• Yves Dauvilliers, Emmanuel Mignot, Rafael Del Río Villegas, Yeting Du, Elizabeth Hanson, Yuichi Inoue, Harisha Kadali, Elena Koundourakis, Seetha Meyer, Raquel Rogers, Thomas E Scammell, Sarah I Sheikh, Todd Swick, Zoltan Szakács, Philipp von Rosenstiel, Jingtao Wu, Heidi Zeitz, N Venkatesha Murthy, Giuseppe Plazzi, and Christian von Hehn.
• From the Sleep and Wake Disorders Center, Department of Neurology, Gui de Chauliac Hospital, and the University of Montpellier, INSERM Institute for Neurosciences of Montpellier - both in Montpellier, France (Y. Dauvilliers); the Stanford Department of Psychiatry and Behavioral Sciences, Center for Sleep Sciences and Medicine, Stanford University Medical School, Palo Alto, CA (E.M.); the Neurophysiology and Sleep Disorders Unit, Vithas Hospitals, and Universidad CEU San Pablo, CEU Universities - both in Madrid (R.R.V.); Takeda Development Center Americas, Lexington (Y. Du, E.H., H.K., E.K., S.M., R.R., S.I.S., T.S., P.R., J.W., H.Z., N.V.M., C.H.), and the Department of Neurology, Division of Sleep Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston (T.E.S.) - both in Massachusetts; Japan Somnology Center, Institute of Neuropsychiatry, and the Department of Somnology, Tokyo Medical University - both in Tokyo (Y.I.); the State Health Center, Budapest, Hungary (Z.S.); and IRCCS, Istituto delle Scienze Neurologiche di Bologna, Bologna, and the Department of Biomedical, Metabolic, and Neural Sciences, University of Modena and Reggio Emilia, Modena - both in Italy (G.P.).
• N. Engl. J. Med. 2023 Jul 27; 389 (4): 309321309-321.

BackgroundNarcolepsy type 1 is caused by severe loss or lack of brain orexin neuropeptides.MethodsWe conducted a phase 2, randomized, placebo-controlled trial of TAK-994, an oral orexin receptor 2-selective agonist, in patients with narcolepsy type 1. Patients with confirmed narcolepsy type 1 according to clinical criteria were randomly assigned to receive twice-daily oral TAK-994 (30 mg, 90 mg, or 180 mg) or placebo. The primary end point was the mean change from baseline to week 8 in average sleep latency (the time it takes to fall asleep) on the Maintenance of Wakefulness Test (range, 0 to 40 minutes; normal ability to stay awake, ≥20 minutes). Secondary end points included the change in the Epworth Sleepiness Scale (ESS) score (range, 0 to 24, with higher scores indicating greater daytime sleepiness; normal, <10) and the weekly cataplexy rate.ResultsOf the 73 patients, 17 received TAK-994 at a dose of 30 mg twice daily, 20 received 90 mg twice daily, 19 received 180 mg twice daily, and 17 received placebo. The phase 2 trial and an extension trial were terminated early owing to hepatic adverse events. Primary end-point data were available for 41 patients (56%); the main reason for missing data was early trial termination. Least-squares mean changes to week 8 in average sleep latency on the MWT were 23.9 minutes in the 30-mg group, 27.4 minutes in the 90-mg group, 32.6 minutes in the 180-mg group, and -2.5 minutes in the placebo group (difference vs. placebo, 26.4 minutes in the 30-mg group, 29.9 minutes in the 90-mg group, and 35.0 minutes the 180-mg group; P<0.001 for all comparisons). Least-squares mean changes to week 8 in the ESS score were -12.2 in the 30-mg group, -13.5 in the 90-mg group, -15.1 in the 180-mg group, and -2.1 in the placebo group (difference vs. placebo, -10.1 in the 30-mg group, -11.4 in the 90-mg group, and -13.0 in the 180-mg group). Weekly incidences of cataplexy at week 8 were 0.27 in the 30-mg group, 1.14 in the 90-mg group, 0.88 in the 180-mg group, and 5.83 in the placebo group (rate ratio vs. placebo, 0.05 in the 30-mg group, 0.20 in the 90-mg group, and 0.15 in the 180-mg group). A total of 44 of 56 patients (79%) receiving TAK-994 had adverse events, most commonly urinary urgency or frequency. Clinically important elevations in liver-enzyme levels occurred in 5 patients, and drug-induced liver injury meeting Hy's law criteria occurred in 3 patients.ConclusionsIn a phase 2 trial involving patients with narcolepsy type 1, an orexin receptor 2 agonist resulted in greater improvements on measures of sleepiness and cataplexy than placebo over a period of 8 weeks but was associated with hepatotoxic effects. (Funded by Takeda Development Center Americas; TAK-994-1501 and TAK-994-1504 ClinicalTrials.gov numbers, NCT04096560 and NCT04820842.).Copyright © 2023 Massachusetts Medical Society.

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