Improvements in Depressive Symptoms in Patients With Major Depressive Disorder: Analysis of Zuranolone Efficacy From 4 Randomized, Placebo-Controlled Trials

The individual studies herein were sponsored by Sage Therapeutics, Inc. (201B, MOUNTAIN); Sage Therapeutics, Inc., and Biogen Inc (WATERFALL); or Shionogi & Co., Ltd. (1818A3731). Zuranolone is an investigational positive allosteric modulator of synaptic and extrasynaptic GABAA receptors and neuroactive steroid in clinical development as an oral, once-daily, 14-day treatment course for adults with major depressive disorder (MDD) and postpartum depression. This analysis of 4 randomized, placebo-controlled trials assessed the efficacy of zuranolone in adults with MDD. Patients received 30-mg zuranolone or placebo in 201B (NCT03000530), MOUNTAIN (NCT03672175; 20-mg data not reported), and 1818A3731 (JapicCTI-205276; 20-mg data not reported), and 50-mg zuranolone or placebo in WATERFALL (NCT04442490). Change-from-baseline (CFB) in 17-item Hamilton Depression Rating Scale total score (HAMD-17) and Cohen’s d were assessed at Day (D)3, D8, and D15, including Kaplan-Meier estimates of median time-to-HAMD-17 response (≥50% reduction from baseline). CFB HAMD-17 significantly improved at D3, D8, and D15 in 30-mg (n=293) and 50-mg (n=265; nominal p 0.05 vs placebo [n=550]); Cohen’s d were 0.1–0.2 (30-mg) and 0.4–0.7 (50-mg). D15 HAMD-17 response rates were 55.4% (50-mg) and 49.1% (30-mg) (both nominal p 0.05 vs placebo), and 40.4% (placebo); estimated median time-to-HAMD-17 response was 11, 15, and, 22 days for 50-mg, 30-mg (both nominal p 0.05 vs placebo), and placebo, respectively. Most D15 HAMD-17 responders maintained response at D42 (30-mg, 62.5%; 50-mg, 70.5%). Most zuranolone-treated patients at D15 (30-mg, 57.0%; 50-mg, 63.7%) had no/mild depressive symptoms (HAMD-17 ≤15). Treatment-emergent adverse events (≥5%) with zuranolone were headache, somnolence, dizziness, sedation, nausea, diarrhea, fatigue, and nasopharyngitis; most were mild or moderate. Adults with MDD treated with zuranolone 30- or 50-mg experienced rapid and sustained depressive symptom improvements.