2026 ECNP Congress

PS04-4137

Double-blind and open-label-extension results from a phase-3 trial of adjunctive seltorexant in adults with major depressive disorder with insomnia symptoms

Ewa Wajs — G. Pandina, M.E. Thase, A.D. Krystal, J.M. Trombello, R. Kelly, Y. Zhang, H. Xu, J. Thipphawong, S. Ruschel, Y. Flossbach, C.M. Canuso, T. Laughren, W.C. Drevets · Johnson & Johnson, Neuroscience, Beerse, Belgium

2026 ECNP Congress

Introduction

Inadequate response to first-line therapies for major depressive disorder (MDD) is a critical treatment challenge. Insomnia symptoms (IS) are prevalent among those with depression and are associated with greater severity and duration of depressive episodes, as well as poorer treatment outcomes.[1] Seltorexant is a first-in-class, selective, high-affinity, orexin-2 receptor antagonist, which normalizes hyperarousal and supports physiological sleep. The antidepressant effects of adjunctive seltorexant versus placebo were shown in a phase 2 study, particularly in participants with MDD with IS.

Aims

We report double-blind (DB) and open-label extension (OLE) results from a Phase 3 study (NCT04533529) of adjunctive seltorexant in participants with MDD on background therapy with an SSRI/SNRI.

Methods

Participants aged 18-74 years had a primary DSM-5 diagnosis of MDD without psychotic features and an inadequate response to 1-2 antidepressants. Eligible DB participants were randomized (1:1) to receive seltorexant 20 mg or placebo for 6 weeks, while continuing their baseline SSRI/SNRI. The primary endpoint was change from baseline to day 43 in MADRS total score. The key secondary endpoints were changes from baseline to day 43 in MADRS-“without sleep item” (MADRS-WOSI) total score and in Patient Reported Outcome Measurement Information System-Sleep Disturbance (PROMIS-SD-8a) T-score. Eligible participants from the DB phase received open-label seltorexant 20 mg for 1 year in the OLE. Efficacy assessments in the OLE included change from OLE baseline in MADRS total score to week 52 and remission (MADRS total score ≤12). Safety was assessed throughout the study.

Results

586 participants with MDD received ≥1 study-drug dose (DB safety set); 419 with MDD with IS received ≥1 study-drug dose and had baseline MADRS score ≥24 (DB efficacy set). Primary and key secondary endpoints significantly improved with seltorexant versus placebo at day 43; the least squares mean difference (95% confidence interval; 2-sided p) in MADRS total score was -2.6 (-4.53, -0.74; p=0.007), in MADRS-WOSI total score was -2.0 (-3.75, -0.28; p=0.023), and in PROMIS-SD-8a T-score was -3.7 (-5.48, -2.00; p<0.001). Treatment-emergent adverse events (TEAEs) occurred in 104/283 (36.7%) seltorexant and 124/303 (40.9%) placebo recipients. TEAEs leading to discontinuation of study drug occurred in 6/283 (2.1%) seltorexant and 7/303 (2.3%) placebo recipients. There were 522 (96.7%) DB participants who entered the OLE and 360 (69.0%) who completed the OLE. In OLE participants with MDD who received ≥1 seltorexant dose, the mean (SD) change in MADRS total score from OLE baseline to week 52 was -11.0 (10.55; n=359). For the placebo-to-seltorexant group, the percentage of participants in remission (observed case) increased from 19.9% (53/267) at OLE baseline to 62.6% (122/195) at OLE week 28 and 73.6% (131/178) by OLE week 52. For the seltorexant-to-seltorexant group, the percentage of participants in remission (observed case) increased from 27.1% (68/251) at OLE baseline to 57.4% (116/202) at OLE week 28 and 74.0% (134/181) by OLE week 52. No new safety concerns were identified.

Conclusions: Adjunctive seltorexant showed significant and clinically meaningful antidepressant effects, beyond improvement of IS, with safety profile similar to that of placebo. Depressive symptoms continued to improve in the OLE.

References

  1. Franzen PL, Buysse DJ. Sleep disturbances and depression: risk relationships for subsequent depression and therapeutic implications. Dialogues Clin Neurosci. 2008;10(4):473-81.