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.

© The Author(s) 2021. Published by Oxford University Press on behalf of CINP.

Figures

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 sigEmax 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.