Effects of the selective orexin-2 receptor antagonist JNJ-48816274 on sleep initiated in the circadian wake maintenance zone: a randomised trial

Abstract

The effects of orexinergic peptides are diverse and are mediated by orexin-1 and orexin-2 receptors. Antagonists that target both receptors have been shown to promote sleep initiation and maintenance. Here, we investigated the role of the orexin-2 receptor in sleep regulation in a randomised, double-blind, placebo-controlled, three-period crossover clinical trial using two doses (20 and 50 mg) of a highly selective orexin-2 receptor antagonist (2-SORA) (JNJ-48816274). We used a phase advance model of sleep disruption where sleep initiation is scheduled in the circadian wake maintenance zone. We assessed objective and subjective sleep parameters, pharmacokinetic profiles and residual effects on cognitive performance in 18 healthy male participants without sleep disorders. The phase advance model alone (placebo condition) resulted in disruption of sleep at the beginning of the sleep period compared to baseline sleep (scheduled at habitual time). Compared to placebo, both doses of JNJ-48816274 significantly increased total sleep time, REM sleep duration and sleep efficiency, and reduced latency to persistent sleep, sleep onset latency, and REM latency. All night EEG spectral power density for both NREM and REM sleep were unaffected by either dose. Participants reported significantly better quality of sleep and feeling more refreshed upon awakening following JNJ-48816274 compared to placebo. No significant residual effects on objective performance measures were observed and the compound was well tolerated. In conclusion, the selective orexin-2 receptor antagonist JNJ-48816274 rapidly induced sleep when sleep was scheduled earlier in the circadian cycle and improved self-reported sleep quality without impact on waking performance.

Fig. 1. Pharmacokinetic profiles.

Plasma concentrations (mean ± SD) of JNJ-48816274 following dosing with either 20 mg (black circles) or 50 mg (open circles) 15 min before bedtime. Orange triangles indicated the timing of the psychometric test battery in the morning.

Fig. 2. Hypnograms during baseline and three treatment nights.

Representative hypnograms for participant 2018 indicating the time course of sleep stages across the night with associated slow wave activity (SWA) plots.

Fig. 3. EEG power density during NREM and REM sleep.

EEG power density (mean and 95% confidence intervals) a averaged across the entire night and expressed relative to placebo, and b averaged across the first third of the night and expressed relative to baseline (blue circles indicate 20 mg, red circles indicate 50 mg, black circles indicate baseline, open circles indicate placebo). Horizontal lines indicate significant differences between JNJ-48816274 treatment (20 and 50 mg) and placebo (*p < 0.05 and **p < 0.01).

Fig. 4. Subjective assessments of sleep measured by visual analogue scales in the Subjective Quality of Sleep Questionnaire (SQSQ) following the baseline and three treatment nights.

White bars indicate baseline, black bars indicate placebo, hatched bars indicate 20 mg and grey bars indicate 50 mg. Significant differences between placebo and JNJ-48816274 treatment are indicated by *p < 0.05 and **p < 0.01.