The agent will be evaluated in 2 pivotal trials of 225 patients requiring varying levels of assistance with daily living activities.
AGITATION IS AMONG THE most common symptoms reported by the more than 6 million Americans impacted by Alzheimer disease (AD). Drug development, however, has focused on reversing the cause of the disease, leaving few therapies to treat less-pronounced symptoms like agitation.
The investigational BXCL501 (Igalmi; BioXcel Therapeutics, Inc) is an orally dissolving thin-film formulation of dexmedetomidine that received FDA approval in April 2022 for agitation associated with schizophrenia and bipolar I or II disorder.1 It will now be assessed in a phase 3 program for AD-related agitation.
This program, called TRANQUILITY, consists of 2 randomized, placebo-controlled, adaptive, parallel group pivotal trials—TRANQUILITY II (NCT05271552) and TRANQUILITY III (NCT05276830)—that will enroll 150 and 75 patients with dementia 65 years and older, respectively. BXCL501 will be self-administered in doses of 40 mcg or 60 mcg during a 3-month period. Patients will be randomized to study drug or placebo and will be assessed on changes in agitation based on the Positive and Negative Syndrome Scale, Excitatory Component (PEC) and Pittsburgh Agitation Scale (PAS) total scores (TABLE).2
TRANQUILITY II will enroll those in assisted living or residential facilities requiring minimal assistance with activities of daily living (the first patient was dosed in May 2022),3 whereas TRANQUILITY III will include patients in nursing homes with moderate to severe dementia requiring moderate or greater assistance with activities of daily living.
Robert Risinger, MD, chief medical officer of BioXcel Therapeutics, said in a statement3 that it is “expanding TRANQUILITY II to more than 10 clinical trial sites in the US and [that] with no current FDA-approved treatments for agitation associated with this disease, we are making strong and swift efforts to potentially bring BXCL501 and its proven ability to address agitation to this large market.”
The primary efficacy end point for both studies will be change in PEC score from baseline at 2 hours after the initial dose and subsequent doses. The PEC rating evaluates 5 elements associated with agitation: poor impulse control, tension, hostility, uncooperativeness, and excitement. Those who complete either study will be eligible to enter an open-label extension, in which investigators will assess efficacy and safety of the study drug during a 52-week period.
BXCL501 was granted breakthrough therapy designation by the FDA based on data from the phase 1b/2 TRANQUILITY ascending-dose finding study (NCT04251910). That trial included 54 patients in assisted living facilities with agitation related to dementia, 87% of whom had AD. The participants were treated with either BXCL501 30 mcg (n = 16), 60 mcg (n = 20), 90 mcg (n = 4), or placebo (n = 14).
The study’s primary end points were met, with no severe or serious adverse events (AEs) reported. The AEs observed included hypotension (60 mcg, 10%; 30 mcg and placebo, 0%), orthostatic hypotension (60 mcg, 5%; 30 mcg, 6.3%; placebo, 0%), and dizziness (60 mcg, 5%; 30 mcg, 6.3%; and placebo, 0%). Higher exposure levels of BXCL501 were observed in the older patient population compared with earlier trials, so the company focused on studying the 30- and 60-mcg doses.4
The group receiving BXCL501 60 mcg met the secondary efficacy end points on all 3 primary agitation scales—PEC, PAS, and the Modified Cohen-Mansfield Agitation Inventory—demonstrating statistically significant and clinically meaningful reductions in total scores at 2 hours post dosing. Investigators observed the rapid and sustained reductions in PEC total as early as 30 minutes following dosing and in both PEC and PAS total scores at 60 minutes, lasting through 8 hours post dosing.
The FDA’s decision to approve the medication for agitation associated with schizophrenia or bipolar I or II disorder in adults was based on data from 2 pivotal randomized, double-blind, placebo-controlled parallel group phase 3 trials—SERENITY I (NCT04268303) and SERENITY 2 (NCT04276883)—that evaluated the drug for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder, respectively.
In both trials, BXCL501 in 120-mcg and 180-mcg doses met its primary end point in change from baseline in PEC total score assessed at 2 hours. The mean changes from baseline in PEC total score were –10.4 (SD, 4.4) for sublingual BXCL501 180 mcg and –9.0 (SD, 5.3) for 120 mcg compared with –4.9 (SD, 4.7) for placebo. On the key secondary end point, statistically significant treatment effects were evident 20 minutes after initial treatment for both doses (180 mcg, P = .007; 120 mcg, P = .009) compared with placebo.5 The company said it expects to launch BXCL501 the second quarter of 2022.1