Study Result

Jul 20, 2020

Hello, and welcome to the BioXcel Therapeutics Conference Call. At this time, all participants are in a listen only mode. As a reminder, this conference is being recorded. A question and answer session will follow the formal presentation. It's now my pleasure to turn the call over to CEO, Vimal Mehta. Please go ahead, sir. Thank you, operator. Good morning, everyone, and thank you for joining our conference call today to discuss the top line results from our 2 pivotal Phase III SINITY trials. We appreciate everyone's time and attention and hope that you and your loved ones are staying safe. A press release announcing these results crossed the wire earlier today and is available on BioXcel Therapeutics' website. As a reminder, we will be making forward looking statements regarding our financial outlook in addition to regulatory product development and commercialization plan. 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.bioxcelltherapeutics.com. Joining me today on today's call are Doctor. Rob Rissinger, Vice President of Clinical Development and William Kane, Chief Commercial Officer. I will start this morning's call by providing a summary of the extraordinary clinical data we are reporting today from the Serenity 1 and 2 trials. I will then turn the call over to Rob, who will bring us through the details of the data. Will Kane will then provide a high level commercial plan before turning the call back to me to wrap up and discuss what's next for BXCL501 before opening the call for Q and A. Agitation is a common and difficult to manage symptom associated with multiple neuropsychiatric conditions, including schizophrenia and bipolar disorder. But also in patients with dementia, delirium and other disorders, More than 30,000,000 people suffer from agitation annually in the U. S. In indications we are focused on and of that approximately 3,100,000 are associated with diagnoses of schizophrenia and bipolar disorder. It is clear that there is a high unmet need for an effective and easy to use treatment to address agitation. Current therapies are suboptimal and fail to directly target an underlying driver of agitation. Any treatment that is easy to administer is effective and fast acting and does not cause sedation would be a significant improvement over available options. As you saw in our press release this morning, serenity 12 demonstrated highly statistically significant and clinically meaningful improvement in PAC score, our primary endpoint and a validated regulatory endpoint for measuring agitation. We also reported that there were statistically significant improvements in PECS score as early as 20 minutes after treatment, which was our key secondary endpoint and an important benefit for both the caregiver and patient. In addition, results of our exploratory endpoints also demonstrated highly statistically significant and clinically meaningful reductions in agitation measures, and these results were durable, lasting at least 4 hours. BXCL501 was well tolerated with no serious adverse events. These strong and encouraging data represent an important milestone for schizophrenia and bipolar patients and their caregivers, who often struggle to manage episodes of agitation. One of the more exciting outcomes from today's data is that BXCL501's mechanism of action, how it delivered its calming effect appears to work independently of an underlying neuropsychiatric disease. This opens the potential of BXCL501 to be an effective treatment for acute and even chronic agitation in a broad range of diseases. And as you know, we are already well underway with this effort to expand its use to patient suffering from dementia, delirium and opioid withdrawal symptoms. Finally, before turning the call over to Rob to review the data in detail from serenity 12, I quickly want to remind everyone on how we discovered BXCL501, our proprietary sublingual formulation of dexmedetomidine. BXCL BioXcel LLC, the parent company to BioXcel Therapeutics has pioneered a powerful machine learning and artificial intelligence platform. This platform not only identifies potential candidates that may have new or even better utility in other disease states, but also identify where there is a significant need in the market place for better therapeutic options. These two components came together for BXCL501. Excusely, it is our 1st product candidate developed out of this platform. And we look forward to building on this success with BXCL701, our immuno oncology candidate in Phase II development as well as others in our emerging pipeline. With that, I would now like to hand the call over to Rob, who will take you through these exciting results in great detail. Rob? Thank you, Vimal. I'm pleased to report the results of our top line analysis. Our first two pivotal trials for BXCL501, a sublingual film formulation of the selective and potent alpha-two agonist dexmedetomidine. The 2 Serenity trials were similarly designed at double blind, placebo controlled, parallel group trials at 15 U. S. Sites in patients with acute symptoms of agitation. Patients were randomized to 1 of 3 arms. Each arm consisted of self administering a film, which was either 120 micrograms, 180 micrograms or a matching placebo. The primary objective was to determine the effect on agitation at 2 hours. We used the PANSS excitatory component scale or PEC total score as a validated means to quantify the degree of agitation. The key secondary endpoint was the earliest time at which an effect on agitation may statistically separate from placebo. Entry criteria were similar for each study. Patients with schizophrenia or schizoaffective disorder were eligible for Serenity I. Patients with bipolar I or II disorder in any mood state were eligible for Serenity 2. I will now describe the results for each study separately. The demographics and baseline characteristics of subjects enrolled in Serenity-one is notably consistent with what is known about this illness and its presentation in general practice. The treatment arms were balanced with no meaningful differences. The majority were diagnosed with schizophrenia, with about onefive having schizoaffective disorder. Baseline mean TEC total score was 17.5 and ranged between 14 to 27, 27 considered severely agitated. By CGI severity, each arm was judged to be moderately agitated, although this ranged from mildly to markedly agitated at entry. Very few subjects dropped out. A total of 98% completed the trial. The primary endpoint for each arm was analyzed using a mixed model repeated measures analysis. That included covariates for age, gender, race, site and demographic strata. The effect of BXC-five zero one was highly statistically significant for each dose at 2 hours. The primary endpoint was a mean reduction of 10.3 for the 180 microgram dose, a mean reduction of 8.5 for the 120 microgram group as compared with 4.84 placebo. The secondary objective was to determine the earliest time at which an effect on agitation is apparent. Rapid onset of action was observed significant efficacy as early as 20 minutes for the 180 microgram dose. At 30 minutes, both the 120 and 180 microgram doses were highly significant versus placebo. In addition, we observed a relatively high proportion of responders at each dose. At the primary to our endpoint, 87% responded to the 180 dose, while 67% achieved response with the 120 microgram dose, each highly statistically significant at 2 hours versus 37% for placebo. Response criteria was a greater than or equal to 40% reduction from baseline. To further confirm the primary endpoint, we used 2 independent scales: the Clinical Global Impression of Improvement or CGI Scale, which focused on agitation and the Agitation Calmness Evaluation Scale, or ACES, focused on calming. On Slide 12, consistent with PAC, we see a highly statistically significant proportion of responders for each dose in contrast with placebo. This was evident as early as the first CGI eye rating at 30 minutes. At 2 hours, 86% responded in the 180 group, 66% responded in the 120 microgram group, which was a highly significant difference compared to 36% in the placebo group. On the ACEs scale, both doses demonstrated a highly statistically significant calming effect. The low dose increases calmness by a mean of 2.7 points, while the high dose improves 3.7 versus placebo, which calmed by 1.1 point. This magnitude represents moving a moderately or severely agitated patient to normal behavior or mildly calm. Next, I'll describe the results for the Serenity 2 study. On Slide 15, you see subjects with bipolar I or II were enrolled in Serenity-two. Treatment arms were balanced. There were no meaningful differences in demographics. With respect to mood state, to nobody's surprise, about and those with depressed episode. Baseline mean PEC total score for this population was 18, about a half a point greater than the Serenity 1 study and rated by CGI severity as moderate to severely agitated with PEC scores ranging from 14 to 30. Like the prior study, very few subjects dropped out before day 7. The analysis was the same as for Serenity 1. This is the effect of BXCL501 in bipolar patients. It was highly significant at the 2 hour primary endpoint. There was a reduction of 10 points for the 180 microgram dose, 9.1 points for the 120 microgram group compared with 5 points for the placebo. Rapid onset of action was observed with significant efficacy as early as 20 minutes for both doses. At each time measured after 20 minutes, specifically at 30, 45, 60, 90 and 120 minutes, each dose was highly statistically significant. A robust and highly significant proportion responded 85% in the 180 group, 69% responded to the 120 dose at 2 hours versus placebo. Starting at 30 minutes, both doses demonstrated clinically meaningful response rates relative to placebo. By 60 minutes, the majority of those dosed with BXCL501 were responders. They were judged to be very much or much improved. At 2 hours, the proportion achieving response was 86.5% in the 180 group, 69.8% for the 120 microgram group and a highly statistically significant comparison to 38.1% of placebo group. Turning to the ACEs scale, both doses demonstrated a highly statistically significant calming effect. The low dose increases calmness by a mean of 2.8, while the high dose improved 3.5 versus placebo by only 1.1. This magnitude of calming represents moving a moderately to severely agitated patient to normal behavior or mildly calm as rated by the ACEs. Turning to safety. Slide 19 shows the combined treatment emergent adverse events from the two studies. Safety was in fact very similar between trials. As you can see, the XCL501 was well tolerated in both trials. All treatment emergent adverse events were mild to moderate in severity, with none categorized as severe or requiring further intervention or monitoring. Overall, the 3 most commonly reported were somnolence, dry mouth and dizziness. Sominilence is usually described as dozing off, drowsiness or sleepiness. Most subjects had no somnolence. Of those who did, 75% were classified as mild. All subjects were able to interact and respond appropriately. Reports of hypotension and orthostatic hypertension were about 5% for each dose. The majority were mild and transient, and they resolved without any intervention. With this data demonstrating rapid and robust efficacy, combined with the well tolerated safety data, we now have a very strong scaffolding to begin to build out our regulatory filing packages. Let me now turn it over to Will Cain, our Chief Commercial Officer. Thank you, Rob. The results of the Phase 3 trials are very impressive, especially the rapid onset of action across both patient populations. Given the strength and consistency of these data, I am certainly fortunate to have joined the BioXcel team and I'm eager to build a top notch commercial organization to prepare for a successful U. S. Launch. So let's spend a moment talking about the marketplace and some key initiatives that are underway. Agitation is a common and pervasive symptom that impacts millions of patients across a wide range of neuropsychiatric conditions, among them schizophrenia and bipolar disorder. Globally, these 2 psychiatric diseases are prevalent in more than 65,000,000 people with approximately 8,000,000 people in the United States alone. We estimate that approximately 40% of these patients experience episodes of agitation that result in millions of visits to emergency rooms, community mental health centers, urgent care treatment centers, as well as hospitalizations. There remains significant unmet medical need and managing agitation among these patients. New treatments that are effective at calming patients without over sedation and that don't cause respiratory distress or movement disorders would provide improved options for clinicians. Non invasive, easy to administer oral medications would be welcome and be in line with treatment guidelines that recommend the use of oral medications after verbal de escalation to support a positive collaborative patient clinician relationship. Maintaining this collaborative relationship is important as patients can experience frequent episodes of agitation each year. In addition, healthcare utilization associated with such a highly prevalent and frequently occurring condition like agitation places a significant financial burden on the healthcare system, not only in terms of direct medical expense, but also in terms of workers' compensation costs that arise when a hospital employee has been injured when caring for an agitated patient. Clearly, the opportunity to help patients and their healthcare providers is an important one and BioXcel will be ready. Our planning will now shift into high gear as we build commercial and medical teams for the U. S. Hiring within the commercial group has begun and I look forward to welcoming very soon marketing and marketing analytics leaders, individuals with whom I have worked previously and who have solid launch experience as well as experience in the institutional setting. Rayna Benebou, our Chief Development Officer, who recently joined the company to lead neuroscience development and medical affairs is forming her core team as well. Together, we are planning a steady cadence over the next 12 to 18 months as we field an MSL team, a managed care team and then a 75 to 100 representative hospital based sales force. As we advance our commercial plan, we will make final decisions on sales force size and deployment in order to ensure we can cover all high priority customers and institutions. Lastly, while we are preparing to commercialize ourselves in the United States, we are seeking partners for the Europe and Japan markets. The prevalence of schizophrenia and bipolar disorder in these regions of the world is high at approximately 22,000,000 people with up to 9,000,000 patients experiencing agitation. I'll now turn the call back over to Vimal to wrap up. Thanks, Will. I hope you can all see why we are so excited about the results unveiled today. As you just heard, the serenity trials achieved and exceeded the objective we set out for ourselves to bring a better treatment to patients suffering with agitation. The Serenity trials delivered consistent improvements in agitation across 2 neuropsychiatric disorders. Importantly, 501 was well tolerated with no serious adverse events. All patients in the trials were able to successfully self administer our sublingual film, which will be a key benefit for health care providers and for patients. BXCL501 has the potential to fill a significant void in availability of suitable treatment options for patients with agitation. We look forward to discussing these data with the FDA and submitting new drug application for both indications in schizophrenia and bipolar disorder. During the Q1 of 2021, BXCL501 had already been given fast track designation from FDA for the treatment of acute agitation associated with both of these disorders. Finally, BXCL501's mechanism appears to be independent of disease state and therefore has the potential to address agitation in multiple neuropsychiatric condition. We will be busy expanding the pipeline throughout the 2020. As you can see, serenity 1 and 2 trials in schizophrenia and bipolar disorder are just the beginning of our plans to develop a neuropsychiatric franchise around BXCL501. We estimate that there are 13,000,000 patients in need of better treatment for agitation in our current development plans that go beyond schizophrenia and bipolar disorder and include patients with dementia, delirium and opioid withdrawal symptoms. These additional indications are easily incorporated into our commercial marketing infrastructure, meaning we will be able to easily expand marketing to these additional indications if approved by FDA with our resources. We are also exploring additional uses of BXCL5, including in patients suffering from PTSD, traumatic brain injury, alcohol withdrawal and to treat phobias. We look forward to providing you with updates on all our development and regulatory plans through 2020. With that, I'd like to open the call to questions. Operator? Thank you. We'll now be conducting a question and answer Our first question today is coming from Geoff Meacham from Bank of America. Your line is now live. Hey, guys. Congratulations on the data. I just had a couple of questions. Maybe for Rob or for Will, I wanted to put maybe this 20 minute benefit into context, maybe clinical and commercial context. How do you think that's going to play out commercially? Are there sort of what are the comps that we should use to evaluate that? And then more importantly, when you look to the dementia study, maybe help us with the speed of onset and how valuable that would be in that market? And then final question, have you guys picked the dose yet to file? Thank you. So why don't I this is Will. Jeff, good morning. Why don't I start with a commercial perspective on the time to onset of action? So I personally was very pleased to see the data from both Phase 3 trials that demonstrated significance at 20 minutes, obviously with immediate action, but statistical significance at 20 minutes. I think this will be very important commercially in conversations with customers. Onset of action is particularly important to them. When you consider that the film is so easily administered, can people right under the tongue and begin to work immediately without the need such as with an I'm medication to prep it reconstituted for inclusion. I think there will be benefit there to clinician and to patients. Relative to other treatments, I think it is quite competitive, if not potentially quicker, when you consider the process to treat patients with other medications. And the safety profile, the tolerability profile, I think is one that will also support adoption and use given that it works pretty quickly and unlike other products there's not too much concern around over sedation respirator stress etcetera. So I think it's actually quite important. The market at least initially in the work we've done has underscored that. And so I think 20 minutes is a particularly strong showing, especially since it occurred in both studies across the patient populations. So it makes it easy. In clinical practice, 20 minutes is quite reasonable. Treatments for current treatments in an acute situation often involve an invasive injection. Those it isn't quite as simple in practice to give an injection, especially in a patient who may not want an injection. Obviously, approaching someone with a needle involves a certain increase in anxiety, their anxiety, as well as yours in the case of an agitated patient. And you may have to orchestrate speaking as a physician who's worked in many emergency rooms, you have to orchestrate security guards and group, making sure that everyone is safe to administer that. So in practical terms, 20 minutes from the time of placing the film under the tongue to an effect is really remarkable and makes it clinically highly useful. I should also say that swallowing is often a problem with respect to the elderly. And this so far has no problems with what would be called dysphagia or captured as dysphagia, let's say, as an adverse event, because it's not invasive. It also doesn't have extrapyramidal symptoms, other movement disorders like standard treatments often have. So there's no risk for example of NMS with antipsychotics. And so let me ask let me answer your last question and that is what dose will we be filing? We'll be filing 2 doses, the 120 and the 180 microgram dose. So I think that gives physicians an opportunity to tailor their dosing to patients, the patient in front of them. It may weigh different factors, but having 2 doses gives them a choice. Okay. Thanks guys. Thank you. Our next question today is coming from Robin Kronoskis from SunTrust Robinson Humphrey. Your line is now live. Hi, guys. Thanks for taking my question and congratulations on the data. I guess two questions. The first on this trial. So looking at the baseline, you had some patients that were pretty high up there. If I recall, above 18 could be a more severe patient. Could you talk and I know that the initial indication was for mild to moderate agitation. Could you talk a little bit about how this drug works in severe patients and your thoughts around a market opportunity and severe agitation? And second, for the read to, dementia, I know dementia you're not looking at as higher doses because you're potentially concerned about the falling or the static hypotension. When you look at this data, how comfortable are you that at the doses you're looking at for dementia that you'll be to see a PEG score improvement of 2 or 3 that you've talked about is what would be clinically meaningful? And would that be what you're looking for, 2 to 3 clinically meaningful? Thank you. Sure. So, in general, a PEC improvement of 3 to 4 points equates with a 1 point improvement on the CGI. And that has been the mathematical definition of what is a clinically meaningful improvement. So as you can see, all of our data supports that. That seems to be exactly what we're seeing. We're seeing that very rapidly within 30 minutes. And so I think we can say that we're seeing clinically meaningful improvements not only by the CGI, but by the ACEs, and as well as the primary measure of the PEC change. With respect to our indication, our indication hasn't actually changed. The indication is likely to be, of or subject to approval by the FDA for the treatment of agitation associated with schizophrenia or bipolar disorder without regard to the severity. So physicians in the emergency room actually don't look at severity. If some staff member comes to the physician and says, hey, this person is agitated, that's severe. That's severe enough to require treatment. And so that's why the indication doesn't necessarily have to say the severity of the illness. Now we did enroll patients who were clearly agitated. The caveat is all of these patients had to be cooperative. So the patients were able to take the film themselves. There's a smaller proportion of patients, of course, who won't cooperate and therefore won't take the film. That's a different development plan. Got it. And just to follow-up, so the read to dementia which you're looking at lower doses then, do you think you can see the 3% to 4% reduction in the PEC score to get that one point improvement in those patients? Yes, we saw it across 2 illnesses for no reason. Yes, I'm sorry. Yes, we just saw it in 2 different illnesses, schizophrenia and patients with bipolar disorder. We saw it across the spectrum of bipolar disorders, bipolar I and II. We saw it across the spectrum of mood states in bipolar disorder. There's no reason why we cannot replicate this in any other disorder where agitation is a core symptom. But even though they're at lower doses. That's the the reason why I keep asking is just because it's lower doses. And I know it's older patients. That was the only clear across these doses in these populations, but at a lower dose, you're still comfortable. So recall, yes, so let me turn to our prior data, not this data set, but our prior data tested lower doses than the 120 even. And 80 micrograms was statistically significant in a very few number of patients, I believe it was 18 patients, total dosed at 18 versus the lower doses. So again, lower doses are likely, I mean, they've been proven to be efficacious. It's just a matter of us completing the initial trial and we'll move on with dementia. Got it. And one last if I can, any heart rate changes that you saw in this trial? I know you mentioned orthostatic hypotension, didn't see anything on hypertension or anything like that, but any heart rate changes at all, Dean? We haven't analyzed the data in that granular detail. Obviously, that's part of the analysis required for our NDA submission. And so we'll be performing that and many more analyses prior to submission, but at this point there's no indication of that. Got it. Thank you so much. Thanks for taking all my questions. Thanks. Thanks, Robin. Thank you. Thank you. Our next question today is coming from Yatin Srinajah from Guggenheim Partners. Your line is now live. Thank you. Congrats, everyone for great results. Just a couple of questions for me. With respect to the durability, have you looked at data beyond 4 hours? And could you comment if or what percent of patient might have received more than one film after the 2 hour endpoint? I do have a couple of other follow ups. Yes. So thank you for the question. That's an excellent point. In the trial, patients were allowed to receive a rescue medication. None received a rescue medication up through 2 hours. So the data that I've just shown you is pristine. There was no use of rescue. There was no use of another antipsychotic or Benzodiazepine and no patient during those 2 hours received a second dose. There was a proportion of patients who received a second dose after 2 hours. It tended to be past 4 hours. Very few received it after the 2 hour endpoint up to 4 hours. And so we're not presenting that day because we have to review it. It wasn't really part of top line, but we did see efficacy past 2 hours, well past out to 4 hours. And after the 4 hours, we now need to very accurately account and technically it's called censoring data. Once someone received either a rescue medication or a second dose, you need to analyze that in a different way. We don't want to show you data that's actually 3 doses, let's say. They were allowed to receive a repeat dose up to 3 times over a 24 hour period. So we're in the process of analyzing that and we'll be presenting that at a later date. Got it. Thank you. And then with regard to the SAM lens, is it possible for you to sort of quantify using the RASCO that you have used in Phase 1b? And just maybe talk about how arousable the sum of influenza was and how it might differ from antipsychotics in terms of how long does it take to resolve? Right. So the somnolence in Medra terms is captured and that includes reports of, let's say, nodding is a common term sleepiness, drowsiness. So this is by no means an extent of sleepiness that impaired the patients. All patients were able to interact with the interviewers, complete the ratings. A PEC rating takes about 4 to 5 minutes And it's not an observation just by a physician or a rater. It's an interaction with the patient. So the patient has to answer a lot of questions from the rater. All patients were able to do that even when they reported Somnidge as an adverse event. It did not impair them. They were not stuporous, for example. They did not feel disoriented. No patient was unaware of their environment, where they were, who they were, what they were doing. So I can't unfortunately, in English, we don't have a good terminology for the gradation of calming. But when patients reported somnolence, this was not severe somnolence. So you can't really call this even, let's say, severe calming. They were calmer. Some patients did report somnolence. It was mild at most moderate, but in no way did this impair them cognitively, for example. Got it. Thank you. Just one final question. Now with regard to the NDA filing, what are the gating factors? What specifically, if there is any particular thing that you sort of need to clarify from the FDA in the pre NDA meeting that you're going to have? And what sort of a safety database requirement? Thank you. Yes. Excellent question. We wanted to have these kinds of numbers to present at our pre NDA meeting, because we know that the FDA likes to have a fairly large database. We know it's a new formulation. This drug has never been given sublingually, certainly not with our film. So the plan is to take the sum total of our data, including every patient who's been dosed with BXCL501 in the prior studies as well as Serenity 1 and Serenity 2. We feel that's a robust data package. And so the focus, for example, of the pre NDA meeting is a presentation of how we're going to analyze this data, what we're going to present, what else they may want to include in the filing and then we execute. And so that's our plan. Got it. Thank you very much. Congrats again on very good results. Thank you. I couldn't be more pleased myself. We are fortunate. Thank you. Our next question today is coming from Sumant Kulkarni from Canaccord Genuity. Your line is now live. Morning. Thanks for taking my questions on what's an exciting day for the company and for patients here. So I have three questions. First, what specifically happens to patients after the response wears off? Do the patient get quickly agitated again? I'm asking because this product will be administered in the caregiver setting. I'm trying to get a quantitative sense of how long the patient needs to remain in that setting after taking this product? Sumant, thank you so much. Again, excellent question. This duration of effect continues to arise. We have not analyzed the duration in a specific tactical manner. We're willing to say it goes out to 4 hours and beyond. Once we complete the analysis, a quantitative analysis of duration of effect, I'll be much better placed to provide those kinds of answers. In the care setting, given the adverse event profile that you see, it's hard to envision where this specifically might not be able to be used. Certainly, outpatient, corner mental health clinics, many of which I've worked in, we've had to see patients who are agitated even in the waiting room, call the ambulance and take them to the hospital. In this setting, there is very limited medical supervision. That's why they're transported to the hospital in an ambulance. I don't see why this could not be used at least in that kind of a setting. And so we'll be looking at the profile in terms of the spectrum of safety. And again, I don't think we need to necessarily think of this as a hospital only use drug. Got it. And then I'll ask my next 2 all in one shot. So the first part is, do you have any quantitative or qualitative details on what fraction of the patients in the trials in these two indications were between the ages of 5575 and how the product performed on efficacy and safety in this age group because we're all trying to get a read through to dementia here. And the second question is on a filing strategy, can you confirm that your first filed NDA for 501 will be in schizophrenia and bipolar disorder? And how you're thinking about that as there's a potential to accelerate approval in the COVID-nineteen delirium indication with other indications to follow as sNDA? Wow, excellent question. So let me nail those. We've not done a sub analysis for the ages of 55 and up or 65 and up to 75. We'll be doing that. We're keenly interested in the safety in that population to see if there is a difference in the dose range that we're dosing. I'll tell you at this point, we don't really see any differences, but we're going to do that specific analysis. We'll present that data in a scientific forum, and we're going to thoroughly look at that, especially because we have the current dementia study dosing in patients with dementia ongoing. With respect to the filing, the filing we believe the indication will be for the treatment of acute agitation associated with schizophrenia and bipolar disorder. We may bolster that with our key secondary finding, but we'll be looking at that and considering that. The FDA did agree to the analysis for our key secondary that is a rapid onset of action as early as 20 minutes. And so I think we have it's certainly going to be our first filing. We now have 2 pivotal trials with P values of less than 1. Typically, the FDA agrees, for example, that a p value in a single trial of 0.025 or greater indicates the same regulatory significance as 2 adequate well controlled trials. So this data in a way is proving like we have 4 positive trials, not 2. That's the degree of robust data that we've just shown you. Coming back to your question about delivery on COVID-nineteen, you noticed that last week or prior to that week, we had announced that we have entered into a relationship where we are providing 501 on a compassionate use. FDA agreed to that. That will be done with MGH investigators. So that's one thing to show that like how we can help the patients who are on intubation due to the COVID-nineteen experiencing deliriumagitation. So that work is in progress. In addition, we are developing our plan for delirium, which is company's strategic plan to initiate a trial, which may and we are in the process of planning include an arm which is related to the delirium for COVID-nineteen as well as an arm that will be more hospital based delirium, which has always been a very prevalent problem. And as you might have seen in my slide that there are about 4,000,000 patients. So delirium indication in our view is as big as dementia. And I know Bill is extremely excited about it because this indication is very, very synergistic with our sales force that we will be developing for both schizophrenia and bipolar. So there is a lot of synergy to move delirium indication forward. Regarding your question that with COVID-nineteen, if FDA we could and we get positive data, could we go for emergency use authorization? All those things are being planned and they will be explored. Now, serenity data is positive. We have a lot of like learned a lot from this data and we will use all this knowledge to expand in delirium, dementia and opioid withdrawal. Those two trials, Tranquility and Relyze are ongoing and then embark on other indications that have already online. So we are very excited that this could be a very large opportunity, what we have seen, robustness in the efficacy as well as the safety profile. Got it. Thanks. I'll jump back in the queue. Thank you. Our next question today is coming from Do Kim from BMO Capital Markets. Your line is now live. Thank you. Good morning, everyone. Congrats on the data. First question, I wanted to go back to the prior comment on pursuing both doses commercially. Could you expand on what other factors that physicians will be considering since the safety between the two doses look fairly similar? Yes. So I'll start clinically though. The safety does look similar. There's very few adverse events that, let's say, might be dose responsive. And so being similar, there's no reason, we wouldn't want to take both doses to market, but we're evaluating that I believe from a commercial standpoint. So I'll let Will speak to that. Sure. Thanks, Rob. So yes, we'll evaluate 1 or 2 doses to the market. The good news is that we have that option. The Phase 3 data were very, very strong. Obviously, the 20 minute onset at 180 micrograms across both patient populations is very motivating to pursue obviously that dose. But the 120 also, very, very strong, in both trials as well. It gives the clinician more optionality, in terms of again, as Rob talked to the spectrum of PEC scores that the patients presented at baseline may as as clinicians get more familiar with the drug when they ultimately hopefully have it for use, they may be able to tailor the dosing appropriately and they may be able to tailor it for different populations, the older patient versus the younger patient etcetera. So having the 2 doses I think commercially makes sense, but we'll complete the evaluation and as a process of filing in discussions with the FDA and filing, we'll finalize those decisions. I see. Okay. Thank you. And my other question is the dosing in the Alzheimer Phase onetwo study, could you remind us what the highest dose that study could go up to? And considering that it's an adapted design, you could exceed the doses that's currently in the clinical study. Is that correct? There was no limit in the prior study. I'm talking about the ongoing Alzheimer's study. Yes. There was again, there was no limit. So we started with 30 just to do the ascending dose study and we're finding tolerable and effective dose in the dementia patient. But there is no limitation. What your question is, can we go beyond 90? What we have stated 30, 60 90, yes, we can go beyond that. And we can also expand cohort if needed. We are measuring 3 instruments and we want to take this data to the FDA and convince them to initiate a late stage clinical trial. The goal of that study is very simple, find that tolerable effective dose, get the data on the instruments and go to the FDA to initiate a late stage development on dementia. So the Phase 3 dose could end up being the same as the doses in the schizophrenia and bipolar studies? It could be. We're not making an assumption. We're doing this very methodically. Okay, great. Thank you. Thank you. Our next question today is coming from Ram Selvaraju from H. C. Wainwright. Your line is now live. Thanks very much for taking my question. So just to further clarify the dosing question regarding these different indication populations in which you'll be studying 501 for the treatment of agitation. Can you give us a sense of how differential you expect the dosing paradigms to be across these different populations? If there's any one population in which you would a priori expect the effective dose range that you would employ to be lower or higher as the case may be? And then also if you could give us a sense of whether there is a rationale for employing dosages higher than 180 micrograms in case you might require additional efficacy or you might expect to require additional efficacy in certain differential contexts, given the solid safety profile that you've seen so far? So, we believe and this data suggests that schizophrenia clearly has a response to the higher doses and we believe that that would be the illness where agitation might require very high exposures. Other illnesses under study are likely to respond to those doses and lower. And so that's why we're doing dose ranging, including this dose, but lower at in say dementia populations and other illnesses may require lower doses or for example, with opiate withdrawal, it tends to occur over many days, longer exposures of days. So we're again, we're methodically testing this and coming up with the dose range specific for these in the other indications in order to cover the symptoms and the duration of the symptoms in each illness. Okay. And then a couple of other quick ones. Given the rapid onset of action in the case of the sublingual formulation that you've seen so far in the generic onset, can you give us an idea of what the purpose of developing a potential injectable formulation might be? In other words, it probably isn't that likely that you would get a significantly faster onset of action than what you have already seen with the sublingual. But there might still be a rationale for such a formulation specifically to manage the truly intractable and difficult to control patients for whom it's going to be challenging for the caregiver to put the sublingual formulation in their mouth. Is that a reasonable way to think about this? It's an excellent way to think about it. It is in fact the manner that we're looking at development. We have demonstrated now that with the sublingual formulation, we have relatively rapid onset and a magnitude of effect exactly in the range that we would like to see. Now we know that there are more agitated patients and the higher the agitation, there tends to be less cooperation. And so for patients who are truly uncooperative, unmanageable, we may need to deliver in a different form. And so we're looking at a different formulation to treat uncooperative agitation, which is really the extreme, if you will, of this population. Okay. And then just 2 very quick items, if I may. Can you comment on the potential read through from Serenity, the Serenity studies in terms of the statistical powering assumptions you might need to utilize in other indications and if other pivotal studies in these other indications where you'll be studying 501 for agitation treatment could potentially see a similar type of overall trial size relative to what you used in serenity or if it's really too early to tell at this point? And then lastly, just a question for Vimal. Maybe you could give us some additional details, some additional background on the phobias indication. What does that mean? What kind of phobias? And with what timeline do you anticipate clarifying 501's path forward specifically in that arena? Thank you. So let me thank you. I think specifically, we're looking at phobias that include anxiety disorders like OCD. Many people have fear of public speaking. Some people have fear of heights and they are going to visit the Empire State Building, for example. So there's situational phobias, if you will. So there's a range of anxiety disorders, including phobias that this degree of calming could be very useful. Okay. That's helpful. What about the powering assumptions? Or is it too early to tell? So, yes, powering assumptions, I mean, here's the bottom line. This is really an amazing effect size. It was robust, clinically significant as well as numerically significant. So to the degree that patients with agitation and schizophrenia and bipolar can then be equated to other indications, we will be able to more accurately power these other studies and other indications. We have yet to have a trial where we don't see these kinds of robust effects. So with respect to the total numbers of patients required, that becomes a balance of regulatory needs as well as statistical needs. So we'll be balancing that for each indication moving forward. Thank you very much and congratulations again. Thank you. Thanks. Thank you. We've reached the end of our question and answer session. I'd like to turn the floor back over to management for any further or 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 regulatory filings and advance the development of BXCL501 into additional indications. Have a great day and please reach out to us if you have additional questions. Thank you. Thank you. That does conclude today's teleconference. You may disconnect your lines at this time and have a wonderful day. We thank you for your participation today.