Chen, Dan

Abstract Introduction Narcolepsy is a chronic neurologic condition associated with severe symptom burden, impaired functioning and reduced quality of life. Patients commonly report comorbid mood disorders. AXS-12 (reboxetine) is a selective norepinephrine reuptake inhibitor and cortical dopamine modulator under investigation for the treatment of narcolepsy. In the Phase 3 SYMPHONY trial, AXS-12 met the primary endpoint, a statistically significant reduction in weekly cataplexy attacks from baseline to Week 5 versus placebo. Here, we report secondary endpoints assessing symptom severity, daily functioning, and mood. Methods SYMPHONY was a randomized, double-blind, placebo-controlled trial in patients with narcolepsy type 1 (NT1). Participants (15-75 years) were randomized 1:1 to AXS-12 or placebo for 5 weeks. Stable, concurrent modafinil/armodafinil use was allowed. Secondary endpoints included: the Clinical Global Impression of Severity (CGI-S) for narcolepsy, the Functional Outcomes of Sleep Questionnaire short version (FOSQ-10), and the EuroQol 5-Dimension 5-Level (EQ-5D-5L) questionnaire anxiety/depression domain. Results Ninety participants were enrolled. At baseline, mean (SD) CGI-S for narcolepsy score was 5.2 (1.0) in the AXS-12 arm and 4.9 (1.0) in the placebo arm. AXS-12 led to a significant reduction versus placebo in CGI-S for narcolepsy at Week 5 (LS mean difference [95% CI]=0.72 [0.29, 1.16]; p=0.001). At baseline, mean FOSQ-10 total score was 11.1 (3.1) in the AXS-12 arm and 11.6 (3.2) in the placebo arm. AXS-12 led to a statistically significant improvement from baseline to Week 5 in FOSQ-10 total scores compared to placebo (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). A numerically greater proportion of participants achieved improvements on this domain with AXS-12 (55.0%) versus placebo (31.6%) at Week 5 (p=0.146). Conclusion AXS-12 demonstrated significant reductions in clinical impressions of narcolepsy symptom severity. Functional impairment due to EDS was also significantly reduced, in-line with previously reported improvement in clinician-rated assessments. Anxiety and depression-related symptoms showed trends favoring AXS-12. Combined with prior findings on cataplexy and cognitive improvements, these results highlight the potential of AXS-12 as a therapeutic option addressing multiple symptoms of narcolepsy which affect QoL and functioning. Support (if any) Axsome Therapeutics, Inc.