Impact of AXS-12 on Symptom Severity and Functional Impairment in Narcolepsy: Results From the Phase Three SYMPHONY Trial
Michael Thorpy1, Lois Krahn2, Richard Bogan3, Bruce Corser4, Colin Shapiro5, Dan Chen6, Angad Chhabra6, Eileen Leary7, Herriot Tabuteau6
1Montefiore Medical Center, Sleep-Wake Disorders Center, 2Department of Psychiatry and Psychology, Mayo Clinic College of Medicine, 3Medical University of South Carolina, 4Intrepid Research, 5University of Toronto, 6Axsome Therapeutics, Inc., 7Formerly of Axsome Therapeutics, Inc.
Objective:
To evaluate secondary endpoints assessing symptom severity, mood, and daily functioning, from the Phase 3 Symphony trial of AXS-12 (reboxetine) in narcolepsy type 1 (NT1).
Background:
NT1 is a chronic neurologic condition associated with severe symptom burden, impaired functioning, and reduced quality of life. Comorbid mood disorders, such as anxiety and depression, are also common and can further impact daily life. AXS-12 is a selective norepinephrine reuptake inhibitor and cortical dopamine modulator under investigation for narcolepsy. In the Phase 3 SYMPHONY study, AXS-12 met the primary endpoint, significantly reducing weekly cataplexy attack frequency versus placebo.
Design/Methods:
SYMPHONY was a randomized, double-blind, placebo-controlled study in patients with NT1. Participants (15-75 years) were randomized to AXS-12 or placebo for 5 weeks. Secondary endpoints included the Clinical Global Impression of Severity (CGI-S) for narcolepsy, the Functional Outcomes of Sleep Questionnaire-10 (FOSQ-10), and the EuroQol 5-Dimension 5-Level (EQ-5D-5L) anxiety/depression domain.
Results:
Ninety participants were enrolled. Baseline mean (SD) CGI-S for narcolepsy scores were 5.2 (1.0) for AXS-12 and 4.9 (1.0) for placebo. At week 5, AXS-12 significantly improved CGI-S versus placebo (LS mean difference [95% CI]=0.72 [0.29, 1.16]; p=0.001). Baseline mean FOSQ-10 total scores were 11.1 (3.1) for AXS-12 and 11.6 (3.2) for placebo. At Week 5, AXS-12 significantly improved FOSQ-10 score versus placebo (LS mean difference [95% CI]=1.66 [0.51, 2.82]; p=0.005). At baseline, 47.8% of participants in the AXS-12 arm and 45.5% in the placebo arm reported anxiety/depression (EQ-5D-5L); numerically more participants improved ≥1 level with AXS-12 (55.0%) versus placebo (31.6%) at Week 5 (p=0.146).
Conclusions:
AXS-12 demonstrated a reduction in clinical impression of overall narcolepsy symptom severity, functional impairment due to EDS, and improved mood-related symptoms. Combined with prior findings, these results highlight the potential of AXS-12 to address narcolepsy symptoms affecting quality of life and functioning.
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