Norepinephrine Reuptake Inhibitor Treatment Significantly Reduced Cataplexy Attacks in People with Narcolepsy Type 1

Treatment with AXS-12 (reboxetine; Axsome, New York, NY), a highly selective norepinephrine reuptake inhibitor (NRI) and cortical dopamine modulator, was associated with significant reductions in cataplexy attacks in people with narcolepsy type 1 (NT1), according to results from the phase 3 SYMPHONY trial (NCT05059223) presented at the American Academy of Neurology (AAN) 2025 Annual Meeting. Participants taking AXS-12 also showed improvements in excessive daytime sleepiness (EDS) and cognitive function without experiencing any serious adverse events, suggesting AXS-12's potential as a safe and effective treatment for multiple NT1 symptoms.

The multicenter, double-blind, placebo-controlled trial included 90 patients aged 15 to 75 years with NT1, who were randomized 1:1 to receive treatment with either AXS-12 or placebo for 5 weeks. Approximately 30% of participants in both groups continued stable concurrent Provigil (modafinil; Apotex, Toronto, Canada) or Nuvigil (armodafinil; Apotex, Toronto, Canada). The primary end point was the ratio of weekly cataplexy attacks at week 5 compared with baseline (a mean 27.7 weekly attacks in the AXS-12 group and 35.4 in the placebo group). Secondary end points included EDS, inadvertent naps, and cognitive function.

Key findings at week 5:

• An 83% reduction in cataplexy attacks in the AXS-12 group compared with 66% for placebo (rate ratio, .49; P=.018), with results seen in the first week (56% vs. 31%; ratio rate=.65; nominal P=.007).
• Complete cataplexy remission occurred in 33% of AXS-12-treated patients versus 9.5% in those who took placebo (nominal P=.008), with significantly more cataplexy-free days (84.5% vs. 22.6%; nominal P=.014).
• EDS improvement, measured on the Clinical Global Impression-Severity (CGI-S) scale, was also better for patients taking AXS-12 (-1.8 vs. -0.9; nominal P=.027).
• 54% of patients taking AXS-12 reported fewer inadvertent naps versus 28% for placebo (nominal P=.016).
• AXS-12-treated patients showed greater improvement on the Functional Outcomes of Sleep Questionnaire-10 (FOSQ-10) compared to placebo (1.6 vs. 0.7 points; nominal P=.004).

Source: Thorpy M, Krahn L, Bogan R, et al. AXS-12 for the treatment of narcolepsy: topline results from the phase 3 SYMPHONY trial. Presented at: American Academy of Neurology Annual Meeting; April 5–9, 2025; San Diego, CA.