Good morning, welcome to the BioXcel Therapeutics TRANQUILITY II Top Line Results Conference Call. At this time, all participants are in listen-only mode. If during the conference you require operator assistance, please press star zero on your telephone keypad. After the presentation, there will be a question-and-answer session. If you'd like to register a question, you may press star one on your telephone keypad. 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 31st, 2023, as updated by the company's 8-K file 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. Robert 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.
Thank you, Operator. Welcome, everyone, 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 agitation at two hours with a 60 mcg dose and a key secondary endpoint with a statistically significant reduction in agitation at 1 hour with the same 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 two 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 conducted before we received our breakthrough therapy designation, showed a 7.1 absolute PEC change in the 60 mcg arm.
TRANQUILITY II showed a 7.5 absolute PEC change in the 60 mcg arm, meeting the primary endpoint at this dose. A 5.4 absolute PEC change was shown for our 30 mcg dose in TRANQUILITY I, which is consistent with our 40 mcg 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?
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 mcg dose of BXCL501, with a significant reduction in agitation symptoms from baseline at two hours after dosing compared to placebo. In this trial, the 40 mcg 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 mcg may be the lowest effective dose for reducing symptoms of agitation, and both doses were well tolerated in the study. Notably, with 60 mcg, the earliest significant separation from placebo was at one 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 mcg 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 adults 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 in assisted living facilities or ALFs and in residential care settings. Patients were randomized to self-administer 40 mcg or 60 mcg of BXCL501 or placebo, as needed, for agitation episodes occurring over a 12-week period....
We chose to test these two 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-Excited Component, or PEC, total score at two hours post-dose for the first treated agitation episode. This five 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 one 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 and 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 criterion 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 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 mean Mini-Mental State Examination, 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 17-18, similar across all three 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 mcg dose group, as measured by a group mean change from baseline in PEC total scores starting at one hour post-dose.
The 60 mcg treatment group showed statistically and clinically meaningful results at the primary endpoint of two hours, with PEC score reduced by 7.5 points and a compelling p-value of 0.01 versus placebo. The 60 mcg dose separated at both one and four hours following dosing. The group mean PEC total score for the 40 mcg group was reduced by 5.7 at two 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 mcg. BXCL501 significantly reduced agitation symptoms at one 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 mcg dose reduced agitation symptoms as early as one hour, as well as two 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 reduction at one and two hours following the first dose in the 60 mcg dose group. Data on the right-hand side show that each time we administered 60 mcg over 12 weeks, patients had a similar total PEC score reduction versus placebo at both one and two 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 endpoint with BXCL501 60 mcg. These secondary efficacy measures include response rates by CGI-I and ACES, which showed similar effects for the 60 mcg dose. At two hours after the first dose, 76% of patients responded to therapy as measured by CGI-I, defined as achieving an assessment of very much or much improved, meaning one or two 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 mcg over 12 weeks, patients had a similar response by CGI-I versus placebo at both one and two 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 mcg dose at one and two 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 non-specific sedation is desirable for the treatment of acute agitation. The Agitation and 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 mcg dose at one, two, and four hours post-dose. This is exemplified by a shift of 2 points or greater for the 60 mcg dose, such that agitated patients were rated as normal two 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 two 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 five or fewer agitation episodes, and as shown previously, BXCL501 at 60 mcg reduced agitation symptoms as measured by PEC change from pre-dose at both one and two 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 interests, or AESIs, 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 IGALMI. 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, that was in the placebo arm. With regard to deaths, three deaths occurred, all greater than one 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 pre-existing 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. Two discontinued within 24 hours of a treatment, one subject in the 40 mcg 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 mcg dose, as measured by the change from baseline PEC score at two 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?
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 symptom. 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 will be conducting an independent data integrity audit. With that, I would like to turn it back to the operator to begin our Q&A session. Operator?
Thank you. We'll now be conducting your question- and- answer session. We ask you please ask one question and one follow-up, return to the queue. If you'd like to be placed in the question queue, please press star one at this time. Once again, that's star one to be placed in the question queue. We ask you, please ask one question, one follow-up, return to the queue. Our first question today is coming from Colin Bristow from UBS. Your line is now live.
Hey, good morning, congrats on the data. You certainly kept us all waiting. Yeah, I'll give you my sort of my question and follow-up, up front. I just wanted to touch on the Form 483. Can you talk about what gives you comfort that the findings won't impact your ability to seek approval on this data set? Then can you talk about if there's any other sites being inspected and why the inspection at the sort of the main site is still showing as open? Then maybe just as a follow-on point, too, on that, is the site which is the focus of the Form 483 a major participant in TRANQUILITY III? Thank you.
I'm gonna start and work backwards. The site in question is not a participant in TRANQUILITY III.
Oh, the other site.
Oh, the other site. Yeah. There were other sites that were involved in the inspection. Of course, we have continuing audits.
Not by FDA.
Not by FDA. We have audits of our own for quality.
Gives you comfort file.
Let me just say that what provides us with comfort is the fact that we see consistency across trials. The effects that we describe here, the results of this study, are very consistent with the prior trials. Obviously, the prior trial in TRANQUILITY I, as well as our other 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're in the process of reviewing this, and an independent auditor will be providing us with a full report.
Colin Bristow, this is Vimal. All the things Rob has said, plus the processes we follow for each trial, like pivotal trial, including what processes our CROs follow, to ensure the integrity of the data. We provided the data because, as Rob said, that it is very consistent between all our trials, and we are excited about this data.
Let me add one other point. The investigator in question in this Form 483, the investigator conducted none of the efficacy ratings. Efficacy ratings were conducted by trained, qualified, and monitored raters throughout the trial. We have very high confidence in the quality and the integrity of the data. Otherwise, we would not have reported these results.
That's really helpful. Just why it's still being considered as open?
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 Form 483 and provide a final response. The site, to our knowledge, has not received that yet.
Okay, great. This has been really helpful. Congrats again, guys. You know, really great positive top line.
Thank you.
Thank you. Next question today is coming from Robyn Karnauskas from Truist Securities. Your line is now live.
Hi, thanks for taking my question, congrats on the data, and on the quality. Let me ask you, I've got one that I've been getting this morning. Do the efficacy results hold up when you exclude this 40% enroller site? That's really a question really about how consistent this response is on the absolute response. I have a follow-up.
In terms of consistency, we've done several analyses where, for example, we remove all of the subjects, all the entire dataset 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.
Got it.
There is likely to be some concern about safety reporting. The FDA does not generally exclude any dosed 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. Throughout the trial, we had 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. This level of diligence provides us with a level of confidence in reporting the trial results today.
Great. Just a follow-up. When we think about TRANQUILITY III, you know, given what you saw in the situation, have you done any assessments or, you know, reached out to the site to make sure this wouldn't happen again? You know, I've not seen this in my career but is there any precedent for a Form 483 like this having an impact on approvability? Thanks.
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, analyses 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. 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.
Great. Thank you so much.
Yeah, we do believe.
Go ahead, sorry.
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.
Okay, great. Thank you so much, guys, and congrats.
Thanks, Robyn.
Thank you. Next question is coming from Greg Harrison from Bank of America. Your line is now live.
Hey, good morning. Thanks for taking the question. 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?
Thanks, Greg. The 30-minute efficacy in this trial really wasn't powered. I know that in our SERENITY I, SERENITY II, and schizophrenia and bipolar, we used both greater doses and 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 two hour efficacy endpoint. Nonetheless, we separated as early as one hour. In discussing the design and timing of efficacy, we discovered that 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.
In terms of safety, this trial demonstrates BXCL501 was generally well-tolerated, with a safety profile for both the 40 and 60 mcg 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 two 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/II, the TRANQUILITY I trial, as we label it, the placebo was only 2.5 reduction in PEC. We had essentially a doubling of the magnitude of placebo response at two hours. As you see from our line plot, that almost completely overlaps with placebo. We did have a very high placebo response.
Got it. That's helpful. 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?
Well, we actually look forward to our discussions and the ongoing work and partnership with the 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. 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.
Great. Thanks again for taking the question.
Thank you. Next question today.
Thanks.
is coming from Ram Selvaraju from H.C. Wainwright. Your line is now live.
Thanks so much for taking my questions. Can you hear me?
Yes.
Firstly, you know, 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 mcg dose? Do you think that further dose optimization may be necessary in order to define the best possible dose for this population? How does that compare to the best effective dose for the IGALMI label as well as the at-home setting in schizophrenia?
That's a multilayered question, and I really appreciate the thought that went into that. 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 mcg dose is an effective dose for the majority of patients in an acute episode. Because it separates at two hours, multiple secondary endpoints support the efficacy of the primary measure. The 60 mcg dose sort of passes muster in terms of a regulatory standard, demonstrating efficacy in a double-blind, placebo-controlled, well-controlled fashion. The 40 mcg 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 mcg dose in addition to a 60 mcg dose.
That is part of the discussions we'll be having with them. We, we do know that the 60 separated, and for some smaller proportions, 40 may work or special populations. In this elderly patients with dementia, we know we're treating, you know, both kidneys and liver and blood flow, for an 80-year-old is vastly different than a patient who's 20 or 30 or 40. We'll be conducting a variety of modeling and simulations to determine, you know, what the most effective dose may be and any subtleties of instruction for dosing. Again, that'll be reviewed with the FDA as part of our ongoing dialogue under breakthrough therapy.
Okay, that's very helpful.
I'm not sure if I answered your question adequately. Yeah, please.
No, that's definitely helpful. You know, our impression just generally is that the 60 mcg dose appears to have a significant degree of applicability across both indication arenas, but clearly, you know, there's additional exploration that you could do around both the 60 mcg and other doses that perhaps lie between the 60 mcg and the 120 mcg dosage level. You know, 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 timeline to be for reporting of top-line data from TRANQUILITY III?
Right. 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 mcg, intermediate doses, and 80 mcg is a very likely 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.
No, that's very helpful. On TRANQUILITY III, the timeline for top-line data, if you could remind us if you're providing any more granular guidance on that at this time?
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. Once we have an accurate accrual and a recruitment curve, we'll be able to report with confidence a completion, estimated completion date.
Thank you.
For TRANQUILITY III.
Thank you. Next question is coming from Sumant Kulkarni from Canaccord Genuity. Your line is now live.
Good morning. Thanks for taking my questions. What's the earliest you can announce the results of an independent audit of the data? Do the audit results date your ability to request interaction with the FDA to file? Asked another way, how confident are you in your ability to interact with the FDA in the second half on a potential path for NDA submission? I have a follow-up.
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 that does auditing is different than the review division that approves from a regulatory standpoint. This is the division of psychiatry that has been reviewing our agitation and dementia. They are the same division, although now under neurology, same division that approved IGALMI for schizophrenia and bipolar disorder. The internal audit results may be available as early as two or three months. Obviously, because we're in the process of contracting and hiring, you know, an independent auditing group.
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 three to four months. 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.
Got it. If we look at the trial results from the episodes, you had 443 episodes for 149 patients over a roughly three month period. That translates to about three episodes per patient in a three month period, or about 1 episode a month. How does the frequency of agitation episodes compare to the number of episodes per month in the real world? What average number of episodes per patient per year drive your multi-billion-dollar market assessment?
Sumant-
Maybe I'll ask Matt.
Yeah, 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. What you're seeing in a clinical trial may be very different than what we see in the real world.
Got it. Thanks for that.
Thank you. Next question is coming from Yatin Suneja, from Guggenheim. Your line is now live.
Good morning. This is Yatin Suneja, thanks for taking my questions and all the added color this morning. Were you surprised by the patient variability and that, you know, only, you know, that in only 12 weeks, somebody needed 28 doses versus 42% only needing one dose? Was there any stratification in sort of baseline episodes and how that may influence efficacy? 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 influenced the PEC response? Thanks.
We did not stratify by baseline severity, and there was extensive discussion with the FDA around how to handle the baseline severity as it may change over the 12 weeks. Any given episode may be 14. It had to be at least 14 on the PEC in order to be qualified as an acute episode. A particular episode could be 18 or 20 or 23 versus another episode that's 14. 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 demented, as their Mini-Mental State Examination score drops, there is a greater both severity and frequency of agitation.
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. 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.
on exposure rates.
I'm sorry, you were breaking up.
I just sort of a follow-up on if there was any sort of information about how different exposure may have impacted the efficacy. If there was variability across, you know, this elderly population obviously is affected by dex differently. I was curious if the difference in the variability in efficacy could have been related to the variability exposure.
Yes. As we have been collecting PK data in the trial, our analysis indicates the exposure is very similar in this trial to what we saw in TRANQUILITY I. Yes.
Okay.
We've been maintaining that there is a difference in exposure in the elderly and especially these patients up to age 95. That is what we're seeing.
Were those patients more likely to get a sort of, a second dose after the two 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?
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 mcg. We're 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. Those finer grain analyses will be coming out in posters, presentations, and abstracts.
Thank you so much.
Thank you. Our next question today is coming from Graig Suvannavejh from Mizuho. Your line is now live.
Hi, good morning. 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?
With respect to the particular SAE process, the FDA didn't actually find this. We found that information. The FDA did the audit back in December. We were aware of it, and we've been monitoring that site even more closely. Again, the investigator failed to follow the process of reporting an SAE, although she did enter the adverse event in our database. We have captured that particular event and all events according to our monitoring and source data verification.
Richard, this is Vimal. I'd just like to add, we learned of this situation as, like, you know, almost late last week. It's a very recent event, and that's why we reported it.
Thanks. 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 just, you know, exclude all of these patients from this one site?
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.
Okay, great. what are your-
By the way, that patient was on TRANQUILITY III now. Yeah, by the way, that patient was on placebo, so it's not an effect of the drug that we're worried about, per se. Your question about TRANQUILITY III was?
what are your-
Could you repeat it?
for TRANQUILITY III? Yep. What are your expectations for TRANQUILITY III now that you have results from TRANQUILITY II?
Well, 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. With these results from TRANQUILITY I, we'll now evaluate whether or not, 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 reason to change.
Both doses are going to stay the same, or are you just gonna move forward with 60 mcg?
The randomization is similar. We have two 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. Let's say, for example, a 40 mcg dose patient is poorly responsive in terms of efficacy. They are allowed to receive another dose, so that patient would therefore receive 80 mcg with two doses of 40 over time in the same day.
Thank you. I appreciate it.
Thank you. Next question is coming from Corinne Jenkins from Goldman Sachs. Your line is now live.
Good morning. maybe, you know, recognizing it's not your base case, to the extent that this study isn't admissible or some portion of it isn't admissible, would you be prepared to run an additional trial, and are you sufficiently funded to do 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. 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. That confirms. That is our confirmation, if you will, and that is typically sufficient for the FDA.
Okay. Okay. Maybe can you help me understand the reasons for discontinuation in the study that was, I think, 42% in the 60 mcg dose? It wasn't, it looked like just at safety, that was only 9%. Can you help us understand the other drivers for discontinuation there?
Principally, 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.
Okay, thank you.
I'll just add a little bit more color. There were a few patients who, for example, were lost to 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.
I'd just like to add, we also saw discontinuation in the placebo arm also.
Thank you. Our next question today is coming from Samir Devani from Rx Securities. Your line is now live.
Yeah. Hi, guys, and thanks for taking my question. Congrats on the data. It's a shame about the Form 483, which is probably gonna overshadow what 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. That seemed 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?
Those patients, so we haven't done that fine of an analysis. For example, analyze those who had 10 or greater episodes versus nine 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 effect of all doses. We did not see that.
Great. maybe just one on the Form 483. I think the 8-K talks about, not necessarily getting informed consent. How many patients would fall into the bubble of not having informed consent?
I believe there were four.
Okay, that's great. Thanks very much, and congrats on the data.
Thank you.
Thank you. Next question is a follow-up from Sumant Kulkarni from Canaccord Genuity. Your line is now live.
Thanks for taking the follow-ups. I have two. Were you surprised at all by one site contributing 40% of patients, and what drove that skewed distribution on enrollment? Second, on the Adverse Events of Special Interest, how confident are you that the FDA's potential, you know, assessment of risk benefits would utilize the same 24-hour cutoff period for events to be not attributed to the study drugs?
Okay. The half-life of the drug is two to three hours in the plasma. Therefore, at 24 hours, the exposure to drug or plasma levels are much lower than 97% clearance. 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 past any reasonable expectation of a drug-related or exposure-related event. In, 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. This is. We're doing both the standard analyses and the full extensive, if you will, what-if analyses.
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.
How about the 40% enrollment at one site? What drove that distribution?
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.
I'll sneak one in. Assuming that you're 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?
That would be likely to be considered, you know, either post-approval or come in during approval. That will be part of the discussion with the FDA.
Thanks.
Thank you. We've reached the end of.
Thank you.
question- and- answer session. I'd like to turn the floor back over to Dr. Mehta for any further closing comments.
Thank you, everyone, for joining us this morning. Have a great day.
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.