BXCL501 seen to ease Alzheimer’s agitation in Phase 3 trial

Developer BioXcel to meet with FDA to discuss potential path to approval

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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On-demand treatment with BXCL501, an orally dissolving film formulation of dexmedetomidine, significantly eased episodes of agitation among Alzheimer’s disease patients in a Phase 3 clinical trial, according to topline results announced by the therapy’s developer, BioXcel Therapeutics.

“We believe these results represent a significant milestone for BioXcel Therapeutics and a potential important step forward in our goal to helping those impacted by Alzheimer’s disease,” Vimal Mehta, CEO of BioXcel, said in a company press release.

Robert Risinger, MD, chief medical officer of neuroscience at BioXcel, noted the therapy’s safety data were favorable, and said the company was “extremely pleased with the positive topline results of this trial in elderly patients with Alzheimer’s disease-related agitation.”

BioXcel is planning to meet with the U.S. Food and Drug Administration (FDA) later this year to discuss a potential path toward approval of BXCL501 for agitation in Alzheimer’s.

“We believe this body of evidence lays the foundation to potentially bring a differentiated acute agitation treatment option for patients with Alzheimer’s disease,” Risinger said.

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TRANQUILITY II trial finds BXCL501 safe, effective, well tolerated

Dexmedetomidine, the active agent in BXCL501, works to activate certain brain proteins, known as alpha-2a adrenergic receptors, which prompt sedative effects. Another oral film formulation of this drug, sold by BioXcel under the brand name Igalmi, has been approved in the U.S. since the late 1990s to treat agitation associated with schizophrenia or bipolar disorder.

Following positive data from a  Phase 1b/2 trial (NCT04251910), completed in January 2022, BioXcel launched a Phase 3 study called TRANQUILITY II (NCT05271552). It aimed to test the efficacy, safety, and tolerability of BXCL501 in people with agitation related to Alzheimer’s.

The TRANQUILITY II study specifically enrolled patients who have mild-to-moderate dementia and don’t require much assistance with day-to-day tasks. Another similar trial, TRANQUILITY III (NCT05665088), is testing the therapy in patients with more advanced dementia who need more day-to-day help. That study is still enrolling participants at several sites in the U.S.

A total of 149 people were enrolled in the TRANQUILITY II trial. Whenever these patients experienced an episode of agitation, they were given either BXCL501 — at doses of 40 or 60 micrograms (mcg) — or a placebo. Over the course of the three-month study, a total of 443 episodes of agitation were treated.

The study’s main goal was to assess how well the therapy eased agitation as measured by total scores on a standardized assessment called the Positive and Negative Syndrome Scale-Excitatory Component, or PEC. PEC scores range from 5 to 35, with higher scores indicating worse agitation.

The new results showed that, at two hours after dosing, the average PEC score for patients given the 60-mcg dose of BXCL501 was reduced significantly more than it was for those individuals on the placebo (7.5 vs. 5.4 points). This represented a 39% greater reduction with the therapy’s higher dose.

Improvements seen with the therapy’s lower dose were not significantly different from a placebo, with a finding of 5.7 points on average.

We believe that our data from TRANQUILITY II show that BXCL501 has the potential to treat acute episodes of agitation in patients with mild to moderate Alzheimer’s disease.

The higher BXCL501 dose also met one of the study’s key secondary goals — outperforming a placebo at reducing PEC scores one hour after dosing during the first agitation episode.

However, there was not a significant difference from the placebo at 30 minutes after dosing.

Among patients who had more than one agitation episode treated, the higher dose showed consistent effects for each episode in which it was used.

In physician-rated measures, more than three quarters of the patients (76%) given the higher BXCL501 dose were rated as “much improved” or “very much improved,” compared with half (50%) of those given the placebo.

“We believe that our data from TRANQUILITY II show that BXCL501 has the potential to treat acute episodes of agitation in patients with mild to moderate Alzheimer’s disease,” Mehta said.

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Safety data suggested that BXCL501 was generally well-tolerated, with no serious side effects reported.

“The favorable safety data, along with the consistent efficacy observed for the 60 mcg dose, underscores BXCL501’s potential in mitigating a condition that impacts millions of patients and their families annually,” Risinger said.

The observed safety profile of the experimental therapy overall was similar to that of Igalmi, which is known to cause side effects such as sleepiness, dry mouth, tingling or prickling sensations, dizziness, low blood pressure, and orthostatic hypotension — when blood pressure suddenly drops upon standing. There were no reports of falls or episodes of fainting due to BXCL501.

“I believe that the results from the TRANQUILITY II trial are an exciting development for potentially addressing Alzheimer’s disease-related agitation,” said George Grossberg, MD, a professor at St. Louis University School of Medicine.

“In this trial, BXCL501 showed a desirable onset of action and a meaningful reduction in agitation at 2 hours with the 60 mcg dose, and was well tolerated in this patient population. I believe it has potential to be a new treatment option for a condition that not only impacts patients but also caregivers and families,” added Grossberg, also the director of the division of geriatric psychiatry at the university.

In addition to announcing TRANQUILITY II’s topline data, BioXcel also provided an update on trial problems that were flagged in an inspection of one of the study sites, conducted by the FDA late last year. 

The agency’s inspection suggested that one of the trial investigators — who enrolled about 40% of the total participants — may not have adhered to all required protocols for documenting safety in the study. Specifically, trial investigators are required to inform BioXcel’s safety monitoring vendor of any serious safety-related issues within 24 hours of their occurrence.

BioXcel has now confirmed that the investigator failed to provide information for a serious event in the required timely fashion. The investigator then fabricated email correspondence to make it look like the information had been submitted on time.

The company additionally confirmed that, despite this issue, the event was appropriately recorded in the trial’s safety database — and once trial data were unblinded, it was determined that the event occurred in a patient in the placebo group.

BioXcel is now in the process of hiring an independent group to audit the trial results and ensure there were no further issues. The company noted that this process might delay its planned submission of an application seeking BXCL501’s approval, but said it expects the trial findings will still be usable for such an application once the audit is concluded.