Efficacy and Safety of Seltorexant as Adjunctive Therapy in Major Depressive Disorder: A Phase 2b, Randomized, Placebo-Controlled, Adaptive Dose-Finding Study

Abstract

Background: Seltorexant, a selective antagonist of human orexin-2 receptors, demonstrated antidepressant effects in a previous exploratory study in patients with major depressive disorder (MDD).

Methods: To replicate and extend this observation, a double-blind, adaptive dose-finding study was performed in patients with MDD who had an inadequate response to 1-3 selective serotonin/serotonin-norepinephrine reuptake inhibitors in the current episode. Patients were randomized (2:1:1) to placebo or seltorexant (20 mg or 40 mg) once-daily, administered adjunctively to the antidepressant the patient had been receiving at screening. After an interim analysis (6 weeks post-randomization of 160th patient), newly recruited patients randomly received (3:3:1) placebo or seltorexant 10 mg or 20 mg; the 40-mg dose was no longer assigned. Patients were stratified by baseline Insomnia Severity Index (ISI) scores (ISI ≥ 15 vs < 15). The primary endpoint was change from baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score at week 6.

Results: Mixed-Model for Repeated Measures analysis showed a greater improvement in MADRS total score in the seltorexant 20-mg group vs placebo at weeks 3 and 6; least-square means difference (90% CI): -4.5 (-6.96; -2.07), P = .003; and -3.1 (-6.13; -0.16), P = .083, respectively. The improvement in MADRS score at week 6 for seltorexant 20 mg was greater in patients with baseline ISI ≥ 15 vs those with ISI < 15; least-square means difference (90% CI) vs placebo: -4.9 (-8.98; -0.80) and -0.7 (-5.16; 3.76), respectively. The most common (≥5%) adverse events with seltorexant were somnolence, headache, and nausea.

Conclusions: A clinically meaningful reduction of depressive symptoms was observed for seltorexant 20 mg. In the subset of patients with sleep disturbance (ISI ≥ 15), a larger treatment difference between seltorexant 20 mg and placebo was observed, warranting further investigation. No new safety signal was identified.

Registration: ClinicalTrials.gov Identifier: NCT03227224.

Previous presentation: Poster presented at 58th Annual Meeting of American College of Neuropsychopharmacology (ACNP), December 8-11, 2019, Orlando, FL.

Keywords: Adjunctive therapy; major depressive disorder; orexin-2; seltorexant.

Figure 1.

Study design and patient disposition (A) and screen failures (B). ^aOne patient was screened but was neither randomized nor screen failed and was not included in any of the analysis sets. ^bInitial randomization ratio was 2:1:1 (placebo, seltorexant 20 mg, and 40 mg). A pre-planned interim analysis was conducted with the data cutoff at 6 weeks after randomizing 160 patients in the study; after the interim analysis, the seltorexant 10-mg dose was added to randomization and the seltorexant 40-mg dose was dropped from randomization. The allocation ratio after the interim analysis was adjusted to 3:3:1 (placebo, seltorexant 10 mg, and 20 mg).

Figure 2.

Change in MADRS total score from baseline to week 6: MCP-Mod test results with model estimated treatment effects and MMRM treatment effects and 90% CI (full analysis set). Note: solid points and dashed lines represent estimates and 90% CI from MMRM with change from baseline as the response variable and the fixed effect model terms for treatment (placebo and seltorexant dose groups), time, region, baseline insomnia status, and time-by-treatment and baseline value as a covariate. Negative change in score indicates improvement. *Caution is needed for interpreting the model fitted values and confidence curves for Exponential and sigE_max models, for which some model parameters were fit on boundaries. Abbreviations: MADRS, Montgomery-Asberg Depression Rating Scale; MMRM, mixed model for repeated measures; Selt, seltorexant.

Figure 3.

LS mean change in MADRS over time (observed case MMRM; Full analysis set). *Seltorexant 20 mg vs placebo 2-sided P < .10. Abbreviations: LS, least squares; MADRS, Montgomery-Asberg Depression Rating Scale; MMRM, mixed model for repeated measures; SE, Standard error; Selt, seltorexant.

Figure 4.

Mean change in MADRS over time by baseline ISI total score (per IWRS) (observed case; Full analysis set). Abbreviations: ISI, Insomnia Severity Index; IWRS, interactive web response system; MADRS, Montgomery-Asberg Depression Rating Scale; Selt, seltorexant.