FDA Approves Axsome's Auvelity for Agitation in Alzheimer's Dementia

The FDA has approved Axsome Therapeutics' Auvelity (dextromethorphan HBr and bupropion HCl) for the treatment of agitation associated with dementia due to Alzheimer's disease, the company said on April 30 in a release filed with the Securities and Exchange Commission.

Auvelity was first approved in 2022 for major depressive disorder in adults. Axsome said the supplemental application for Alzheimer's agitation was reviewed under Priority Review and that the drug had received breakthrough therapy designation for the indication. The label states that the drug should not be used as an "as needed" treatment for agitation.

Agitation is reported in up to 76% of patients with Alzheimer's disease and can range from pacing and restlessness to verbal and physical aggression, according to the company. Healio reported that the Alzheimer's Association described the decision as the first approval of a treatment for Alzheimer's agitation that is not an antipsychotic.

The Phase 3 trials

Axsome said the approval is supported by two Phase 3 studies. ADVANCE-1 was a five-week, double-blind trial that randomized patients to Auvelity, placebo or bupropion alone; the bupropion arm was stopped early for futility. Auvelity was statistically significantly superior to placebo on the primary endpoint, change in the Cohen-Mansfield Agitation Inventory total score at week 5, the company said. On the key secondary endpoint, a greater share of Auvelity patients were rated by clinicians as at least minimally improved on the modified ADCS Clinical Global Impression of Change.

ACCORD-2 was a randomized withdrawal trial in which patients who had responded to Auvelity were assigned for up to six months to keep taking it or switch to placebo. Those who continued had a statistically significantly longer time to relapse of agitation symptoms, Axsome said. The company did not give effect sizes or patient numbers in its approval announcement.

"Treatment for agitation associated with Alzheimer's disease dementia has been a critical unmet medical need," said Jeffrey Cummings of the UNLV Kirk Kerkorian School of Medicine, in the company's release.

Safety and mechanism

In ADVANCE-1, the most common adverse reactions were dizziness and dyspepsia, and 1.3% of patients stopped Auvelity because of an adverse event, the same rate as placebo, according to Axsome. The drug's label carries a warning that antidepressants may increase suicidal thoughts and actions in children, adolescents and young adults.

The dextromethorphan component acts on the NMDA receptor and the sigma-1 receptor in the brain, while bupropion raises blood levels of dextromethorphan by inhibiting the liver enzyme CYP2D6, the company said. Axsome added that the exact mechanism of action in Alzheimer's agitation is unclear. The company said a patient support program will be available at launch.