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SELTOREXANT, ADJUNCTIVE TO ANTIDEPRESSANTS, IN ADULTS WITH MAJOR DEPRESSIVE DISORDER WITH INSOMNIA SYMPTOMS: PHASE 3 STUDIES

Gahan Pandina — Michael E. Thase2, Andrew D. Krystal3, Ewa Wajs4, Joseph M. Trombello1, Katherine Bevans1, Ryan Kelly1, Yun Zhang1, Haiyan Xu1, Sandra Ruschel5, Yanina Flossbach6, Sofie Mesens4, Lu Xia1, Thomas Laughren7, Wayne C. Drevets1 1Johnson and Johnson,2Perelman School of Medicine, University of Pennsylvania, and Corporal Michael J. Crescenz VAMC, 3UCSF School of Medicine, San Francisco, 4Johnson and Johnson, Beerse, Belgium, 5Ruschel Medicine and Clinical Research, Rio de Janeiro, Brazil, 6Johnson and Johnson, Allschwil, Switzerland, 7Laughren Psychopharm Consulting, LLC Gahan Pandina, Johnson and Johnson

2026 ASCP Annual Meeting

Background

Seltorexant is a first-in-class, selective, orexin-2 receptor antagonist being investigated as adjunctive treatment to standard antidepressant therapy for major depressive disorder (MDD) with insomnia symptoms (IS) in randomized, international, phase 3 studies. We report results from the placebo (PBO)-controlled, double-blind (DB) phase of NCT04533529, (Study 1) with open-label extension (OLE), and from NCT04513912 (Study 2), a DB study with quetiapine extended release (XR) as an active comparator.

Methods

Participants (pts) aged 18-74 years with DSM-5 diagnosis of MDD without psychotic features who had an inadequate response to 1-2 SSRI/SNRI (while continuing their current regimen) were included in both studies. In the DB phase of Study 1, pts (with and without moderate-to-severe IS) were randomized 1:1 to adjunctive seltorexant 20 mg or PBO for 6 weeks. The primary endpoint was change from baseline to Day 43 in MontgomeryÅsberg Depression Rating Scale (MADRS) total score; key secondary endpoints were changes from baseline to Day 43 in MADRS without sleep item (WOSI) and in Patient Reported Outcome Measurement Information System-Sleep Disturbance (PROMIS-SD) 8a T-score. In the OLE, eligible DB phase pts received adjunctive seltorexant 20 mg for an additional 52 weeks; long-term MADRS total score change was assessed. In Study 2 pts with moderate-to-severe IS were randomized 1:1 to adjunctive seltorexant 20 mg or quetiapine XR (labeled dosage) for 26 weeks. The primary endpoint was Week 26 MADRS total score response rate (≥50% improvement from baseline); key secondary endpoint was change from baseline to Week 26 in body weight. Treatment-emergent adverse events (TEAEs) were assessed in both studies.

Results

In Study 1, 586 (283 seltorexant, 303 PBO) pts with MDD received ≥1 dose of study drug in the DB phase. Primary and key secondary endpoints significantly improved with seltorexant (n=196) vs PBO (n=195) at Day 43 in pts with IS; least squares mean difference (95% CI; 2-sided p) of change in MADRS: -2.6 (-4.53, -0.74; p=0.007), in MADRS-WOSI: 2.0 (-3.75, -0.28; p=0.023), and in PROMIS-SD 8a T-score: -3.7 (-5.48, -2.00; p < 0.001). TEAEs occurred in 104/283 (36.7%) seltorexant and 124/303 (40.9%) PBO pts. 522 (96.7%) DB phase completers received ≥1 dose of study drug in the OLE; 360 (69.0%) completed the OLE. Mean (SD) change in MADRS from OLE baseline to OLE Week 52 was -11.0 (10.55; n=359). No new safety concerns were identified. In Study 2, 756 (366 seltorexant, 390 quetiapine XR) pts with MDD with IS received ≥1 dose of study drug. Week 26 MADRS response rate was 57.4% (201/350) for seltorexant and 53.4% (194/363) for quetiapine XR. Mean (SD) change from baseline to Week 26 in body weight (kg) was 0.5 (2.89; n=268) for seltorexant and 2.1 (3.93; n=263) for quetiapine XR. TEAEs occurred in 198/366 (54.1%) seltorexant and 264/390 (67.7%) quetiapine XR pts. Lower incidences of somnolence and fewer TEAEs leading to study drug discontinuation occurred with seltorexant vs quetiapine XR.

Conclusion

In Study 1, adjunctive seltorexant showed significant and clinically meaningful antidepressant effects in the DB phase, beyond improvement of IS. Depressive symptoms continued to improve up to 1 year. In Study 2, both treatments demonstrated comparable robust antidepressant response rates, with no statistical difference between groups. Safety findings suggest seltorexant is well tolerated and a potentially good alternative to long-term antipsychotics for MDD with IS.