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Investigational seltorexant improved symptoms of major depressive disorder (MDD) and insomnia in people with an inadequate response to antidepressants, a phase III trial indicated.

By week 6, the least-squares mean difference in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score change from baseline was -2.6 with the study drug plus current antidepressant treatment compared with placebo (95% CI -4.53 to -0.74, two-sided P=0.007), reported Andrew Krystal, MD, of the University of California San Francisco Weill Institute for Neurosciences, and colleagues.

"A between-group difference of two points on the MADRS is generally considered clinically meaningful," Krystal told 番茄社区app.

According to the poster presentation at Psych Congress in Boston, participants on seltorexant also reported significant improvements in two key secondary endpoints compared with placebo:

• Least-squares mean difference in the Patient-Reported Outcome Measurement Information System-Sleep Disturbance 8-item short form T-score change from baseline: -3.7 (95% CI -5.48 to -2.00, two-sided P<0.001)
• Least-squares mean difference in the MADRS without sleep item total score change from baseline: -2.0 (95% CI -3.75 to -0.28, two-sided P=0.023)

The least-squares mean difference in Patient Health Questionnaire-9 total score, measuring self-reported depression symptoms, change from baseline was -2.1 points (95% CI -3.30 to -0.93).

With the potential to be a first-in-class drug, seltorexant is a potent, selective orexin-2 receptor antagonist that normalizes manifestation of hyperarousal and enhances physiological sleep.

Seltorexant "is unique," as there are currently no other antidepressants or insomnia therapies with the same mechanism of action, said Krystal, adding that if the FDA approves the drug, it would be the first depression therapy that acts via blocking orexin receptors.

"Although there are FDA-approved insomnia agents that act by blocking orexin receptors, these agents are 'dual orexin receptor antagonists,' blocking both OX1 and OX2 receptors. In contrast, seltorexant will be the only insomnia therapy that blocks only the OX2 receptors," he explained.

"Seltorexant has the potential to fill a significant unmet need for new therapies to treat patients experiencing depression and insomnia, and most importantly, to improve outcomes and quality of life for these patients," he said. "Approximately 70% of patients with depression have insomnia and optimal care requires targeting treatment to the insomnia, along with delivering antidepressant therapy. Yet we do not have any medications FDA approved for treating depression in those with insomnia."

Krystal added that among the commonly used antidepressants, the tetracyclic antidepressant mirtazapine has the potential to help some patients with depression and insomnia. However, it hasn't been tested for this indication in prior studies and many patients cannot tolerate this medication because of side effects, the most common of which are daytime sedation and weight gain.

"Seltorexant is the first agent developed and demonstrated in rigorous large-scale trials to be efficacious for treating depression with insomnia," he said. "As a result, it will likely be the first FDA-approved therapy specifically for treating patients with depression with insomnia."

In the trial, 588 adults ages 18 to 74 with MDD were randomized to receive seltorexant 20 mg once daily (n=284; 216 with insomnia) or placebo (n=304; 228 with insomnia). Median age was 47, 76.6% were women, and 77.1% were white. Of the participants, 69% were taking selective serotonin reuptake inhibitors (SSRIs) and 31% were taking serotonin-norepinephrine reuptake inhibitors (SNRIs).

All participants had to have a primary DSM-5 diagnosis of MDD without psychotic features and a Hamilton Depression Rating Scale (HDRS)-17 total score of 20+ and 18+ at the first and second screening interviews. In addition, participants had to have an inadequate response to one to two SSRIs or SNRIs given at an adequate and stable dose for at least 6 weeks but less than 2 years.

Mean baseline HDRS-17 score was 26.5 (ranges from 0-52) and mean Insomnia Severity Index score was 20 (ranges from 0-28). The mean duration of current depressive episode was 35.4 weeks.

Seltorexant was safe and generally well-tolerated, with fewer participants experiencing at least one treatment-emergent adverse event compared with the placebo group (36% vs 40.3%). Few participants discontinued treatment due to adverse events (six seltorexant patients vs seven placebo patients). Only one participant in each arm experienced a serious event, neither of which were related to treatment. About 9% of both groups experienced headache.

Overall, these findings support further development of seltorexant as a potential therapy for people with MDD and insomnia, Krystal said. He added that they've also recently initiated a phase III study of seltorexant in MDD patients with no or mild insomnia symptoms, with results to come.

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