To evaluate the efficacy and safety of oveporexton (TAK-861), an oral orexin receptor 2 (OX2R)-selective agonist, in narcolepsy type 1 (NT1).

NT1, a chronic, rare, neurologic disorder of hypersomnolence, is caused by loss of orexin-producing neurons in the hypothalamus. Oveporexton activates OX2R to restore signaling and address the underlying orexin deficiency in NT1.

In this double-blind, phase 3 study (TAK-861-3002) participants were randomized 2:1 to oveporexton 2 mg or placebo twice daily ≥3 hours apart for 12 weeks. Eligible participants were age 16–70 years with International Classification of Sleep Disorders, Third Edition (ICSD-3) or ICSD-3-text revision diagnosis of NT1. The primary endpoint was change from baseline to week 12 in mean sleep latency on the Maintenance of Wakefulness Test (MWT). Secondary endpoints included change from baseline to week 12 in ESS total score, weekly cataplexy rate (WCR) at week 12, and treatment-emergent adverse events (TEAE).

105 participants (50 [47.6%] female, mean 30.7 years) were enrolled across Asia, Australia, and Europe (oveporexton 2 mg/2 mg, n=70; placebo, n=35). Baseline mean ESS score was 17.5, mean MWT sleep latency was 4.5 minutes and median WCR was 23.5 attacks/week. At week 12, significant least square (LS) mean (95% CI) changes from baseline were achieved with oveporexton 2mg/2mg vs placebo in MWT sleep latency (20.09 [16.57, 23.61] minutes, P<0.001, for ESS total score (-9.53 [-11.10, -7.97], P<0.001) and WCR (Incidence rate ratio [95% CI] vs placebo: 0.25 [0.15, 0.42], P<0.001). Sixty (85.7%) oveporexton-treated participants experienced ≥1 TEAEs vs 15 (42.9%) placebo-treated participants; there were no serious TEAEs. The most common TEAEs with oveporexton were pollakiuria (43 [61.4%]) and insomnia (40 [57.1%]). Of 101 participants who completed study treatment, 100 (99.0%) enrolled into the long-term extension.

Oveporexton treatment significantly improved measures of sleepiness and cataplexy frequency versus placebo, and was generally well tolerated.