AXS-05 delays relapse of Alzheimer's disease agitation

Treatment with AXS-05 significantly delayed the time to relapse of agitation in patients with Alzheimer’s disease (AD) compared with placebo, according to the phase III ACCORD-2 trial presented at AAN 2025.

AXS-05, also known as dextromethorphan-bupropion, was approved by the US FDA for the treatment of major depressive disorder in adults, said Dr George Grossberg from Saint Louis University School of Medicine, Missouri, US, who presented the study.

AXS-05, an oral N-methyl-D-aspartate receptor antagonist, sigma-1 receptor agonist, and aminoketone CYP2D6 inhibitor, is being investigated for the treatment of AD agitation and has been granted Breakthrough Therapy Designation by the FDA, he noted.

To assess the efficacy and safety of AXS-05, the researchers conducted a multicentre, double-blind, placebo-controlled, withdrawal study involving 295 patients aged 65–90 years with AD-related agitation. In the open-label period, all participants were initially treated with AXS-05 for ≥8 weeks during the open-label period, of whom 167 patients achieved a sustained clinical response and were randomized to either continue AXS-05 (n=83) or switch to placebo (n=84) for up to a 26-week double-blind period. Baseline mean CMAI* total scores were 44.3 and 45.4, respectively. [Grossberg, et al, AAN 2025]

During the double-blind period, patients receiving AXS-05 demonstrated a significant delay in the time to relapse of AD agitation as compared with placebo (hazard ratio [HR], 0.276; p=0.001), indicating a 3.6-fold lower risk observed with AXS-05.

Moreover, only 8.4 percent of patients in the AXS-05 group experienced an agitation relapse, while 28.6 percent were reported in the placebo group (p=0.001).

AXS-05-treated patients also achieved a significantly reduced worsening of AD agitation, as shown by CGI-S** score (20.5 percent vs 41.7 percent; p=0.004), than placebo-treated patients.

Taken together, the ACCORD-2 trial met its primary and key secondary endpoints by substantially and statistically significantly delaying the time to relapse of AD agitation and preventing relapse and worsening of AD agitation, said Grossberg.

In terms of safety, the incidence of treatment-emergent adverse events (TEAEs) was lower in the AXS-05 group than in the placebo group (29.3 percent vs 32.1 percent), with no serious TEAEs or treatment discontinuation observed with AXS-05.

Notably, AXS-05 treatment was not associated with sedation or cognitive decline, Grossberg noted.

No deaths were reported in either treatment group.

“Overall, these results support the use of AXS-05 as a safe and effective treatment for AD agitation, building on data from previous positive phase II/III studies,” said Grossberg.

“If approved, AXS-05 would be a new therapy with a novel mechanism of action for the treatment of AD agitation,” he added.