AXS-12 for Narcolepsy Effective in Reducing Cataplexy Attacks in Phase 3 Trial

The experimental treatment, AXS-12 (reboxetine), compared with placebo, significantly reduces the number of weekly cataplexy attacks and additional symptoms of narcolepsy, according to study results presented at the 2025 American Academy of Neurology (AAN) annual meeting, held from April 5 to 9, 2025, in San Diego, California.

Narcolepsy is a chronic neurologic disorder that interferes with the brain’s ability to regulate the body’s sleep-wake cycle. Hallmark features of narcolepsy include sudden, brief losses of muscle tone (cataplexy), excessive daytime sleepiness, and cognitive impairments.

AXS-12, a potent, highly-selective, norepinephrine reuptake inhibitor and cortical dopamine modulator produced by Axsome Therapeutics, is currently under investigation as a potential treatment for narcolepsy.

Researchers from the United States and Canada conducted a randomized, phase 3, placebo-controlled clinical trial (SYMPHONY; ClinicalTrials.gov Identifier: NCT05059223) to investigate the efficacy and safety of the experimental drug, AXS-12, in 90 participants between the ages of 15 and 75 years diagnosed with cataplexy. Of these 90 participants, 32.6% in the AXS-12 intervention group and 29.5% in the placebo group took concurrent modafinil/armodafinil.

To evaluate efficacy, the researchers calculated the ratio of weekly cataplexy attacks compared to baseline over a period of 5 weeks. They also assessed changes in excessive daytime sleepiness using the Clinical Global Impression-Severity (CGI-S) outcome measure, inadvertent naps using the Narcolepsy Symptom Assessment Questionnaire (NSAQ), and cognitive function items, such as concentration and memory, using the Functional Outcomes of Sleep Questionnaire-10.

At week 1, AXS-12 reduced cataplexy attacks by 56% compared to 31% in the placebo group (rate ratio=.65; nominal P =.007). At week 5, AXS-12 reduced cataplexy attacks by 83% compared to 66% in the placebo group (rate ratio=.49; P =.018). After 5 weeks, 33% of individuals in the interventional group experienced complete remission from cataplexy attacks compared to only 9.5% in the placebo group (nominal P =.008).

Correspondingly, when compared to the placebo group, those in the AXS-12 intervention group reported decreased excessive daytime sleepiness on the CGI-S (-1.8 vs -0.9; nominal P =.027), fewer inadvertent naps on the NASQ (54% vs 28%; nominal P =.016), and improved concentration and memory on the Functional Outcomes of Sleep Questionnaire-10 (1.6 vs 0.7 points; nominal P =.004) after 5 weeks of treatment.

To evaluate the safety of AXS-12, the researchers analyzed the occurrence of serious adverse events related to the treatment. No serious adverse events were reported; however, more common treatment-emergent adverse events that were mild to moderate in nature included dry mouth, nausea, and constipation.

“AXS-12 met its primary endpoint, leading to a substantial, statistically significant reduction in weekly cataplexy attacks…[and] improvements in [excessive daytime sleepiness] and cognition…,” the researchers stated. “AXS-12 may offer effective treatment for multiple narcolepsy symptoms with a favorable safety profile.”