Operator
Good morning, and welcome to the BioXcel Therapeutics TRANQUILITY II Top Line Results Conference Call. [Operator Instructions]
Just to remind everyone, certain matters discussed in today's conference call and/or answers that may be given to questions asked are forward-looking statements that are subject to risks and uncertainties related to future events and/or the future financial or business performance of the company. Actual results could differ materially from those anticipated in these forward-looking statements. Risk factors that may affect future results are detailed in the company's quarterly report on Form 10-Q for the quarterly period ended March 31, 2023, as updated by the company's 8-K filed today, which can be found at www.bioxceltherapeutics.com or on www.sec.gov. As a reminder, today's conference call is being recorded.
Joining us on today's call are Dr. Vimal Mehta, Chief Executive Officer; and Dr. Rob Risinger, Chief Medical Officer of Neuroscience. Richard Steinhart, Chief Financial Officer; Dr. Frank Yocca, Chief Scientific Officer; and Matt Wiley, Chief Commercial Officer, will also join us for the Q&A.
It's now my pleasure to turn the call over to Dr. Mehta, the CEO and Founder of BioXcel Therapeutics. Please go ahead, doctor.
Vimal Mehta
Thank you, operator. Welcome, everyone, and thank you for joining us today to discuss the positive top line results from our Phase III TRANQUILITY II trial. This trial met the primary endpoint with statistically significant reduction in addition at 2 hours with a 60-microgram dose and a key secondary endpoint with statistically significant reduction in agitation at 1 hour with the dose. With today's positive data, I want to take a step back and look at our holistic results from across the TRANQUILITY studies. We have conducted 2 independent studies in patient populations with Alzheimer's related agitation, TRANQUILITY I and TRANQUILITY II, where we have demonstrated positive results for BXCL501. TRANQUILITY I, which was contained before we received our Breakthrough Therapy designation, showed a 7.1% absolute back change in the 60-microgram arm. TRANQUILITY II showed a 7.5% absolute pack change in the 60-microgram arm, meeting the primary endpoint at this dose; and a 5.4% absolute pack change was shown for our 30-microgram dose in TRANQUILITY I, which is consistent with our 40-microgram dose in TRANQUILITY II, which was 5.7%. We also observed favorable and consistent safety data across these trials. We are extremely pleased to share our trial outcome, which we believe represents a major milestone in our development of a potential new treatment option for Alzheimer's disease-related agitation. .
I would like to turn it over to Rob to provide more detail. Rob?
Robert Risinger
Thank you, Vimal. As Vimal expressed, we are very pleased with our strong results from TRANQUILITY II that we're sharing today. We met the primary endpoint with the 60-microgram dose of BXCL501 with a significant reduction in agitation symptoms from baseline at 2 hours after dosing compared to placebo. In this trial, the 40-microgram dose, did not meet the primary endpoint, in part due to a higher placebo response observed in this trial compared to our Phase II trial. On the whole, we believe these data suggest that 60 micrograms may be the lowest effective dose for reducing symptoms of agitation and both doses were well tolerated in the study.
Notably, with 60 micrograms, the earliest significant separation from placebo was at 1 hour. Separation from placebo was not significant at 30 minutes. Multiple independent secondary endpoint measures corroborated the improvement seen in agitation symptoms and calming. In addition, when administered as needed throughout the 12-week trial, 60 micrograms showed a similar average reduction in agitation symptoms as seen after the first dose. Importantly, we demonstrated that BXCL501 was generally well tolerated with no drug-related serious adverse events throughout the trial.
We designed TRANQUILITY II as a pivotal Phase III randomized, placebo-controlled trial to evaluate the safety and efficacy of BXCL501 for the acute treatment of mild to moderate Alzheimer's associated agitation in adult 65 and older. The trial was designed to enroll 50 patients per arm. Enrolled patients had mild to moderate Alzheimer's disease and required minimal assistance with activities of daily living and assisted living facilities or ALS, and in residential care settings. Patients were to self-administer 40 micrograms or 60 micrograms of BXCL501 or placebo, as needed for agitation episodes occurring over a 12-week period. We chose to test these 2 doses based on PK and efficacy data from prior trials in the elderly and our Phase II in demented patients, where exposure differs compared to younger populations.
Our primary efficacy endpoint was the change from baseline in the positive and negative syndrome scale, Excitatory Component, or PEC, total score at 2 hours post dose for the first treated agitation episode. This 5-item scale the FDA has agreed to is our registration efficacy endpoint measuring agitation dimensions that include excitement, hostility, tension, uncooperativeness and poor impulse control. The key secondary objective was the earliest time when efficacy was observed as defined by the change from baseline in PEC at 1 hour and at 30 minutes post-dose for the first treated agitation episode.
We evaluated additional efficacy and safety measures, including the Clinical Global Impression of Improvement Scale, or CGI-I, and the agitation Calmness Evaluation Scale, or ACES, as well as a change in PEC scores for all treated episodes throughout the 12-week period. These are the inclusion and exclusion criteria, we believe are most important. We treated patients having reached a level of agitation representing a change from their usual behavior according to the International Psychogeriatric Association Criterion. A PEC score of 14 or greater represents an acute agitation event that is readily apparent to a caregiver or a family member.
Here are the demographics and baseline characteristics of patients enrolled in this trial. The age range from the lowest age allowed, 65 up to age 95, with a mean age nearly 80. The main Mini-Mental Status Exam or MMSE, was indicative of a moderate level of Alzheimer's dementia. In terms of agitation, what's noteworthy is that the baseline PEC score was 17 to 18, similar across all 3 treatment groups. This represents a moderate level of agitation that is readily apparent to an untrained eye. This is comparable to baseline PEC levels in our TRANQUILITY Phase Ib/II trial.
About half the patients were prescribed concomitant antipsychotics, which is representative of how agitation is normally treated in these patients. We believe this is a representative sample comparable to the vast majority of patients who experience agitation. Here, the efficacy data indicates that agitation symptoms improved for BXCL501 treated patients in the 60-microgram dose group as measured by a group mean change from baseline in PEC total score starting at 1 hour post dose. The 60-microgram treatment group showed statistically and clinically meaningful results at the primary endpoint of 2 hours with PEC score reduced by 7.5 points and a compelling p-value of 0.01 versus placebo. The 60-microgram dose separated at both 1 and 4 hours following dosing.
The group mean PEC total score for the 40-microgram group was reduced by 5.7 at 2 hours, which was not statistically different from 5.4 for placebo. This was a greater reduction for placebo than observed in our Phase Ib/II trial. We are also pleased to have met a key secondary endpoint with 60-micrograms. BXCL501 significantly reduced agitation symptoms at 1 hour with a reduction of 6.2. It achieved a p-value of 0.02 compared to placebo, which reduced PEC by 4.2. These results indicate the 60-microgram dose reduced agitation symptoms as early as 1 hour as well as 2 hours after the first dose.
Now let's compare this first dose efficacy data with that across all doses as needed during the 12-week trial. The left-hand side depicts what we showed on the previous slide, a PEC score at 1 and 2 hours following the first dose in the 60-microgram dose group. Data on the right-hand side show that each time we administered 60 micrograms over 12 weeks, patients had a similar total PEC score reduction versus placebo at both 1 and 2 hours after treatment. As you can see, our efficacy analysis, including all doses, retains a consistent magnitude of response as seen after the first dose. We believe that this suggests continued efficacy for intermittent use with BXCL501.
The next series of slides corroborate the results seen with our primary end point with BXCL501 60-microgram. The secondary efficacy measures include response rates by CGI-I and ACES, which showed similar effects for the 60-microgram dose. At 2-hour, after the first dose, 76 print of patients responded to therapy as measured by CGI-I, defined as achieving an assessment of Very Much or Much Improved, 1 or 2 on the CGI rating. This compares to a 50% CGI response rate in the placebo group.
Regarding all doses, the data on the right-hand side show that each time we administered 60 micrograms over 12 weeks, patients had a similar response by CGI-I versus placebo at both 1 and 2 hours after a treatment. As you can see, our efficacy analysis of all doses showed an improvement in multiple measures of agitation with the 60-microgram dose at 1 and 2 hours post dose. The proportion of responders by CGI-I was similar to that seen after the first dose. We are pleased to see continued improvement with intermittent use of BXCL501.
Distinct calming rather than nonspecific sedation is desirable for the treatment of acute agitation. The agitation calmness evaluation scale assesses calmness in acutely agitated patients. We saw an overall calming effect as measured by change in ACES score for the 60-microgram dose at 1, 2 and 4 hours post dose. This is exemplified by a shift of 2 points or greater for the 60-microgram dose, such that agitated patients were rated as normal 2 hours after dosing. For context, a patient who was pacing shouting or combative could receive an ACES score of 1 or 2 before dosing, and became or become normal with an ACES score of 4 defined as without agitation symptoms at 2 hours. We believe these top line data show the potential of BXCL501 to calm patients and potentially become a desirable treatment option for acutely agitated patients, if approved.
Let's move now to dosing frequency. Throughout the trial, a total of 443 agitation episodes occurred in 149 patients. Most patients received treatment for 5 or fewer agitation episodes. And as shown previously, BXCL501 at 60 micrograms reduced agitation symptoms as measured by PEC change from pre-dose at both 1 and 2 hours when measured across all treated episodes. Notably, all subjects irrespective of baseline agitation were able to successfully administer the 501 film.
Summarizing our safety and tolerability data. Here, we highlight treatment-emergent adverse events of special interest, or AESI, observed in the 24 hours following first dose and across all treatments over the full 12-week period. In TRANQUILITY II, BXCL501 was well tolerated with side effects observed in the trial, consistent with prior 501 trials, and the current label for Agomi. No unexpected AEs occurred within 24 hours of dosing, and all AEs observed were mild or moderate in severity and consistent with 501's mechanism. Notably, repeat administration for all subsequent episodes did not meaningfully increase the incidence of side effects. No treatment-related serious adverse events occurred throughout the 12-week trial period.
The elderly population is at a particularly high risk for falls. When these patients become agitated, the risk of falls further increases. The overall incidence of falls in TRANQUILITY II was low. All were determined to be unrelated to 501 as they occurred between episodes. There were no treatment-related falls. Only one fall occurred within 24 hours of dosing, and that was in the placebo arm. With regard to deaths, 3 deaths occurred, all greater than 1 month after the final treatment dose with one in each arm. There were discontinuations due to adverse events occurring during the trial. In this elderly, relatively frail population, discontinuations for adverse events are not uncommon due to multiple preexisting concomitant medical conditions. For example, over the 12 weeks, there were 13 patients or 9% of the total subjects enrolled that discontinued due to adverse events, 2 discontinued within 24 hours of a treatment, one subject in the 40-microgram arm and one in the placebo arm.
To wrap up, we are very pleased to share the positive top line results from the pivotal Phase III TRANQUILITY II trial. We demonstrated a statistically significant and clinically meaningful improvement in agitation for the 60-microgram dose as measured by the change from baseline PEC score at 2 hours. Efficacy of the first dose was further confirmed with secondary measures and supported by CGI response. We also showed continuing efficacy when dosed as needed by the primary measure and CGI-I. We believe these top line data demonstrate the potential of BXCL501 for as needed, acute treatment of agitation in dementia associated with Alzheimer's disease. We believe that BXCL501, if approved, has the potential to offer a unique treatment paradigm providing treatment only when necessary.
I'll now turn the call back over to Vimal. Vimal?
Vimal Mehta
Thank you, Rob. Before Q&A, let me again remind folks that there are no approved episodic treatment for these patients with Alzheimer's-related agitation and a significant opportunity exists in this large underserved and potential $10 billion market. Our next step for 501 is to develop a potential path to sNDA for Alzheimer's associated agitation in the second half of the year, subject to further discussions with the FDA. We believe that the positive top line TRANQUILITY data, our robust 1,200-patient safety database from the full 501 program and breakthrough therapy designation for this indication will support our efforts to develop a much needed therapeutic option to manage this difficult-to-treat neurological symptoms. Our commercial team is hard at work developing the market entry strategy.
I would also like to acknowledge the 8-K filed earlier today regarding one of our clinical sites, we are proud of our quality control team for promptly initiating an investigation into this issue upon becoming aware of it. We take this seriously, and we'll be conducting an independent data integrated audit.
With that, I would like to turn it back to the operator to begin our Q&A session. Operator?
Operator
[Operator Instructions] Our first question today is coming from Colin Bristow from UBS.
Colin Bristow
Congrats on the data. You certainly kept us all waiting. I'll give you my sort of my question and follow-up upfront. So I just wanted to touch on the 483. Can you talk about what gives you comfort that the findings won't impact your ability to seek approval on this data set? And then can you talk about if there's any other sites being inspected and why the inspection of the sort of the name site is still showing as open? And then maybe just as a follow-on point to that, is the site, which is the focus of the 483 a major participant in TRANQUILITY III?
Robert Risinger
So I'm going to start and work backwards. The citing question is not a participant in TRANQUILITY III. The -- the other site, yes, there were other sites that were involved in the inspection. Of course, we have continuing audits and this...
Vimal Mehta
Not by FDA.
Robert Risinger
Not by FDA, we have audits of our own for quality.
Vimal Mehta
Gives you comfort...
Robert Risinger
Let me just say that what provides us with comfort is the fact that we see consistency across trials. The effects that we described here, the results of this study are very consistent with the prior trials. Obviously, the prior trial in TRANQUILITY I as well as our trials demonstrating efficacy in agitation, in general. We have not changed our development strategy as a result of this. We believe that this data is robust, and we are diligently pursuing -- our inspection of this and auditing, we are hiring an independent. We're in the process of reviewing this and an independent auditor will be providing us with a full report.
Vimal Mehta
Colin, this is Vimal. All the things Rob has said, plus the process that we follow for each trial, like pivotal trial, including what processes our CROs follow to ensure the integrity of the data. And we applied the data because, as Rob said, that it is very consistent between all our trials. And it's -- and we are excited about this data.
Robert Risinger
Let me add one other point. The investigator in question and this 483, the investigator conducted none of the efficacy ratings. Efficacy ratings were conducted by trained, qualified and monitored raters throughout the trial. So we have very high confidence in the quality and the integrity of the data. Otherwise, we would not have reported these results.
Colin Bristow
That's really helpful. And just why it's still being considered as open?
Robert Risinger
Well, it's open because Unfortunately, we don't control the FDA. They have not closed it. It's up to them to close a 483 and provide a final response. And so the site to our knowledge has not received that yet.
Colin Bristow
Okay. Great. This has been really helpful. And congrats again, guys, really great positive top line.
Operator
Next question today is coming from Robyn Karnauskas from Truist Securities.
Robyn Karnauskas
Congrats on the data and on the quality. So let me ask you, and I've got one that I've been getting this morning. So do the efficacy results hold up when you exclude this 40% enroller site? And that's really a question really about how consistent this response is on the absolute response? And then I have a follow-up.
Robert Risinger
So in terms of consistency, we've done several analyses where, for example, we removed all of the subjects, all the entire data set from this particular site, and there is no effect on the results in terms of directionality, it remains directional. And the magnitude of change is at least the same as when that site's subject data are included. We believe this indicates the site is neither positively or negatively biasing the efficacy results. The site is, in fact, simply contributing numbers to adequately power the trial.
Let me also say there is likely to be some concern about safety reporting. The FDA does not generally exclude any dose subject from safety reporting. We and our CRO have conducted rigorous monitoring of the trial. 100% of this data has been verified according to source documentation and medical records. So throughout the trial, we have quality audits of this and other sites that we routinely conduct and we have not identified trends or detected a particular bias in the safety data. So this level of diligence provides us with a level of confidence in reporting the trial results today.
Robyn Karnauskas
Great. And then just a follow-up. So when we think about TRANQUILITY III, given what you saw in the situation, have you done any assessments or restart the site to make sure that this wouldn't happen again -- I've not seen this in my career, but is there any precedent for 483 like this having an impact on approvability?
Robert Risinger
So in terms of precedent, the FDA typically will look at the data from each individual subject, specifically those from a site that may be in question. They may repeat the efficacy, let's say, analysis with individual subjects that may be of question. And they're not looking for statistical evidence at that point, they're looking for a trend or a bias. And having done those analyses with the large number of patients excluded and still seeing a directional effect, we have very high confidence that the efficacy of BXCL501 will not be in question. We do believe that our safety and efficacy results are complete. They're intact, and we do believe this is a reliable indication of our efficacy and an accurate assessment of the safety.
Operator
Next question is coming from Greg Harrison from Bank of America.
Greg Harrison
Wanted to get a sense of if you have an idea why you didn't see separation from placebo at 30 minutes? And then also, if you have any thoughts on what drove the outperformance in the placebo arm?
Robert Risinger
Thanks, Greg. So the 30-minute efficacy in this trial really wasn't powered. So I know that in our SERENITY I, SERENITY II in schizophrenia and bipolar, we used both greater doses and much, much larger numbers of subjects in order to power the trial to separate from placebo early. This trial was not powered to show a difference prior to the primary 2-hour efficacy. And nonetheless, we separated as early as 1 hour. In discussing the design and timing of efficacy, we discovered the geriatricians and providers are not at all focused on the speed of onset in dementia. But perhaps to nobody's surprise, they're far more focused on the safety. And in terms of safety, this trial demonstrates 501 was generally well tolerated with the safety profile for both the 40- and 60-microgram, that is consistent with the IGALMI label for our current approved and marketed doses. I'll add orthostatic hypotension did not contribute to the incidence of falls that we just reported.
As to why did 40 fail? Or why, in fact, the placebo effect was greater in a Phase III trial. That is typical and routine when moving from Phase II to Phase III, you do tend to see a greater placebo response and a greater variability. In this case, we had a group mean PEC total score of 5.7 at 2 hours for the 40 and 5.4 points for placebo. If you compare the placebo response of 5.4 in this trial with the prior trial, our Phase Ib to the TRANQUILITY I trial as we label it, the placebo was only 2.5 reduction pack. So we had essentially a doubling of the magnitude of placebo response at 2 hours. And as you see from our line plot, that almost completely overlaps with placebo. So we did have a very high placebo response.
Greg Harrison
Got it. That's helpful. And one more, if I can. How should we think about the amount of data that you think is necessary to move forward with an sNDA in Alzheimer's? Given today's readout as well as upcoming TRANQUILITY III? And when could we get an update on your FDA interaction?
Robert Risinger
Well, we actually look forward to our discussions and the ongoing work in partnership with FDA. We have been granted breakthrough designation. We've been working with them closely on every aspect of this trial in particular, down to the nitty-gritty details, for example, of the statistical analysis plan. This is exactly what the FDA wanted to see in terms of not just the first dose, but they wanted to see how frequently patients are using this when they're treated for acute episodes. And so we believe that we can work with the FDA expeditiously in order to potentially bring a much needed treatment for acute agitation episodes to those suffering from Alzheimer's dementia, just as we have for those suffering from schizophrenia and bipolar disorders with the approval of IGALMI.
Operator
Next question today is coming from Ram Selvaraju from H.C. Wainright.
Raghuram Selvaraju
So firstly, relating to the optimal dose, when we look at the TRANQUILITY target patient population, target indication relative to, for example, the patient population covered by the existing approval of IGALMI. Is it reasonable to assume that this patient population in TRANQUILITY might benefit most optimally from the 60-microgram dose? Or do you think that further dose optimization may be necessary in order to define the best possible dose for this population? And how does that compare to the best effective dose for the IGALMI label as well as the at-home setting in schizophrenia?
Robert Risinger
That's a multilayered question, and I really appreciate the thoughts that went into that. So let me elaborate. We believe that on the whole, the simplest interpretation of the data we've just shown is these results suggest the 60-microgram dose is an effective dose for the majority of patients in an acute episode. Because it separates at 2 hours, multiple secondary endpoints support the efficacy of the primary measure. The 60-microgram dose sort of passes muster in terms of a regulatory standard, demonstrating efficacy in a double-blind, placebo-controlled well-controlled fashion. The 40-microgram did not separate from placebo. It will be a matter for discussion with the FDA. We don't know if the FDA will consider allowing, if you will, a 40-microgram dose in addition to a 60-microgram dose. That is part of the discussions we'll be having with them. But we do know that the 60 separated. And for some smaller proportion, 40 may work or special populations. So in this elderly patients with dementia, we know we're treating both kidneys and liver and blood flow for an 8-year-old is vastly different than a patient who's 20 or 30, 40. So we'll be conducting a variety of modeling and simulations to determine what the most effective dose may be. And any subtleties of instruction for dosing, again, that will be reviewed with the FDA as part of our ongoing dialogue under breakthrough therapy. I'm not sure if I answered your question adequately. Yes, please.
Raghuram Selvaraju
No, that's definitely helpful. Our impression just generally is that the 60-microgram dose appears to have significant degree of applicability across both indication arenas. But clearly, there's additional exploration that you could do around both the 60-microgram and other doses that lie between the 60-microgram on the 120-microgram dosage level. Feel free to opine on that. The only other question I wanted to ask was if you could just remind us what you expect the time line to be for reporting of top line data from TRANQUILITY III?
Robert Risinger
Right. So let me be very concise. This results demonstrate efficacy of 60 in an agitated elderly demented population, that's good enough. We don't need any more dose ranging or exploration, for example, of higher doses. In terms of SERENITY, now we're looking in SERENITY III, we are examining dosing of BXCL501 at home in patients with schizophrenia and bipolar disorder. These are far younger patients, and it is at home dosing, that's a very different question. And as we've reported earlier, we are exploring higher doses than the 60-microgram, intermediate doses and 80-microgram is a very like dose to take forward. Very shortly, we'll have the information necessary to have the dialogue with the FDA about other doses and additional doses, meaning doses above 60 and below 120 in schizophrenia and bipolar disorder.
Raghuram Selvaraju
No, that's very helpful. And on TRANQUILITY III, the time line for top line data, if you could remind us if you're providing any more granular guidance on that at this time?
Robert Risinger
At this time, we're not. Our sites have been switching over, the sites that not this particular investigator in question, but other sites that we have high confidence in the quality of their data and their raters are switching over to the TRANQUILITY III study. And so once we have an accurate accrual and recruitment curve, we'll be able to report with confidence a completion -- estimated completion date TRANQUILITY III.
Operator
Our next question is coming from Sumant Kulkarni from Canaccord Genuity.
Sumant Kulkarni
So what's the earliest you can announce the results of an independent audit of the data? And do the audit results gate your ability to request interaction with the FDA to file? Asked another way, I guess, how confident are you in your ability to interact with the FDA in the second half and a potential path for India submission? And then I have a follow-up.
Robert Risinger
So under breakthrough for this particular indication, we're able to very rapidly go to the FDA. We did inform them -- I think it was yesterday or the day before, of this investigator and site issue. What happens typically is a sort of parallel track. The review division does auditing is different then the review division that approves from a regulatory standpoint, this is the division of psychiatry that has been reviewing our agitation in dementia. They are the same division, although now under neurology, same division that approved IGALMI for schizophrenia and bipolar disorder. And so the internal audit results may be available as early as 2 or 3 months, obviously, because we're in the process of contracting and hiring an independent audited group. And by the way, we're trying to find the highest quality auditing group because this data is robust. We'll be able to do that and then report those results probably within 3 to 4 months. And then I simply can't speak to the FDA process and what might result. We'll definitely keep you appraised of that as it goes and any changes, we will let you know.
Sumant Kulkarni
Got it. And then if we look at the trial results on the episodes, you had 443 episodes for 149 patients over a roughly 3-month period. That translates to about 3 episodes per patient in a 3-month period, or about 1 episode a month. How does the frequency validation episodes compared to the number of officials per month in the real world? And what average number of episodes per patient per year to drive your multibillion-dollar market assessment?
Robert Risinger
So maybe I would ask...
Unknown Executive
Yes. I'll jump in on this one because what we've seen in market research is that mild Alzheimer's dementia patients, on average, have about 3.4 episodes per month, those with moderate Alzheimer's dementia who have agitation average about 10 episodes per month. So what you're seeing in a clinical trial may be very different than what we see in the real world.
Operator
Next question is coming from Yatin Suneja from Guggenheim.
Eddie Hickman
This is Eddie on for Yatin. I'll be added color this morning. Were you surprised by the patient variability? And that only in only 12 weeks, somebody needed 28 doses versus 42% on any one dose? Was there any stratification in sort of baseline episodes and how that may influence efficacy. And then given the high placebo rate you saw and the PK variability that's known in this elderly population. Can you talk about anything you know about the exposure rates? And if there was any differences in how exposures to Dex maybe influence the pack response?
Robert Risinger
So we did not stratify by baseline severity. And there was extensive discussion with FDA around how to handle the baseline severity as it may change over the 12 weeks. Any given episode maybe 14. It had to be at least 14 on the pack in order to be qualified as an acute episode. But a particular episode could be 18 or 20 or 23 versus another episode that's 14. So handling that from a statistical standpoint was a majority of our discussions with the FDA. It does not surprise us that there was such a range of frequency. In general, we know from the literature that as dementia progresses, as patients become more demanded as their Mini-Mental status exam score drops, there is a greater both severity and frequency of agitation. And so we've been eager. We haven't done it yet, but we are eager to look at whether or not there was some relationship between the frequency of episodes and the Mini-Mental status score. But we know that this patient population now we know that it is not a chronic condition for patients with mild to moderate levels of dementia. What we're seeing is clearly an intermittent dosing. And what gives us great confidence that the FDA will work with us to bring this potential treatment to patients is the fact that this range is eminently treatable when you use it only as needed.
Eddie Hickman
[Technical Difficulty]
Robert Risinger
I'm sorry, you were breaking up.
Eddie Hickman
And then just sort of a follow-up on if there was any sort of any information about how different exposure may have impacted the efficacy if there's variability across this elderly population, obviously, is affected by deck differently. So I was curious if the difference in -- the variability in efficacy could have been related to the variability exposure.
Robert Risinger
Yes. As we've been -- we have been collecting PK data in the trial and our analysis indicates the exposure is very similar in this trial to what we saw in TRANQUILITY I. So yes, again, we've been maintaining that there is a difference in exposure in the elderly and especially these patients up to age 95. And that is what we're seeing.
Eddie Hickman
Do those patients -- or are those patients more likely to get a second dose after the 2-hour time point because they sort of needed an extra boost of efficacy? Is that something that you saw in those patients that sort of had lower exposures?
Robert Risinger
No. And again, we haven't done the fine-grained analysis, but number one, patients were not allowed to receive another dose after the first dose for a particular episode. And we didn't see evidence that they required, for example, additional treatment for the 60-microgram. So we are conducting those sort of finer grain analyses, and we will be presenting the results of this at scientific conferences, results of TRANQUILITY I as well as this trial TRANQUILITY II. So those fine-grained analysis will be coming out in posters, presentations and abstracts.
Operator
Our next question today is coming from Graig Suvannavejh from Mizuho.
Unknown Analyst
This is Richard on for Graig Suvannavejh. Just a few questions for me is that -- in the 8-K, you mentioned finding this out in December and then again in May, how come the company didn't disclose this sooner? What's the strategy there?
Robert Risinger
So with respect to the particular SAE process, the FDA didn't actually find this. We found that information. FDA did the audit back in December. We were aware of it, and we've been monitoring that site even more closely. So again, the investigator failed to follow the process of reporting an SAE, although she did enter the adverse event in our database. So we have that particular event and all events according to our monitoring and source data verification.
Vimal Mehta
So Richard, this is Vimal. I'd just like to add, we learned of this situation as like almost late last week. So it's a very recent event, and that's why we reported it.
Unknown Analyst
Okay. So then you mentioned something about if the FDA were to exclude some of these patients, they wouldn't exclude the efficacy portion, but if they were to exclude the safety portion, what's your confidence that they won't exclude all of these patients from this one site?
Robert Risinger
So the one patient in question, we have looked at with our analyses, all of our analyses with and without this one patient, and it does not substantially change the results that we've reported today By the way, that is on TRANQUILITY III now. Yes. By the way, that patient was on placebo. So it's not an effect of the drug that we're worried about per se. And your question about TRANQUILITY III was -- What are you, could you repeat it?
Unknown Analyst
What are your expectations for TRANQUILITY III now that you have results from TRANQUILITY II?
Robert Risinger
Well, so there are differences in TRANQUILITY III. I'll remind the audience that TRANQUILITY III is moderate to severely demented patients, patients who do require moderate to extensive assistance with activities of daily life, meaning these patients are more in a, call it, a nursing home setting. They do require 24/7 supervision. Usually, these units prevent these patients from wandering, for example, as well as monitoring their medical conditions, ensuring they get the medications necessary for their multiple medical conditions. So with these results from TRANQUILITY I, we'll now evaluate whether or not TRANQUILITY -- I'm sorry, results from TRANQUILITY II, we'll evaluate whether these results, including the safety should impact anything about the ongoing TRANQUILITY III study. But at this point, at this level, we see no -- no reason to change.
Unknown Analyst
So both doses are going to stay the same? Or are you just going to move forward with 60-microgram?
Robert Risinger
So the randomization is similar. We have 2 shots on goal with TRANQUILITY III, and a major difference, again, is that they are allowed to receive a second dose if necessary in TRANQUILITY III. So let's say, for example, a 40-microgram dose patient is poorly responsive in terms of efficacy, they are allowed to receive another dose. So that patient would, therefore, receive 80 micrograms with 2 doses of 40 over time, in the same day.
Operator
Next question is coming from Corinne Jenkins from Goldman Sachs.
Corinne Jenkins
So maybe it's not your base case. To the extent that the study isn't admissible or some portion of it is an immiscible. Would you be prepared to run an additional trial? And are you sufficiently funded to do so?
Robert Risinger
So let me start by saying I can't see the scenario where the entirety of the data from this trial is unable to be submitted. We're talking about a single investigator, a single site. And again, in our analyses, if you exclude every single patient from that site, under that principal investigator, who did not perform any of the efficacy ratings, we still see a similar effect, at least a directional effect on the efficacy rating. So that confirms -- that is our confirmation, if you will. And that is typically sufficient for the FDA.
Corinne Jenkins
And then maybe can you help me understand the reasons for discontinuation in the study that was, I think, 42% of the 60-microgram does. It wasn't -- it looks like just safety that was only 9%. Can you help us understand the other drivers for discontinuation there?
Robert Risinger
Specially, the drivers for discontinuation had to do with underlying medical conditions, unstable hypertension or they had a serious medical condition that arose, pneumonia, COVID. Those were common reasons. We did have some patients who consented initially and then withdrew because they withdrew consent. There were a few -- I'll just add a little bit more color. There were a few patients who, for example, were lost a follow-up, which literally meant. They had a medical condition, and they were in the hospital and they just never came back to the assisted living center or they transferred to another assisted living center where we could not follow them up and continue to dose maybe in a different state, for example.
Vimal Mehta
And also, I'd just like to add, we also saw discontinuations in the placebo arm
Operator
Our next question today is coming from Samir Devani from Rx Securities.
Samir Devani
Congrats on the data. It's the same about the 483, which is probably going to overshadow with a very good data. I guess my question really is from those patients that received multiple doses. Obviously, had multiple episodes over the 12-week period. They seem to be, I think, 5% that had quite a few double-digit number of episodes. Was the PEC reduction in those patients consistent over the course of the trial?
Robert Risinger
Those patients -- so we haven't done that kind of an analysis. So for example, analyze those who had 10 or greater episodes versus 9 or less. However, patients who had greater numbers of episodes should bias our analysis of all episodes. And they should bias if there was, let's say, less and less effect, it should bias it to demonstrate lesser effective all doses. We did not see that.
Samir Devani
Great. And then maybe just one on the 483. I think the FDA talks about not necessarily getting informed consent, how many patients would fall into the bubble of not having informed consent?
Robert Risinger
I believe there were 4.
Operator
Your next question is a follow-up from Sumant Kulkarni from Canaccord Genuity.
Sumant Kulkarni
I have two. Were you surprised at all by one site contributing 40% of patients and what drove that steel distribution on enrollment? And second, on the adverse events of special interest, how confident are you that the FDA's potential assessment of this benefit would utilize the same 24-hour cutoff period for events to be not attributed to the study drug?
Robert Risinger
Okay. The half-life of the drug is 2, 3 hours in the plasma. Therefore, at 24 hours, the exposure to drug or plasma levels are much lower than 97% clearance. So there's about 3% or less left in the bloodstream at 24 hours. There's even less at 48 or 72. The serious adverse events over the trial occurred well passed any reasonable expectation of a drug-related or exposure-related event. Now as part of our eventual NDA filing, we will be doing all of these analyses, both within 24 hours and over the course of the 12 weeks. We don't believe we'll find an effect. But at this level, typically, this is what is presented to the FDA. And so this is -- we're doing both the standard analysis and the full extensive, if you will, what-if analysis. We've not seen robust differences between dosing arms or doses, both the 40 and the 60 appear to have very similar safety profiles overall, and it is very consistent with our current label.
Sumant Kulkarni
And how would the 40% enrollment at one site? What drove that distribution?
Robert Risinger
That site was one of the first sites to initiate the trial. That site, in particular, had a sort of head start. They were very successful at enlisting multiple assisted living facilities and residential care. And so they were able to kind of lift off much faster than the other sites involved.
Sumant Kulkarni
And I'll sneak one in. So assuming that you are in a scenario where an sNDA is allowable based on TRANQUILITY II data, what then happens to your ongoing TRANQUILITY III trial? Or what would that be considered?
Robert Risinger
That would be likely to be considered either post approval or come in during approval, that will be part of the discussion with the FDA.
Operator
We reached the end of our question-and-answer session. I'd like to turn the floor back over to Dr. Mehta for any further closing comments.
Vimal Mehta
Thank you, everyone, for joining us this morning. Have a great day.
Operator
Thank you. That does conclude today's teleconference and webcast. You may disconnect your line at this time, and have a wonderful day. We thank you for your participation today.
Access This Content Now
Sign Up Now!
