Abstract Introduction Cognitive symptoms are frequent and disruptive in narcolepsy type 1 (NT1). The effect of oveporexton, an investigational selective orexin-receptor 2-agonist, on cognitive symptoms was investigated in two phase 3 studies (The First Light: NCT06470828; The Radiant Light: NCT06505031). Methods Participants (16–70 years) with a diagnosis of NT1 were randomized to oveporexton 1mg/1mg (The First Light only), oveporexton 2mg/2mg, or placebo, for 12 weeks. Cognitive impairments were assessed with neuropsychological tests of attention (Psychomotor Vigilance Test PVT from 2 intraday sessions), memory (Continuous Paired Associate Learning, CPAL) and executive function (International-Digit Symbol Substitution Test, IDSST-S; One-Back Test, ONB). Patient-reported cognitive difficulties were assessed with the Functional Impacts of Narcolepsy Instrument Cognitive Function domain (FINI-CF) and British Columbia Cognitive Complaints Inventory (BC-CCI). For both trials, PVT and FINI-CF (reported here) were alpha-controlled secondary endpoints. Change from baseline versus placebo were evaluated using linear mixed effects or constrained longitudinal data analysis. Results Compared with placebo, 12-weeks of treatment with oveporexton (1mg/1mg or 2mg/2mg) produced improvements across all objective (PVT, CPAL, iDSST-s, ONB) and subjective (FINI-CF; BC-CCI) cognitive assessments (all p≤0.001). At week 12, differences from placebo (estimated mean) in PVT lapses change from baseline were −9.68 (1mg/1mg) and −10.51 (2mg/2mg; The First Light) and −8.82 (2mg/2mg; The Radiant Light). Differences from placebo (estimated mean) in FINI-CF change from baseline at week 12 were −30.7 (1mg/1mg) and −37.92 (2mg/2mg; The First Light) and −30.17 (2mg/2mg; The Radiant Light). Conclusion In two Phase 3 trials, oveporexton improved cognitive symptoms associated with NT1. Support (if any) These studies were funded by Takeda Development Center Americas, Inc.
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