SELTOREXANT VERSUS QUETIAPINE EXTENDED RELEASE AS ADJUNCTIVE TREATMENT IN MAJOR DEPRESSIVE DISORDER WITH INSOMNIA SYMPTOMS: PHASE 3 TRIAL

Background

Seltorexant, a first-in-class, selective, orexin-2 receptor antagonist, normalizes hyperarousal and promotes physiological sleep. Significant antidepressant effects and a favorable safety profile of adjunctive seltorexant versus placebo were shown in a phase 3, 6week study in major depressive disorder with insomnia symptoms (MDDIS;NCT04533529). Here we present results of a trial comparing adjunctive seltorexant versus adjunctive quetiapine extended release(XR) as comparator in MDDIS (NCT04513912).

Methods

This 26-week, international, active-controlled study enrolled participants 18-74 years with DSM-5 diagnosis of MDD without psychotic features, with moderate-to-severe insomnia symptoms and inadequate response to 1-2 antidepressants. Participants were randomized 1:1 to seltorexant 20mg or quetiapineXR (labeled dosage) while continuing their background SSRI/SNRI. The primary endpoint was response rate (≥50% improvement from baseline in Montgomery-Åsberg Depression Rating Scale [MADRS] score) at Week26. Secondary endpoints included change from baseline to Week26 in body weight (key) and in MADRS score. Safety was assessed.

Results

Of 757 participants randomized, 756 received ≥1 dose of study intervention(seltorexant:n=366;quetiapineXR:n=390). Week26 response rate was 57.4%(201/350) for seltorexant and 53.4%(194/363) for quetiapineXR; %difference:4.0(95%CI:3.3,11.3). Mean change from baseline to Week26 in body weight(kg) was 0.5(SD:2.89,n=268) seltorexant and 2.1(SD:3.93,n=263) quetiapineXR (least squares[LS] mean difference:1.7[95%CI:-2.23,-1.09]), and mean change in MADRS score was -23.0(SD:10.12,n=272) seltorexant and -22.7(SD:9.54,n=263) quetiapineXR (LS mean difference:-0.2[95%CI:1.77,1.35]). Lower incidences of somnolence(6.3%[23/366];24.1%[94/390]) and adverse events leading to study intervention discontinuation(5.7%[21/366];11.3%[44/390]) were observed with seltorexant versus quetiapineXR.

Conclusions

Treatment arms demonstrated comparable robust response rates, without a statistical difference between groups. Safety findings support the better tolerability of seltorexant as long-term adjunctive treatment for MDDIS.