SAN DIEGO — New data confirmed the safety and efficacy of AXS-05, a combination of dextromethorphan and bupropion, for the treatment of agitation associated with Alzheimer’s disease (AD).
In the phase 3 ACCORD-2 study, AXS-05 (Axsome Therapeutics) met the primary and key secondary endpoints by statistically significantly delaying and preventing AD agitation relapse compared with placebo and was generally well tolerated.
Overall, the data “build on the previous positive phase 2/3 studies and support the use of AXS-05 as a safe and effective treatment for Alzheimer’s disease agitation,” George Grossberg, MD, Saint Louis University School of Medicine, St. Louis, said at a press briefing announcing the results.
Grossberg presented the late-breaking findings from ACCORD-2 on April 7 at the American Academy of Neurology (AAN) 2025 Annual Meeting.
A Common Problem, Significant Consequences
Agitation is reported in up to 70% of patients with AD and is characterized by emotional distress, aggressive behaviors, disruptive irritability, and disinhibition.
AD-related agitation has been associated with increased caregiver burden, decreased functioning, accelerated cognitive decline, earlier nursing home placement, and increased mortality.
AXS-05, a combination of dextromethorphan and bupropion, is approved by the US Food and Drug Administration (FDA) for major depression and has received breakthrough therapy designation for AD agitation due to its novel mechanism of action.
Dextromethorphan is an N-methyl-D-aspartate receptor antagonist and sigma 1 receptor agonist, while bupropion functions as CYP2D6 inhibitor.
The ACCORD-2 trial was a randomized withdrawal study, “which simulates a lot of what happens in clinical practice, where patients are put on a medication, they start doing better, and then they decide they don’t need this medicine anymore. And of course, they begin to relapse,” said Grossberg.
The trial included 167 adults aged 65-90 years with a clinical diagnosis of probable AD and clinically significant agitation, who responded to 8 weeks of treatment with AXS-05; 83 were randomly assigned to continue the drug and 84 to switch to placebo for up to 24 weeks.
ACCORD-2 met its primary endpoint with AXS-05 significantly delaying the time to agitation relapse compared with placebo (hazard ratio, 0.276). “The risk of relapse was about 3.6-fold less with AXS-05 compared with placebo,” Grossberg reported.
Agitation relapse was defined as a 10-point or greater increase (worsening) on the Cohen-Mansfield Agitation Inventory (CMAI) for 2 consecutive weeks, or the CMAI total score at assessment was greater than baseline for 2 consecutive weeks, or hospitalization for worsening agitation.
AXS-05 also met the key secondary endpoints of relapse prevention and decreased worsening of AD agitation.
New Drug Application (NDA) On the Way
Only about 8% of those taking AXS-05 had a relapse vs 29% of those taking placebo (P = .001). Worsening of agitation symptoms occurred in 42% of patients taking placebo vs 21% of those on AXS-05 (P = .004).
Importantly, said Grossberg, AXS-05 demonstrated a favorable safety profile, vital for treating on older, vulnerable population.
No new safety signals emerged. Falls were reported in two patients taking AXS-05, with only one deemed related to the study medication. Dizziness was reported in one patient taking AXS-05. The drug was not associated with sedation or cognitive decline. No deaths occurred in either group.
The safety and efficacy findings from ACCORD-2 are in line with earlier phase 2/3 trials of AXS-05 for AD agitation.
Axsome Therapeutics plans to submit a supplemental NDA for AXS-05 for AD agitation in the third quarter of 2025.
“If approved, it would be a new therapy with a novel mechanism of action for the treatment of Alzheimer’s disease agitation,” Grossberg said.
The FDA approved the antipsychotic brexpiprazole (Rexulti, Otsuka and Lundbeck) for agitation AD in 2023, making it the first FDA-approved drug for this indication.
An Important Part of Care
Reached for comment, Heather M. Snyder, PhD, senior vice president of Medical and Scientific Relations, Alzheimer’s Association, Chicago, said, individuals with moderate to severe AD and other forms of dementia require, and are entitled to, care that enhances their quality of life, including access to effective treatments for the behavioral and psychiatric symptoms linked to these conditions.
“Effective strategies to treat [agitation] symptoms are an important aspect of care and care planning for overall highest possible quality of life for the individual with dementia, as well as the person(s) providing care,” Snyder told Medscape Medical News.
“The Alzheimer’s Association is a strong proponent of nondrug approaches as a first line of defense to address the behavioral symptoms of Alzheimer’s. However, for some individuals, symptoms do not respond to nondrug approaches, so it is important to have multiple treatment choices in order to find the best approach for each individual,” Snyder added.
She noted that since 2004, the Alzheimer’s Association has funded 18 projects related to agitation in AD and other dementias, with nearly $3 million in support. Additional guidance on recognizing and managing agitation is available on the Alzheimer’s Association website.
The study was funded by Axsome Therapeutics. Grossberg provided consultation to Acadia, Alkahest, Avanir, Axovant, Axsome Therapeutics, Biogen, BioXcel, Genentech, Karuna, Lundbeck, Otsuka, Roche, and Takeda. Snyder had no relevant disclosures.
