0058 Scientific Rationale and Clinical Development of AXS-12 for Narcolepsy.

Abstract

0058 Introduction: Narcolepsy is a serious neurological condition causing sleep-wake dysregulation and is characterized by excessive daytime sleepiness (EDS) and cataplexy. Cataplexy is seen in approximately 70% of patients and is a sudden reduction or loss of muscle tone while a patient is awake. Narcolepsy interferes with cognitive, psy- chological, and social functioning, increases the risk of accidents, and is associated with greater mortality. Depression is reported in up to 57% of patients. Currently-approved treatments are few for this under-diagnosed orphan condition, and are limited by variability in efficacy, tolerability issues and the need for scheduling. AXS-12 (reboxetine) is a highly selective and potent inhibitor of norepineph- rine reuptake. The scientific rationale for developing AXS-12 for the treatment of narcolepsy is based on in vivo nonclinical physiological and pharmacological studies suggesting a strong role for adrenergic neurotransmission in cataplexy, anti-cataplectic effects of rebox- etine in orexin-deficient mice, and positive preliminary clinical evi- dence from an open-label pilot study of reboxetine in patients with narcolepsy. Methods: Reboxetine has been investigated in animal models of narcolepsy as well as in an open-label study in patients with nar- colepsy. AXS-12 is being evaluated in a randomized, double-blind, crossover, placebo-controlled Phase 2 trial in narcoleptic subjects with cataplexy and EDS. Subjects are randomized equally to placebo for three weeks followed by AXS-12 for three weeks, or to AXS-12 for three weeks followed by placebo for three weeks. Outcomes measured include the change in the number of cataplexy attacks, maintenance of wakefulness, and reduction in sleepiness. Results: In orexin-deficient mice, reboxetine treatment markedly reduced episodes of cataplexy and sleep attacks. In an open-la- bel pilot trial in patients with narcolepsy, reboxetine significantly improved EDS and cataplexy versus baseline. Results from the double-blind, placebo-controlled Phase 2 study of AXS-12 in nar- colepsy may be presented. Conclusion: There is strong scientific rationale for the clinical de- velopment of AXS-12 for narcolepsy. If nonclinical and prelim- inary clinical findings are confirmed in late-stage studies, AXS-12 would represent a significant advance in the identification of safer, more effective treatments for narcolepsy without abuse potential.