0733 Effect of Oveporexton (TAK-861), an Oral Orexin Receptor 2 Agonist, on Narcolepsy Type 1 Symptom Severity: A Pooled Analysis of Two Phase 3 Studies

Abstract Introduction Narcolepsy type 1 (NT1) is a neurologic disorder of hypersomnolence caused by loss of orexin producing neurons. We report a pooled analysis of NT1 symptom severity using data from two randomized, double-blind, phase 3 studies (The First Light: NCT06470828; The Radiant Light: NCT06505031) of oveporexton (TAK-861). Methods Participants were aged 16–70 years with an established diagnosis of NT1 according to International Classification of Sleep Disorders, Third Edition (ICSD-3) or ICSD-3-text revision; Epworth Sleepiness Scale score ≥11; and ≥4 partial/complete episodes of cataplexy/week. Participants were randomized to twice daily oveporexton 1mg (The First Light only), 2mg, or placebo, ≥3 hours apart for 12 weeks. Secondary/exploratory endpoints: Narcolepsy Severity Scale for Clinical Trials (NSS-CT; a 15-item scale assessing sleepiness, cataplexy, sleep paralysis, hallucinations, and disrupted nocturnal sleep, score range 0–57), Patient Global Impression Scales of Severity (PGI-S) and Change (PGI-C), and Clinical Global Impression Scales of Severity (CGI-S) and Change (CGI-C). Results Overall, 273 participants were randomized to oveporexton 1mg/1mg (n=61), 2mg/2mg (n=136), or placebo (n=76). Mean baseline NSS-CT total scores were 30.8 (8.45) and 31.5 (9.37) for oveporexton and placebo, respectively. At baseline, 66.5% and 63.2% of oveporexton- and placebo-treated participants rated narcolepsy symptoms as severe/very severe on PGI-S and most participants were rated as markedly-to-extremely ill on the CGI-S (oveporexton, 155/196 [79.1%]; placebo, 62/76 [81.6%]). At week 12, least square mean difference vs placebo (95% CI) for change from baseline in NSS-CT was −14.8 (−17.5, −12.0; 1 mg/1mg) and −17.4 (−19.6, −15.2; 2mg/2mg; both nominal P< 0.0001). At week 12, 3.7% and 52.9% of oveporexton- and placebo-treated participants rated NT1 symptoms as severe/very severe on PGI-S, while 2.7% and 77.1% of participants, respectively, were rated as markedly, severely or extremely ill on the CGI-S. At week 12, symptoms measured using the PGI-C and CGI-C were reported as ‘much or very much improved’ by 87.8% and 80.6% of oveporexton-treated and 18.6% and 15.7% of placebo-treated participants, respectively. Conclusion This analysis confirmed significant improvements in the frequency, severity, and impact of narcolepsy symptoms over 12 weeks with oveporexton vs placebo. Support (if any) Funding by Takeda Development Center Americas, Inc.