Journal Article

Oral Orexin Receptor 2 Agonist in Narcolepsy Type 1

Szakács, Zoltan, Dauvilliers, Yves, Hanson, Elizabeth, Kadali, Harisha, Plazzi, Giuseppe, Zeitz, Heidi, Sheikh, Sarah I., Scammell, Thomas E., Inoue, Yuichi, von Hehn, Christian, Wu, Jingtao, Koundourakis, Elena, Murthy, N. Venkatesha, del Río Villegas, Rafael, Swick, Todd, Du, Yeting, Mignot, Emmanuel, von Rosenstiel, Philipp, Meyer, Seetha, Rogers, Raquel

2023

Overview

Narcolepsy type 1 is caused by severe loss or lack of brain orexin neuropeptides. We 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. Of 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. In 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.).

• Publisher: Massachusetts Medical Society
• Subject: Administration, Oral / Adverse events / Agonists / Brain Chemistry / Brain Chemistry - drug effects / Cataplexy / Cataplexy - complications / Cataplexy - drug therapy / Cataplexy - epidemiology / Cerebrospinal fluid / Chemical and Drug Induced Liver Injury / Chemical and Drug Induced Liver Injury - etiology / Clinical outcomes / Cognitive science / Critical Care / Critical Care General / Double-Blind Method / Drug dosages / Drug withdrawal / Humans / Latency / Liver / Narcolepsy / Narcolepsy - complications / Narcolepsy - drug therapy / Narcolepsy - epidemiology / Neurology / Neuropeptides / Neuroscience / Neurosurgery / Orexin Receptors / Orexin Receptors - agonists / Orexin Receptors - therapeutic use / Orexins / Orexins - analysis / Orexins - deficiency / Orexins - pharmacology / Patients / Placebos / Pulmonary / Sleep / Sleep and wakefulness / Sleep disorders / Sleepiness / Sleepiness - drug effects / Treatment Outcome / Vital signs