Potential Agitation Treatment, AXS-05, Shows Efficacy and Safety in Phase 2/3 Trial

Axsome Therapeutics‘ investigational oral therapy AXS-05 significantly and rapidly lessened agitation in patients with Alzheimer’s disease, top-line results from a Phase 2/3 trial show.

The therapy also was found to be generally well-tolerated and safe, without affecting cognition.

“I am very pleased to see the promising results of the ADVANCE-1 trial, providing clear evidence of reduced agitation in Alzheimer’s disease by this investigational medicine,” Jeffrey Cummings, MD, ScD, director emeritus of the Cleveland Clinic Lou Ruvo Center for Brain Health, and Chambers professor of brain science at the University of Nevada Las Vegas, said in a press release.

AXS-05 aims to treat agitation — an umbrella term that refers to feelings of restlessness, emotional distress, aggression, irritability, and a loss of social awareness — in people with Alzheimer’s. Currently, no treatments are approved for this frequent disease complication. 

“Agitation occurs in the majority of patients with Alzheimer’s disease, is very distressing to patients and their families, and is associated with greater risk of institutionalization and accelerated progression to severe dementia and death,” Cummings said. “Given the lack of approved treatments … and the safety concerns and modest or uncertain efficacy of currently used off-label treatments, the AXS-05 study results represent a meaningful step forward.” 

AXS-05 has two main active components, dextromethorphan and bupropion. Dextromethorphan works by modulating the activity of neurotransmitters (chemicals used to send signals between nerve cells), including glutamate, serotonin, and norepinephrine, which have been linked to cognitive and behavioral changes in people with Alzheimer’s disease. 

Bupropion complements the action of dextromethorphan by stabilizing it, so it can be more effective. It also increases the availability of dopamine and norepinephrine, and acts on another neurotransmitter called acetylcholine, which is also thought to be involved in agitation.

The ADVANCE-1 Phase 2/3 trial (NCT03226522) was a double-blind and multicenter U.S. study in 366 patients diagnosed with probable Alzheimer’s disease and related agitation, ages 69 to 90. The study’s primary endpoint, or goal, was to evaluate the efficacy and safety of AXS-05 in this patient group.

It concluded a few months earlier than planned to ensure the safety of study participants during the COVID-19 pandemic.

Patients were randomly allocated to either AXS-05 (159 patients), bupropion only (49 patients), or placebo (158 patients) tablets for five weeks.

Escalating doses of AXS-05 (dextromethorphan/bupropion at 30 mg/105 mg once daily, rising at week three to 45 mg/105 mg twice daily) or bupropion (105 mg once daily, rising to 105 mg twice daily at week three) were given.

Agitation severity was assessed using the Cohen-Mansfield Agitation Inventory (CMAI), the study’s primary effectiveness measure. This 29-item scale assesses the frequency with which patients manifest physically aggressive, physically non-aggressive, and verbally agitated behaviors. The higher the score, the greater the level of agitation.

Participants’ CMAI scores at the study’s start (baseline) were 60.8 in the AXS-05 group, 66.1 in the bupropion group, and 59.3 in the placebo group. After two weeks of treatment, a drop of 11.5 points in the CMAI score was observed in the AXS-05 group, compared to an 8.7-point reduction in the placebo group. However, at this point, the difference was not statistically significant.

After three weeks of treatment, patients in the AXS-05 group had a mean CMAI total score reduction of 13.8 points compared to 9.7 points for placebo, which reached statistical significance.

Patients in the bupropion group showed a similar response to those on placebo up to week three of the trial, according to results presented in an Axsome conference call.

At week five, patients in the AXS-05 group showed a statistically significant 48% reduction in their CMAI score (corresponding to 15.4 points) compared to baseline, while those in the placebo group had a drop of 38% (corresponding to 11.5 points). Scores in the bupropion group patients were 10.0 points lower compared to the beginning of the study.

“We are excited by the rapid and substantial effect of AXS-05 on agitation in patients with Alzheimer’s disease observed in this trial,” said Herriot Tabuteau, MD, CEO of Axsome.

“With the ADVANCE-1 trial, AXS-05 has now demonstrated efficacy in Alzheimer’s disease agitation, depression, and smoking cessation trials. Additionally, AXS-05 has shown a rapid onset of action in both Alzheimer’s disease agitation and depression against both active [bupropion] and placebo comparators,” said Cedric O’Gorman, MD, senior vice president of clinical development and medical affairs at Axsome.

Importantly, 73% of patients who received AXS-05 achieved a clinical response defined as a 30% or greater improvement in their initial CMAI score. This was statistically significantly higher than the 57% of participants who achieved a clinical response in the placebo group.

AXS-05 was also superior to placebo in lessening agitation as measured by the Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change for Agitation — a clinician’s global assessment of agitation.

No evidence of cognitive decline was observed in patients treated with AXS-05, as assessed by the Mini-Mental State Examination — a measure of general cognitive function.

The most common adverse events reported by patients taking AXS-05 were somnolence, dizziness, and diarrhea. However, AXS-05 was not associated with sedation.

In the AXS-05 and placebo groups, 1.3% of patients decided to stop the trial due to adverse events. The same reason for discontinuing the trial was reported by 2.0% of people in the bupropion group.

No serious side effects were deemed to be related to the therapy in any of the trial’s treatment groups. 

“The positive ADVANCE-1 Phase 2/3 trial represents a potentially important milestone for Alzheimer’s disease patients, their caregivers, and physicians, particularly given the lack of approved treatments for, and the serious and distressing nature of, Alzheimer’s disease agitation. We look forward to discussing these data with the FDA,” Tabuteau said.

More  study details will be presented at medical meetings and in future scientific journal publications.

AXS-05 was granted fast track designation by the U.S. Food and Drug Administration (FDA) in 2017.  This designation is meant to speed the development and potential approval of medications that meet serious unmet medical needs.