Alzheimer Disease-Related Agitation: AXS-05 Reduces Risk for Symptom Relapse

Oral glutamate receptor antagonist dextromethorphan-bupropion (AXS-05) reduces the risk for relapse of agitation symptoms in patients with Alzheimer disease (AD), according to study results presented at the 2024 American Academy of Neurology (AAN) annual meeting, held from April 13 to 18, 2024, in Denver, Colorado.

Patients with AD are reported to have a high proportion of disease-related agitation symptoms. Researchers of a phase 3 double-blind multicenter, randomized-controlled trial (ACCORD; ClinicalTrials.gov Identifier: NCT04797715) evaluated the safety and efficacy of AXS-05 in AD-related agitation.

Study participants received AXS-05 in the 9-week open-label period, following which responders were randomly assigned to receive AXS-05 or placebo in the 26-week double-blind period.

Response to treatment was defined as at least a 30% improvement from baseline in scores on the Cohen Mansfield Agitation Inventory (CMAI) and the Patient Global Impression of Change (PGI-C) for 4 consecutive weeks or more.

Primary study endpoint was time from randomization to relapse of agitation symptoms; secondary endpoint was rate of agitation relapse. 

A total of 178 participants with AD were enrolled in the open-label phase, with a mean CMAI baseline total score of 70.9. Compared with placebo, treatment with AXS-05 showed statistically significant improvements in CMAI scores from week 1 to 5 (CMAI score, 6.7 to 20.6 points; P <.001 for both).

A total of 108 participants had a response to treatment with AXS-05, among whom 53 continued to receive AXS-05 and 55 received placebo in the double-blind period.

The researchers found that AXS-05 vs placebo had more than a 3.5-fold risk of delaying time to relapse of agitation symptoms (hazard ratio [HR], 0.276; P =.014). In addition, AXS-05 vs placebo improved rates of relapse (7.5% vs 25.9%, respectively; P =.018).

In terms of safety, adverse events (AEs) in the double-blind period were higher among participants who received placebo vs AXS-05 (22.2% vs 28.2%, respectively), with discontinuation due to AEs being 0% with AXS-05 and 1.9% with placebo. There was no evidence of cognitive decline or sedation with AXS-05.

“AXS-05 substantially reduced the risk of agitation symptom relapse in participants with AD and was generally well-tolerated in those who achieved sustained clinical response in the OL [open-label] period.”