Novel selective OX2R antagonist works well for people with insomnia

The novel selective orexin-2 receptor (OX2R) antagonist seltorexant helped promote sleep in people with insomnia, with the efficacy maintained over a 2-week treatment period, according to a phase 2b study.

A dose-response association was observed between seltorexant and the primary endpoint of latency to persistent sleep (LPS), as measured using polysomnography on the first night of treatment, such that higher doses of the drug led to a larger reduction in the time it took to fall asleep (p<0.001). [JAMA Psychiatry 2025;doi:10.1001/jamapsychiatry.2025.1999]

LPS improved by 49 percent with the 20-mg dose (least square mean [LSM] ratio, 0.51, 90 percent confidence interval [CI], 0.41–0.64) and by 36 percent with the 10-mg dose (LSM ratio, 0.64,90 percent CI, 0.51–0.81) relative to placebo. When compared with zolpidem, 20-mg seltorexant improved LPS by 29 percent (LSM ratio, 0.71, 90 percent CI, 0.57–0.88). LPS was calculated as time from lights-out to the first 10 minutes of continuous sleep.

Results for the key secondary endpoint of wake after sleep onset (WASO) over the first 6 h (WASO-6) on the first night of treatment likewise followed a dose-response pattern. An improvement of 40 percent and 32 percent was observed with seltorexant 20 mg (LSM ratio, 0.60, 90 percent CI, 0.48–0.74) and 10 mg (LSM ratio, 0.68, 90 percent CI, 0.55–0.85), respectively, compared with placebo. WASO-6 changes did not differ between seltorexant and zolpidem.

The improvements seen in LPS and WASO-6 on the first night of treatment were maintained through night 13 with seltorexant but diminished with zolpidem. On night 13, LPS improved by 30 percent with the 10-mg seltorexant dose and by 28 percent with the 20-mg dose, while WASO-6 improved by 31 percent with the 20-mg dose relative to zolpidem.

“These data indicate that 10 and 20 mg of seltorexant are efficacious doses for participants with insomnia,” the investigators said.

Selective orexin targeting advantage

The drug is the first potent, selective antagonist of human OX2R to be studied clinically. More recently approved agents such as dual orexin receptor antagonists (DORAs) act on both orexin-1 receptors (OX1Rs) and OX2Rs. Orexin signalling contributes to a state of hyperarousal, which is the main driver of insomnia. However, orexin’s effect on wakefulness is especially mediated by the OX2R, so selective blockade of OX2Rs is sufficient to initiate and prolong sleep, the investigators explained. [Health Psychol Res 2022;10:37400; Front Neurosci 2014;8:28]

In contrast, blocking both orexin receptors can have unwanted side effects on sleep architecture, they added. Studies in rats showed that the administration of an OX1R antagonist in combination with an OX2R antagonist induced an increase in REM sleep duration at the expense of the time spent in non-REM sleep. “Thus, selective OX2R antagonists may afford advantages in the treatment of insomnia.” [Front Neurosci 2014;8:28; Front Neurol Neurosci 2021;45:22-37; J Pharmacol Exp Ther 2015;354:471-482]

The investigators pointed out that the known changes in sleep architecture observed with DORAs did not occur with seltorexant. In the study, the 10- and 20-mg doses yielded similar improvements in both REM and non-REM sleep, which were maintained over time.

Well tolerated

In terms of safety, treatment-emergent adverse events (TEAEs), including disturbance in attention and somnolence, occurred less frequently in the combined seltorexant dose groups vs the placebo and zolpidem groups (33.8 percent vs 49.3 percent and 42.5 percent, respectively). There were no documented cases of sleep paralysis or cataplexy.

Two participants experienced serious TEAEs, one in the seltorexant 20-mg group and another in the zolpidem group. Asymptomatic electrocardiogram-related TEAEs led to treatment discontinuation in three seltorexant-treated participants.

The investigators noted that the inclusion of both adult and older adult participants, a large subpopulation of those with insomnia, was a strength of the study. There were no clinically meaningful differences in seltorexant effects and improvements in sleep parameters between these age subgroups. Furthermore, the use of zolpidem as a comparison increased the clinical meaningfulness of the data, given its widespread use in the clinical management of insomnia, they added.

The analysis included 364 participants (mean age 57.8 years, 67.6 percent female, 69 percent White), including 238 adults (18–64 years) and 126 older adults (65–85 years), who had an Insomnia Severity Index score of ≥15 and no psychiatric comorbidity. These participants were randomly assigned to receive seltorexant (5 mg [n=71], 10 mg [n=74], or 20 mg [n=71]), placebo (n=75), or zolpidem (5–10 mg [n=73]), administered orally every night for 14 days.