Orexin Receptor 2 Agonists Succeed in Phase 3 for Narcolepsy Type 1

A JAMA Network review discussion covers narcolepsy type 1, defined by cataplexy and orexin deficiency, mostly autoimmune in origin, with more than 90% of patients carrying specific HLA variants, versus type 2, where orexin is normal and the mechanism is unknown. Diagnosis rests on sleep history plus a multiple sleep latency test showing mean sleep onset under 8 minutes with at least two REM onsets, and sometimes CSF orexin measurement. Orexin receptor 2 agonists, the first drug class targeting the underlying neurochemical defect, significantly improved wakefulness and cataplexy in two phase 3 trials, and the 2026 Lasker Award went to orexin discoverers Mignot and Yanagisawa.