. Hey guys, good morning. Congrats on the data and thanks for taking my question. Just a couple here. Can you maybe talk about the reason for maybe not evaluating the 90 microgram dose further? Was it driven by the PK exposure? If that the case, can you maybe qualitatively talk about the exposure that you achieved with 60 and how that compare for a same dose in Schizo and Biopolar? And I have another follow-up. So 90 microgram dose was a pretty clear decision that as we were evaluating exposure levels at cohort level with 30 60 microgram, we noticed that we are getting much higher level of exposures than we had reported in our previous trial. Then we compared those exposure levels with the Ivy Tech where we had seen the efficacy signals that gave us a high level of confidence that we are zooming in on the efficacy zone where this drug will show efficacy. So we had to make a choice after 90 dosing when we saw some orthostasis and dizziness that where we deploy our resources and we chose and the team chose to characterize 3060 to understand what is the intersection of tolerability and effectiveness. And we did and that was the primary goal of the trial and we did find with 60 optimal tolerability and effectiveness and even though 30 is also numerically separating and is effective. Got it. And then just a question on the tolerability side. I mean, how are you characterizing somnolence in mild, moderate and what does this rate mean for the real world? Thank you. So as Dhruv indicated in his presentation, this is a very fundamental physiological process in these agitated patients. Samnolence, as you mentioned, was mild and very few patients with moderate. But Rob will give you some context using the ACEs, which is a puts a real quantitative context to the somnolence. So Rob, do you want to describe where they were at the with the ACs and where after coming what this course was? Yes. So, first of all, the AEs of somnolence are reported by the patient, the staff or investigators. They were all for mild drowsiness or sleepiness. Now these occurred when the patient was calming after they were having excessive psychomotor activity, which is their agitation. And that effect is certainly in line with the physiology of agitation and calming effect. The ACES scale rates patients from agitated or severely agitated to calm. And on average, at baseline, these patients had moderate agitation or a score of 2 on the ACEs. The mean score improved by 2.6 points. So they went from moderately calm to being normal in behavior. So I know the scale, a 2 is moderately agitated, 3, 4 is calm and 5 is mildly calm. So this essentially a 2.6 shift that we showed you on the slide, a 2.6 point improvement in the ACEs represents moving a patient from being moderately agitated to normal behavior or mildly calm. And that's when these somnolence was the Medra term, but that's when the drowsiness or sleepiness was reported. And we did not see any patients with 8 and more where the sedation happens. So that's a very important factor here in our trial. Right. Sir, did you have any other questions? We'll move on. Our next question is coming from Sumit Kulkarni of Canaccord Genuity. Please go ahead. Fine. Thanks for taking my questions. I have a few here. So given you are paving a new path to treat acute agitation in dementia and the right scale to use is still evolving, would you be required or is there any merit in setting up this pivotal trial that's coming up with co primary endpoints on a couple of scales? That's entirely possible. That's an option that we'll be discussing with the FDA to use 2 different primary measures. In my through the grapevine, I'll say I understand that the FDA is now more interested in using co primary measures for pivotal trials. And in this case, since there is nothing that's agreed upon for acute agitation in dementia, it's likely that they would agree to a co primary measure. In other words, 2 of the scales that we've shown would satisfy them as adequate, well controlled and demonstration of efficacy. And then moving on to the potential for sub chronic dosing here, how soon after the 8 hour or so duration of effect did the patients in this trial have their next episode of agitation and was that a variable that you tracked in this trial? It's a good question. We didn't really track that. We were tracking their ratings. And so if they had a worsening of agitation after dosing, we would know it. But for the most part, we weren't tracking, for example, another episode or when the next episode occurred. We did see such robust efficacy. I'm not sure when that reoccurrence would be. It's certainly going to be past 8 hours. My last question is more of a bigger picture question on interactions with the agency. Given that this division is undergoing a lot of things with other high profile type products that are pending, have any of those the nature or the quality of the interactions changed? And how has this division or how is this division looking at datasets within dementia given all the other stuff that's going on? All our interactions with FDA have been very positive around dementia, conceding such a high unmet medical need and our mechanism, which is not antipsychotic. If you think about acute agitation last time, anything that was being doubled out was 2 decades ago, I am olanzapine. So we are coming up with a robust treatment equal or better than any of those I'm with a sublingual thin film and very differentiated mechanism. So, Rob, do you want to add anything more? Yes, I would say, the FDA did grant us Fast Track for this development in dementia as well as schizophrenia and bipolar disorder. So they do recognize this as high unmet need and they have been eager to work with us. So we're excited to have this data now to take back to them and I think it will generate a lot of interest on the part of the FDA. Thank you. Thank you. Our next question is coming from Ram Selvaraju of H. C. Wainwright. Please go ahead. Hi, thanks very much for taking my questions and congratulations on this very robust data. I was wondering if you could first of all give us some additional flavor regarding the baseline characteristics of this population and in particular just how fragile they were and to what extent you expect this population to mirror the characteristics of the target dementia focused patient population in the real world setting? This is as real world as you could get, I would say. These patients were not dosed in a research setting. For example, they were not transported after they become agitated. They were actually dosed in VITU in their living circumstances. Now these were several assisted living centers, But the patients were real world, they had multiple medications, comorbidities, medical histories of everything from hypertension to MIs, vascular disorders, you name it, and concomitant medications. I mean, talk about polypharmacy, I recall reviewing one patient who had more than 16 medications. So this is really something that we do well. I think at BioXcel, we try as early as possible to test this in a sample that represents the real world use. We believe this gives us much more robust information, both for regulatory purposes and for labeling, so that we understand the safety and can characterize the tolerability. And in terms of the baseline, their agitation PEC scores were they were moderately agitated. So they were not mildly. So they were representing a broader population through any of the scales we use for measurement. Okay. And let's drill down a couple of those things a little bit further. I was wondering if you anticipate that there might potentially be stratification within this patient population in the real world setting for use of 501 based on the degree to which the patients are agitated at baseline? And also if you could comment on the following two things. Firstly, there are a number of different domains associated with the various scales that you use. And I was wondering whether you saw any specific heterogeneity of responsiveness to the drug on particular subscales, for example, measuring aggression or resistance to cooperating or things like that, or if you anticipate or if you basically observed pretty much a blanket impact of the drug across the board regardless of what the subcomponent of each scale was. And also if you anticipate then needing to be the possibility of future exploration of additional dosing increments, like for example, if you wanted to increase the likelihood of having responses across the board, I know there was a question earlier about non responders. If you think it might be advisable to, for example, look at a 70 microgram dose or if these smaller dosing increments are just not technically feasible or not advisable at this time given that the 60 microgram performed so well? So, our primary goal will be to go to the FDA and initiate a pivotal program. We strongly believe we have dose or doses to initiate that program and we have concordance on the scales to be able to achieve those goals. Currently, this is a top line data. We continue to dig into the data to understand more broadly what the question you asked Ram drilling down into the patient population. Just at a very broad level, as you know, dementia consists of Alzheimer's, vascular dementia and some of the other types of patients, FTD, like frontal temporal Lewy body and other patients. So if at all sub segmentation may be needed will be, should we focus on Alzheimer's and vascular, which is 90% of the patient population. So I would say that's where we are at this point in time. We haven't dug more deep into the data to give a more granular answers what the response was at a FTD level or at other patients' level. Okay. And then just one more thing with respect to the commercial aspect here, I was wondering if Will might be able to comment on differential marketing strategies geared towards the assisted living facility market niche and whether that's really considered to be part of the community setting? And if not, how do you define the community setting specifically segment it's sizable and the triple patient population, as was mentioned early on, is going to grow and grow quite rapidly within the dementia, specifically Alzheimer's disease populations. And so I just want to reiterate that I think the data we've seen today, top line 1b2, really sends a strong signal that the drug works and works well in a patient population living in assisted living. However, I think that again is a springboard to understanding the full spectrum of applications given the need and given the efficacy and the tolerability we've seen so far. And so that allows us to, I think, have dialogue with the FDA and design programs to get ultimately to the at home setting, which is obviously where most patients will be living in terms of Alzheimer's and the increase in the population. So I think it's a great start. I think it sends a strong signal regarding the profile of the drug as we know it today. I think the questions have been very informative in terms of how you're thinking and we should be thinking about market segments. But the opportunity is very broad. The need is very great. And I think we have a good start here to pursue it in multiple settings, starting with assisted living. Thank you very much. Thank you. Our next question is coming from Sameer Devani of Rx Securities. Please go ahead. Let me add my congrats on the good data. I've got three questions. Just you talked about that you didn't think the higher exposure levels in these patients was a function of poly pharmacies. So perhaps you could just give us a better understanding of what is causing the higher exposure in this patient group? That's question 1. Question 2, just on the dose again. Do you think thinking about the Phase III design that it's worth perhaps looking at 45 micrograms considering it's a slightly narrower therapeutic window in this group? And then the final question is just on strip pricing. How do you think you're going to manage this now that obviously, it looks like a much lower dose than for schizophrenia and bipolar? Thanks very much. Samir, just to answer your first question about poly pharmacy, we don't think exposure levels were any different because of the poly pharmacy. They may be different for other reasons and Rob and Lena can elaborate. But we do know in Prasitax label, they recommend using a 50% of the dose and those dose was effective. It's a 505(2) development. We utilize every piece of information that was there that we could use. And in dementia agitated patient, nobody has outlined how much exposure will be there. Now we have that and that's part of our proprietary information. It gives us IP advantage and we are protecting that, those exposure levels to treat these dementia patients using a sublingual thin film redax. So Rayna and Rob, if you want to add anything more on the polypharmacy and the second question is more around the dose for 45 micrograms. So yes, that's right, Vimal. This is very consistent with PresidEx label and also with a number of papers and literature where elderly patients, they have lower dex clearance about 30%. And that lower clearance leads to higher exposure levels. And this is very connected with aging, with a decrease in renal function, decrease in plasma albumin and etcetera. So this is very consistent with what's already there. Do you want to Regarding your question about the 45 microgram, currently 60 is clearly very robust, tolerable effective dose with a rapid onset of action. It's clinically meaningful. This dose, certainly, we will select for the Phase 3. We will continue to do PKPD analysis further and then make the choice that whether we go with the 30 also and 60 or whether we can do PKPD analysis to look for 45. So those choices and decisions will be made as we dig more deep into the data. I'd just add, the drug is very well behaved. In our trials, we have really had nice dose response. We know that elderly have decreased clearance. It's well described. They have decreased renal function as a function of age, and albumin. The reason that lower albumin or protein is important is because in the elderly who have this, there's less opportunity for the drug to bind. So it's just cleared more slowly. And Will, we take your question regarding the pricing? Sure. So, at this point, the way to think about it, for 501 is as an acute treatment for agitation, obviously based on the Sernity trials in schizophrenia, bipolar disorder and the potential here in dementiaalzheimer's obviously has been represented quite well by these data. So I don't think of pricing right now on a dosing level, but on an indication level. Of course, we'll further characterize that as we move forward to the launch, hopefully, of our first indications for schizophrenia. Great. That's very helpful. Thank you very much. Thank you. Our next question is coming from Sumit Kalkarni of Canaccord Genuity. Please proceed with your follow-up. Thanks for the follow ups. I have a couple. So given your experience with these dose cohorts in the Phase Ibtwo setting, what do you expect the pace of enrollment and approximate duration of the pivotal trial program to be in an environment that remains quite variable due to the pandemic? That's the first one. And second, you touched upon this briefly, but do you think there might be a regulatory requirement for retreatment studies or is there any merit in including these studies in a pivotal program prior to submitting what might be an sNDA package for 501 for this indication? So regarding your first question, we don't see because it will take us next couple of months to work with the FDA to initiate a Phase 3 trial. And by the time we start, we hope that COVID-nineteen situation would have improved. Even with our current study, we enrolled 54 patients. And if we open multiple sites, which we plan to do for the Phase 3, we don't see much issues in enrolling these patients. There are a lot of these patients and they have very high unmet need and you can find them. So we don't see much issue. We will provide a guidance once we have trial design, ironed out that when we will start this study and when we can expect the data readout from the Phase 3. It's a little bit premature to come in with those timing. And regarding your next question, I will pass it on to Rob. So Rob, if you want to provide any color on that. Yes. I'm not sure I captured adequately the second half of your question. Could you rephrase it? Sure. So the first part was, would there be any regulatory requirement for retreatment studies? And the second part of that was to kind of preempt that requirement. Do you think there's any merit in actually designing a pivotal trial that includes retreatment components in it? Also retreatment like another dose or the need to repeat a dose was incorporated in the serenity trials and we would likely do a very similar design in the pivotal trials. Got it. Thank you. Thank you. At this time, I'd like to turn the floor back over to Mr. Mehta for his closing comments. Thank you again for joining our call today. We look forward to continuing our dialogue with you as we prepare to submit our NDA with DAKL-five zero one for the acute treatment of agitation in schizophrenia and bipolar disorder and initiate a late stage trial this year in dementia following conversations with the FDA. And finally, before you disconnect, we hope you will take 2 minutes to watch a video, which we produced illustrating the significant need for a treatment that can help manage agitation in patients with dementia. We believe BXCL501 has the potential to be the fast acting easy to administer treatment that addresses this high unmet need. Have a great day and please reach out to us if you have additional questions. Thank you.