Axsome AXS-12 Achieves Primary Endpoint in Phase 3 Trial in Narcolepsy

Rare Daily Staff

Axsome Therapeutics said AXS-12 achieved the primary endpoint and significantly reduced the frequency of cataplexy attacks as compared to placebo in patients with narcolepsy in the SYMPHONY phase 3 trial.

Narcolepsy is a serious and debilitating orphan neurological condition that causes dysregulation of the sleep-wake cycle and is characterized clinically by excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, sleep paralysis, and disrupted nocturnal sleep. Cataplexy is seen in an estimated 70 percent of narcolepsy patients and is a sudden reduction or loss of muscle tone while a patient is awake, typically triggered by strong emotions such as laughter, fear, anger, stress, or excitement. Narcolepsy interferes with cognitive, psychological, and social functioning, increases the risk of work- and driving-related accidents, and is associated with a 1.5-fold higher mortality rate.

AXS-12 (reboxetine), a highly selective and potent norepinephrine reuptake inhibitor and cortical dopamine modulator, also reduced excessive daytime sleepiness severity, improved cognitive function, and reduced overall narcolepsy severity as compared to placebo.

SYMPHONY was a phase 3 multicenter, randomized, double-blind, placebo-controlled trial in which 90 patients with a diagnosis of narcolepsy with cataplexy were randomized to treatment with AXS-12 or placebo for 5 weeks.

AXS-12 met the primary endpoint by demonstrating a substantial and statistically significant reduction from baseline in weekly cataplexy attacks compared to placebo at Week 5, with reductions of 83 percent for AXS-12 and 66 percent for placebo. AXS-12 rapidly reduced weekly cataplexy attacks, demonstrating at Week 1 a reduction of 56 percent compared to a reduction of 31percent for placebo.

AXS-12 induced remission of cataplexy and increased cataplexy-free days compared to placebo. Remission of cataplexy, defined as a 100 percent reduction from baseline, was achieved at Week 5 by 33 percent of AXS-12 treated patients compared to 9.5 percent of placebo patients. AXS-12 increased the percentage of cataplexy-free days per week, defined as days with zero cataplexy attacks, to 84.5 percent at Week 5 compared to 22.6 percent for placebo.

AXS-12 significantly reduced excessive daytime sleepiness (EDS) severity, assessed by the Clinician Global Impression of Severity (CGI-S) scale for EDS, compared to placebo at Week 5 with mean reductions of 1.8 points for AXS-12 compared to 0.9 points for placebo. Rapid improvement on the CGI-S for EDS was seen as early as Week 1 compared to placebo. AXS-12 concurrently improved EDS and cataplexy as compared to placebo. Concurrent EDS and cataplexy response was achieved at Week 5 by 57 percent of patients treated with AXS-12 compared to 33 percent of placebo patients. Concurrent EDS and cataplexy response was defined as a ≥30 percent reduction in inadvertent naps (EDS response), and a ≥50 percent reduction in cataplexy attacks (cataplexy response).

AXS-12 also statistically significantly improved concentration and memory compared to placebo and statistically significantly improved overall function and quality of life compared to placebo.

AXS-12 was well tolerated in the trial. The most commonly reported adverse events in the AXS-12 arm were dry mouth, nausea, and constipation, which were overall mild to moderate. The rates of discontinuation due to adverse events was low. There were no serious adverse events in the trial.

“The SYMPHONY phase 3 trial results confirm the promise and potential of AXS-12 for the treatment of narcolepsy,” said Herriot Tabuteau, CEO of Axsome Therapeutics. “Treatment with AXS-12 resulted in rapid and substantial reduction of cataplexy events, the primary endpoint of the SYMPHONY trial, while evidencing improvement across a range of validated global clinical, patient-reported, quality of life, and functional outcome measures.”

Axsome plans to present the detailed results of the SYMPHONY trial at upcoming scientific meetings. AXS-12 was granted Orphan Drug designation for the treatment of narcolepsy in October 2018

Photo: Herriot Tabuteau, CEO of Axsome Therapeutics