BTAI: Positive Data for TRANQUILITY II Trial Overshadowed by Possible Trial Mismanagement…
NASDAQ:BTAI
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Positive Topline Results for TRANQUILITY II; Possible Trial Conduct Issues at One Clinical Site
On June 29, 2023, BioXcel Therapeutics, Inc. (NASDAQ:BTAI) announced positive topline results for the Phase 3 TRANQUILITY II trial of BXCL501 for the acute treatment of Alzheimer’s disease-related agitation. The trial hit the primary endpoint for the 60 µg dose as BXCL501 showed a 39% greater reduction in PEC score from baseline compared to placebo at 2 hours (P=0.0112). However, in an 8-K the company disclosed that following an FDA inspection of one of the clinical trial sites in December 2022, the FDA issued a Form 483 identifying three inspectional observations. This site enrolled approximately 40% of the patients in the TRANQUILITY II trial. In addition to the FDA investigation, BioXcel will be conducting an investigation into protocol adherence and data integrity at that clinical trial site through an independent third-party audit of data collected at that site. Thus, while we are very encouraged by the topline results from the TRANQUILITY II trial, the uncertainty introduced by potential conduct issues at the site in question have caused us to lower our probability of approval until this matter is resolved.
The TRANQUILITY II trial was a randomized, placebo controlled, parallel group trial that evaluated the safety and efficacy of BXCL501 for the acute treatment of Alzheimer’s related agitation in adults 65 years and older in assisted living facilities and residential care settings that require minimal assistance with activities of daily living. A total of 149 patients with mild to moderate dementia were dosed. The patients self-administered 40 or 60 µg of BXCL501 or placebo for agitation episodes that occurred over a 12-week period. The primary endpoint was the change from pre-dose in PEC total score at two hours post-dose for the first treated episode of agitation. Key secondary endpoints were PEC change from pre-dose at one hour post-dose and PEC change from pre-dose at 30 minutes post-dose.
The following graph shows the change from baseline in PEC total score for placebo, 40 µg BXCL501, and 60 µg BXCL501. The mean (SD) baseline PEC scores were similar between the three treatment groups at 17.5 (2.62), 17.3 (2.26), and 18.0 (2.18) for placebo, 40 µg BXCL501, and 60 µg BXCL501, respectively. The trial met its primary endpoint for the 60 µg dose with a statistically significant reduction in agitation at 2 hours (P=0.0112).
The clinical global impression scale – improvement (CGI-I) is a 7-point scale where a rating of (1) very much or (2) much improved were considered responders. The chart below shows the percentage of patients who achieved a CGI-I score of 1 or 2 through 2 hours after the first dose and after all doses. The P values compared BXCL501 and placebo. The results showed a statistically significant improvement in CGI-I for the 60 µg BXCL501 dose for the first dose and all doses at one hour and two hours post-dose.
The agitation calmness evaluation scale (ACES) consists of a single item that rates overall agitation and calming where 1 = marked agitation, 2 = moderate agitation, 3 = mild agitation, 4 = normal behavior, 5 = mild calmness, 6 = moderate calmness, 7 = marked calmness, 8 = deep sleep, and 9 = unarousable. The following graph shows the change in ACES score from baseline. The 60 µg BXCL501 dose resulted in a statistically significant change in ACES score compared to placebo at 1, 2, and 4 hours post-dose.
In regards to safety, BXCL501 was well tolerated with the most reported adverse events (AEs) being somnolence and hypotension. The following table shows the treatment-emergent adverse events of special interest (AESI), which are defined as those related to the mechanism of action of the drug that were observed within 24 hours after the first dose and occurred with a frequency of at least 2% and greater than placebo. Falls and deaths are of particular concern with the patient demographic in this trial. Importantly, all falls were determined to be unrelated to treatment and occurred in-between agitation episodes. No falls occurred within 24 hours of dosing the 40 or 60 µg doses while one fall occurred within 24 hours of dosing in the placebo arm. There were three deaths in the trial, one in each treatment arm, and each occurred more than one month after the last dose of trial treatment and were not determined to be related to treatment.
Questions Regarding Clinical Conduct
As mentioned above, BioXcel filed an 8-K with information regarding questions surrounding the conduct of a principal investigator at one of the clinical trial sites for the TRANQUILITY study. This site enrolled approximately 40% of the subjects in the trial. The FDA conducted an inspection of the site in December 2022 and at that time issued a Form 483 that identified three inspectional observations related to failures by the principal investigator:
• Failure to adhere to the informed consent form approved by the Institutional Review Board for a limited number of subjects whose records the FDA reviewed;
• Failure to maintain adequate case histories for certain patients whose records the FDA reviewed;
• Failure to adhere to the investigational plan in certain instances
One example given in the 8-K was the FDA cited the principal investigator’s delay in informing the sponsor’s medical monitor or pharmacovigilance safety vendor of a serious adverse event (SAE) for one of the study subjects, with the report to the company’s vendor done outside of the 24-hour time period prescribed by the clinical trial protocol.
The principal investigator for that clinical site has responded to the FDA observations within the time period requested, however the FDA inspection remains open as the agency has not issued an Establishment Inspection Report.
In May 2023, BioXcel learned that the same principal investigator may have fabricated email correspondence that purported to show that the investigator did timely submit to the company’s pharmacovigilance safety vendor a report of an SAE from a different subject than the one cited in the Form 483, and purporting to show that the vendor had confirmed receipt. BioXcel opened an investigation and confirmed that the principal investigator did in fact fabricate the email. The company also confirmed that the SAE had been entered into the electronic data capture system in the proper timeframe even though it had not been separately reported to the company’s pharmacovigilance safety vendor within the 24-hour timeframe required under the protocol.
After unblinding the data, the company determined that the SAE that was the subject of the fabricated email occurred in a subject in the placebo arm. In addition, the study was designed so that staff other than the principal investigator conducted assessments of the primary efficacy measure.
BioXcel will be conducting its own investigation into this clinical trial site through an independent third party that will audit the data collected at the site. We are unsure of the timeframe regarding this investigation, but are confident the company will attempt to complete it as soon as possible.
During the conference call to discuss the TRANQUILITY II data, management indicated that if all the data from the trial site in question was excluded from the data analysis, the data trends still held, although the results would not reach statistical significance due to the study being underpowered. Thus, as it currently stands, and if no additional findings are found at the trial site in question through the company’s independent audit, we don’t believe the FDA will refuse to accept the data from that site and the company should be able to use all the data from the TRANQUILITY II trial in an sNDA filing. However, if additional issues are discovered through the company’s independent audit, the FDA may disallow any data from that trial site, in which case it may be necessary for BioXcel to conduct an additional clinical trial before filing an sNDA seeking approval for BXCL501 for treating agitation in Alzheimer’s patients. It should be noted that when asked about this situation during the conference call, management stated that they did not foresee a situation in which the FDA would disallow the data from the trial site in question to be used for a regulatory filing.
Conclusion
Clearly investors are nervous about the potential for trial misconduct as the stock was down approximately 60% following release of the TRANQUILITY II data. This is in spite of the fact that the topline data were positive, statistically significant, and clinically meaningful. We are hoping that the company’s independent investigation will be finished within the next few months, but until this issue is resolved the regulatory future of BXCL501 for the treatment of Alzheimer’s related agitation is uncertain. We have lowered the probability of approval for BXCL501 in Alzheimer’s related agitation to 25%, which has lowered our valuation to $55.
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