Phase 2/3 Trial of AXS-05 for Alzheimer’s Agitation Enrolls First Patient

Axsome Therapeutics has announced that the first patient was enrolled in the ADVANCE-1 Phase 2/3 trial evaluating the effectiveness and safety of its investigative therapy AXS-05 for the treatment of agitation in Alzheimer’s disease patients.

Agitation is related to anxiety and is reported by nearly 50 percent of Alzheimer’s patients. It’s frequently used as an umbrella term to refer to feelings of restlessness, emotional distress, aggressive behaviors, disruptive irritability, and loss of social awareness.

“Agitation is one of the most distressing and difficult-to-treat behavioral symptoms in patients with Alzheimer’s disease. It is common, being reported in about half of patients, is one of the primary reasons for early nursing home placement, and is associated with increased mortality,” Jeffrey Cummings, MD, director of the Center for Neurodegeneration and Translational Neuroscience at the Cleveland Clinic Lerner College of Medicine, said in a press release.

AXS-05 is a drug that combines dextromethorphan and bupropion that’s being developed for the treatment of central nervous system (CNS) disorders such as Alzheimer’s agitation and treatment-resistant depression (TRD).

Dextromethorphan is an NMDA (N-methyl-d-aspartate) receptor antagonist, sigma-1 receptor agonist, and serotonin and norepinephrine reuptake inhibitor.

Bupropion is a norepinephrine and dopamine reuptake inhibitor, and a nicotinic acetylcholine receptor antagonist used to increase the bioavailability of dextromethorphan.

“NMDA receptor antagonism, sigma-1 receptor agonism, and serotonin and norepinephrine reuptake inhibition may be relevant mechanisms in this condition. New treatments are needed for agitation and progress in this area is a welcome advance,” Cummings said.

The Phase 2/3 clinical study will evaluate the effectiveness of AXS-05 in agitation using the Cohen-Mansfield Agitation Inventory (CMAI) as its primary efficacy measure.

CMAI is a 29-item scale to systematically assess agitation. It is used to measure the frequency with which they manifest physically aggressive, physically non-aggressive, and verbally agitated behaviors.

For the trial, 435 patients will be randomized in a 1:1:1 ratio to receive AXS-05, bupropion, or a placebo for five weeks.

“Agitation places a heavy burden on patients with Alzheimer’s disease and their caregivers,” said Marc Agronin, MD, vice president of Behavioral Health and Clinical Research at Miami Jewish Health.

“Unfortunately there is currently no FDA-approved medication for this condition,” he said. “The mechanisms of action of AXS-05 may hold promise in treating Alzheimer’s agitation. We look forward to learning more about AXS-05 and its potential to relieve the symptoms of agitation through the ADVANCE-1 trial.”

The U.S. Food and Drug Administration (FDA) granted AXS-05 fast track status after its investigational new drug application (IND) was cleared by the agency earlier this year.