Background

Seltorexant is a selective antagonist of the human orexin-2 receptor. The neuropeptide orexin regulates wakefulness; inhibiting orexin receptor signaling promotes sleep. This drug is in advanced clinical development for treating depression, where it is thought to be effective by improving sleep. It is being tested to treat agitation and aggression in people with AD.

In preclinical work in rats, orally administrated seltorexant rapidly entered the brain, and induced and prolonged sleep. In humans, it increased sleepiness after a single dose, with acceptable pharmacokinetics and safety (Bonaventure et al., 2015). 

This compound was originally discovered at Minerva Neurosciences. That company was developing it in collaboration with Janssen, but their partnership ended in 2020, and now Janssen is solely responsible for its development.

Findings

Since 2009, Janssen has completed more than 20 Phase 1 studies of seltorexant. In people with insomnia, the drug reduced time to fall asleep and increased sleep time (van der Ark et al., 2018; De Boer et al., 2018). In patients with major depression and persistent insomnia, it eased core symptoms of depression, and improved sleep (Brooks et al., 2019; Recourt et al., 2019). In a Phase 2 trial, adding seltorexant improved depression in people who had responded poorly to serotonin reuptake inhibitors. The drug was most effective in people with the worst sleep problems at the start of the study (Savitz et al., 2021). The most common adverse effects were headache, sleepiness, and nausea. Two Phase 3 trials are now testing six weeks of suvorexant added on to antidepressants in people with major depression and insomnia. The studies, in a total of 1,270 patients, were anticipated to finish in 2023, with the company planning FDA submission later that year. In May 2024, Janssen’s parent company Johnson & Johnson announced that seltorexant had met all primary and secondary outcomes in one of the Phase 3 trails involving 588 people (press release).

In May 2022, Janssen began a Phase 2 trial of seltorexant in 86 people with probable Alzheimer’s disease and significant agitation or aggression. Patients will take a single 20 mg tablet or matching placebo daily for six weeks, against a primary outcome of the Agitation and Aggression domain scores of the Neuropsychiatric Inventory-Clinician rating. Secondary outcomes are change in Cohen-Mansfield Agitation Inventory, sleep, and plasma drug levels. The study ran at 25 locations in the U.S., and finished in November 2023 with a final enrollment of 70.

In mid-2024, Johnson & Johnson removed seltorexant’s Alzheimer indication from their pipeline. Development for depression will continue.

For details on seltorexant trials, see clinicaltrials.gov.