AXS-12 for the Treatment of Narcolepsy: Topline Results from the Phase 3 SYMPHONY Trial
Michael Thorpy1, Lois Krahn2, Richard Bogan3, Bruce Corser4, Colin Shapiro5, Angad Chhabra6, Eileen Leary6, Herriot Tabuteau6
1Montefiore Medical Center, 2Department of Psychiatry and Psychology, Mayo Clinic College of Medicine, 3SleepMed, 4Intrepid Research, 5Department of Psychiatry; Sleep and Alertness Clinic & Sleep Research Laboratory, Toronto Western Hospital, University of Toronto, 6Axsome Therapeutics, Inc.
Objective:
SYMPHONY, a Phase 3, randomized, double-blind, placebo-controlled trial, assessed the efficacy and safety of AXS-12 (reboxetine) in narcolepsy type 1 (NT1).
Background:
Narcolepsy is characterized by excessive daytime sleepiness (EDS), cataplexy (NT1), and accompanied by cognitive impairment. AXS-12, a potent, highly-selective norepinephrine reuptake inhibitor and cortical dopamine modulator, is under development for narcolepsy.
Design/Methods:
Patients (15-75 years) with NT1 were randomized 1:1 to AXS-12 or placebo for 5 weeks. Stable concurrent modafinil/armodafinil use was allowed. The primary endpoint was the ratio of weekly cataplexy attacks (Week 5/Baseline). Secondary endpoints included EDS (Clinical Global Impression-Severity [CGI-S]), inadvertent naps (Narcolepsy Symptom Assessment Questionnaire [NSAQ]), and Cognitive Function items of Functional Outcomes of Sleep Questionnaire-10.
Results:
Ninety patients were randomized; 32.6% (AXS-12) and 29.5% (placebo) took concurrent modafinil/armodafinil. Baseline mean weekly cataplexy attacks were 27.7 (AXS-12) and 35.4 (placebo). AXS-12 reduced attacks by 83% vs 66% with placebo at Week 5 (rate ratio=0.49; p=0.018). At Week 1, reductions were 56% (AXS-12) vs 31% (rate ratio=0.65; nominal p=0.007). Cataplexy remission occurred in 33% (AXS-12) vs 9.5% (placebo) (nominal p=0.008) at Week 5. Mean percentages of cataplexy-free days at Week 5 were 84.5% (AXS-12) vs 22.6% (placebo) (nominal p=0.014). Changes in CGI-S for EDS at Week 5 were -1.8 (AXS-12) vs -0.9 (placebo) (nominal p=0.027). Patients reporting fewer inadvertent naps (NSAQ) were 54% (AXS-12) vs 28% (placebo) (nominal p=0.016). AXS-12 led to greater improvements in concentration and memory (1.6 vs 0.7 points, nominal p=0.004). AXS-12 was well-tolerated with no new safety signals or serious adverse events; common TEAEs included dry mouth (n=6), nausea (n=6), and constipation (n=4), all mild/moderate.
Conclusions:
AXS-12 met its primary endpoint, leading to a substantial, statistically significant reduction in weekly cataplexy attacks. Improvements in EDS and cognition were also observed, suggesting AXS-12 may offer effective treatment for multiple narcolepsy symptoms with a favorable safety profile.
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