Axsome’s AXS-12 NDA for Narcolepsy Cataplexy Accepted by FDA

The U.S. Food and Drug Administration has accepted Axsome Therapeutics’ New Drug Application for AXS-12 (reboxetine) for the treatment of cataplexy in patients with narcolepsy. The agency assigned a Prescription Drug User Fee Act (PDUFA) target action date of May 1, 2027, and indicated that it does not currently plan to convene an advisory committee meeting to review the application.

If approved, AXS-12 could provide a new treatment option for cataplexy, a disabling symptom of narcolepsy that remains difficult to manage for many patients despite available therapies.

Scientific and Clinical Context

Narcolepsy is a chronic neurological disorder characterized by impaired regulation of the sleep-wake cycle. Patients commonly experience excessive daytime sleepiness, disrupted nighttime sleep, sleep paralysis, hypnagogic hallucinations, and cataplexy.

Cataplexy affects an estimated 70% of people with narcolepsy and causes sudden episodes of muscle weakness or loss of muscle tone while patients remain conscious. These attacks are often triggered by strong emotions such as laughter, excitement, fear, or anger and can significantly impair daily functioning. The disorder is also associated with an increased risk of workplace and driving accidents and a higher long-term mortality rate than the general population.

Phase III SYMPHONY Trial Supports NDA Submission

The NDA is supported by positive results from the Phase III SYMPHONY trial (NCT05059223), a randomized, double-blind, placebo-controlled study that evaluated AXS-12 in 90 patients with narcolepsy.

The trial met its primary endpoint, demonstrating a rapid and statistically significant reduction in weekly cataplexy attacks compared with placebo. By Week 5, patients treated with AXS-12 achieved an 83% reduction in weekly cataplexy attacks from baseline, compared with a 66% reduction in the placebo group.

Treatment with AXS-12 also resulted in higher rates of complete symptom control. Approximately 33% of treated patients achieved complete remission of cataplexy, compared with 9.5% of patients receiving placebo.

Beyond reducing cataplexy attacks, AXS-12 significantly improved excessive daytime sleepiness, concentration, memory, and depressive symptoms in patients with co-existing depression, highlighting its potential to address multiple clinical manifestations of narcolepsy.

The therapy was generally well tolerated throughout the study. The most frequently reported adverse events were dry mouth, nausea, and constipation, with most events classified as mild to moderate in severity.

AXS-12 Targets Key Pathways Underlying Narcolepsy

AXS-12 is an investigational oral formulation of reboxetine, a highly selective norepinephrine reuptake inhibitor (NRI) and cortical dopamine modulator. The therapy increases extracellular norepinephrine by inhibiting the norepinephrine transporter, helping preserve muscle tone during wakefulness while enhancing cortical dopaminergic signaling that supports alertness and cognitive function.

The FDA has granted Orphan Drug Designation to AXS-12 for the treatment of narcolepsy, making the therapy eligible for regulatory incentives, including seven years of U.S. market exclusivity if approved.

Strategic Significance

FDA acceptance of the NDA advances AXS-12 toward becoming a potential new treatment for cataplexy in narcolepsy and reflects the strength of the clinical evidence generated in the Phase III SYMPHONY program. The application also reinforces Axsome Therapeutics’ strategy of expanding its portfolio of innovative therapies for central nervous system disorders with treatments that address significant unmet medical needs.

Path Forward

The FDA is expected to complete its review of the NDA by May 1, 2027. If approved, AXS-12 would expand the treatment options available for patients with narcolepsy-associated cataplexy and further strengthen Axsome Therapeutics’ commercial CNS portfolio, which includes Auvelity® for major depressive disorder and Sunosi® for excessive daytime sleepiness associated with narcolepsy and obstructive sleep apnea

Reference

Axsome Therapeutics Announces FDA Acceptance of New Drug Application for AXS-12 for the Treatment of Cataplexy in Narcolepsy | Axsome Therapeutics, Inc.