0736 Effect of the Oral Orexin Receptor 2 Agonist Oveporexton (TAK-861) on Quality of Life in Individuals with NT1: A Pooled Analysis of Phase 3 Studies

Abstract Introduction Oveporexton (TAK-861) is an orexin receptor 2-selective agonist under investigation for the treatment of narcolepsy type 1 (NT1). We report a pooled analysis of health-related quality of life (HRQoL) measures (Short Form-36 [SF-36], EuroQol 5-Dimension 5-Level [EQ-5D-5L]) and treatment satisfaction (Treatment Satisfaction Questionnaire for Medication [TSQM]) data from two randomized, double-blind, phase 3 studies (The First Light: NCT06470828; The Radiant Light: NCT06505031) of oveporexton in individuals with confirmed NT1. Methods Eligible participants were aged 16–70 years with a confirmed ICSD-3 diagnosis of NT1 supported by polysomnography and/or MSLT and positive HLA-DQB1*06:02 allele, or orexin cerebrospinal fluid ≤110 pg/mL; participants had an Epworth Sleepiness Scale score ≥11, and ≥4 cataplexy episodes/week. Participants received twice daily oral oveporexton 1 mg (The First Light only) or 2 mg, or placebo, at least 3 hours apart, for 12 weeks. SF-36 Mental (MCS) and Physical (PCS) Component Summary scores were secondary endpoints (norm-based score); EQ-5D-5L Visual Analog Scale (VAS) score (0-100 scale), EQ-5D-5L index score (0-1 scale), and TSQM (0-100 scale) were exploratory endpoints. Higher scores represented better outcomes. Results Overall, 273 participants were randomized to oveporexton 1mg/1mg (n=61), oveporexton 2mg/2mg (n=136), or placebo (n=76). At baseline, measures of HRQoL were similar between groups (mean [SD] SF-36 PCS: 48.7 [8.2], SF-36 MCS: 39.6 [9.9], EQ-5D-5L VAS: 62.8 [20.3], and EQ-5D-5L Index score: 0.78 [0.22]). TSQM was not measured at baseline. At Week 12, all scores markedly increased with oveporexton versus placebo, reaching or surpassing normative values. For oveporexton 1mg/1mg and 2mg/2mg, respectively, least square mean changes from baseline vs placebo were 5.5 and 5.7 for SF-36 PCS (p< 0.0001), 7.3 and 10.1 for SF-36 MCS (p< 0.0001), 14.6 and 17.3 for EQ-5D VAS (nominal p< 0.0001), and 0.19 and 0.19 for EQ-5D Index score (nominal p< 0.0001). Mean (SD) TSQM Global Satisfaction domain scores at Week 12 were higher for oveporexton (81.7 [20.1]) vs placebo (38.3 [30.1]). Conclusion In this pooled analysis of two phase 3 clinical trials, oveporexton showed clinically relevant improvements in HRQoL and nominally greater treatment satisfaction compared with placebo in participants with NT1. Support (if any) Funded by Takeda Development Center Americas, Inc.