2026 American Academy of Neurology Abstract Website

Giuseppe Plazzi¹, Emmanuel Mignot², Isabelle Arnulf³, Rafael del Rio Villegas⁴, Ramin Khatami⁵, Gert Jan Lammers⁶, Mitsutaka Taniguchi⁷, Harisha Kadali⁸, Yeting Du⁸, Samuel Hsiao⁸, Tina Olsson⁸, Sarah Sheikh⁸, Christian Von Hehn⁸, Mark Etherton⁸, Yves Dauvilliers⁹
¹Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio-Emilia, Modena, Italy, ²Stanford Center for Sleep Sciences and Medicine, Palo Alto, CA, USA, ³Sleep Clinic, DMU APPROCHES, Pitie-Salpetriere Hospital, Assistance Publique-Hôpitaux de Paris-Sorbonne University, Paris, France, ⁴Neurophysiology and Sleep Disorders Unit, Neurophysiology and Sleep Disorders Unit, Vithas Hospitals, Madrid, Spain, ⁵Center of Sleep Medicine and Sleep Research, Center of Sleep Medicine and Sleep Research, Klinik Barmelweid, Barmelweid, Switzerland, ⁶Department of Neurology, Department of Neurology, Leiden University Medical Centre, Leiden, Netherlands, ⁷Sleep Medical Center, Sleep Medical Center, Osaka Kaisei Hospital, Osaka, Japan, ⁸Takeda Development Center Americas, Inc., Cambridge, MA, USA, ⁹Sleep-Wake Disorders Center, Department of Neurology, Gui-de-Chauliac Hospital, CHU, Montpellier, France

Objective:

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

Background:

NT1, caused by loss of orexin-producing neurons in the hypothalamus, is characterized by excessive daytime sleepiness, cataplexy, disrupted nighttime sleep, sleep paralysis, and hypnagogic/hypnopompic hallucinations.

Design/Methods:

This double-blind, phase 3 study included participants aged 16–70 years across Europe, Japan, and North America with a confirmed diagnosis of NT1. Participants were randomized 3:3:2 to twice-daily oral oveporexton 1 mg, 2 mg, or placebo ≥3 hours apart for 12 weeks. 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 in ESS total score to week 12, weekly cataplexy rate (WCR) at week 12, and treatment-emergent adverse events (TEAEs).

Results:

168 participants (98 [58.3%] female, mean age 31.4 years) were randomized to oveporexton 1mg/1mg (n=61), 2mg/2mg (n=66), or placebo (n=41). At baseline, mean ESS score was 18.5, and MWT sleep latency was 5.0 minutes; median WCR was 26.0 attacks/week. At week 12, least square (LS) mean (95% CI) changes from baseline were statistically significant with oveporexton 1mg/1mg and 2mg/2mg for MWT sleep latency (13.83 [10.23, 17.44] and 17.20 [13.66, 20.73] minutes vs placebo, respectively; both P<0.001), and ESS total score (-8.00 [-9.87, -6.13] and -9.75 [-11.59, -7.90] vs placebo; both P<0.001). Incidence rate ratios of WCR for oveporexton were 0.34 (1mg/1mg) and 0.38 (2mg/2mg; both P<0.001 vs placebo). Overall, 88.1% of oveporexton-treated participants (111/126) experienced ≥1 TEAEs versus 53.7% (22/41) with placebo. The most common TEAEs were pollakiuria and insomnia; there were no treatment-related serious TEAEs. Of 157 participants who completed study treatment, 150 (95.5%) enrolled into the long-term extension.

Conclusions:

Oveporexton significantly improved measures of sleepiness and cataplexy frequency vs placebo and was generally well tolerated.