Background

BXCL501 is an orally dissolvable film formulation of the α2A adrenergic receptor agonist dexmedetomidine. It is approved to treat acute agitation associated with schizophrenia or bipolar disorder in people under medical supervision. Currently, BXCL501 is being tested to treat agitation in people with Alzheimer’s disease.

Dexmedetomidine given intravenously is commonly used for sedation and anesthesia in surgical and intensive care patients. It is also used by veterinarians to sedate cats, dogs, and horses. BioXcel Therapeutics developed BXCL501 to improve oral bioavailability of the drug. It comes in doses of 120 and 180 micrograms on a rectangular film containing 2 microdeposits of dexmedetomidine hydrochloride. After application, dexmedetomidine is absorbed into the blood stream in five to 20 minutes, where it has a half-life of 2.8 hours.

In 2022, the FDA approved BXCL501 for people with schizophrenia or bipolar disorder, after trials showed significant reduction in agitation 20 to 30 minutes after administration (Citrome et al., 2022; Preskorn et al., 2022). Common side effects include sleepiness, numbness or pricking feelings in the mouth, dry mouth, dizziness, and low blood pressure. Users self-administer the drug in the presence of a health care professional who can monitor vital signs and alertness to prevent falls or fainting. It may interact with, and enhance the effects of, other sedatives and β-blockers.

In animal models of amyloid toxicity, dexmedetomidine has been claimed to be neuroprotective and anti-inflammatory (e.g. Ma et al., 2024; Lian et al., 2024; many earlier papers). Previously, α2 adrenergic agonists were reported to promote non-amyloidogenic processing of the amyloid precursor protein (Nizari et al., 2016). On the other hand, dexmedetomidine was shown to increase tau phosphorylation and promote tau aggregation in human Tau expressing mice (Whittington et al., 2015; Huang et al., 2015). As a sedative, dexmedetomidine has been reported to be associated with less delirium in intubated patients compared to lorazepam or midazolam (Pandharipande et al., 2007; Riker et al., 2009).

Findings

In December 2019, BioXcel began the Phase 1/2 Tranquility trial to test safety and efficacy in people with acute agitation and dementia. The dose-finding study enrolled 100 elderly adults with all forms of dementia, who had a history of agitation that required intervention or impaired their social or daily activities. Three cohorts of 10 patients each received 30, 60, or 90 micrograms sublingual film, or placebo, self-administered at the appearance of agitation under the supervision of a trained staff member. In the adaptive study design, an additional fourth cohort of 46 people took 40 micrograms, or placebo. Primary endpoints were change in the Positive and Negative Syndrome Scale-Excited Component (PEC) Total Score between baseline and two hours after dosing, and adverse events. The PEC score is the same endpoint used in previous trials for FDA approval. Secondary outcomes were additional scales of agitation, the time for medication to dissolve, and negative reactions to the film by patients. The trial finished in May 2021; results are posted on clinicaltrials.gov. The 60 and 40 microgram doses significantly reduced the PEC score. Secondary measures of agitation were likewise improved. Half of patients taking 40 micrograms, and three-quarters taking 60 micrograms, reported adverse events, most commonly sleepiness and hypotension, followed by dry mouth, gastrointestinal issues, urinary tract infection, and dehydration. The film took minutes to dissolve, and investigators noted no negative reactions to it. 

Two studies were planned to start in 2022, a Phase 2 trial in patients with all-cause dementia, and a Phase 3 trial in people with agitation due to Alzheimer’s. Both were terminated for business reasons.

In April 2022, a Phase 3 study, called Tranquility II, began in patients with acute agitation and AD. The 12-week study planned to enroll 151 participants from assisted living or residential care facilities. Participants must have a history of acute agitation and require assistance with daily activities. They were randomized to self-administer at least one and no more than 28 doses of 40 or 60 micrograms, or placebo, as episodes of agitation arose. The primary endpoint was change from baseline in PEC score two hours after the first dose. The study was completed in June 2023. On June 29, the company announced positive top-line results (press release). The same day, BioXcel disclosed that the FDA had found protocol violations at one site that enrolled 40 percent of the trial participants (SEC Form 8-K). An independent audit uncovered no indication of misconduct, fraud, or issues with data integrity, the company said (Oct 2023 press release).

According to a poster presented at October 2024 CTAD, the 60-microgram group met the primary endpoint, showing improvement from baseline in PEC compared to placebo. The difference was apparent by one hour and maintained out to the last assessment at four hours. Effects were consistent across secondary endpoints of additional agitation scales. In 12 weeks, 443 episodes of agitation were treated, and the reduction in PEC in subsequent episodes was similar to the first dose. All adverse events up to 24 hours were mild or moderate; they included sleepiness, low blood pressure, and slow heart rate. One fall within 24 hours of medication occurred in the placebo group. Three deaths in the study occurred more than one month after the last dose.

The company is planning a second Phase 3 trial to test the efficacy of 60 microgram dose in 150 AD patients residing in nursing facilities or assisted living memory care units (Apr 2024 press release).

BXCL501 is also being tested for acute stress disorder, alcohol use disorder with comorbid PTSD (Petrakis et al., 2025), opioid use disorder (Jones et al., 2023), and sleep enhancement (Schnider et al., 2024). BioXcel is conducting a trial of at-home treatment in people with schizophrenia or bipolar disorder.

For details on BXCL501 trials, see clinicaltrials.gov