Safety and Tolerability of Zuranolone 50 mg in Patients with Major Depressive Disorder: Results from the Phase 3 WATERFALL and CORAL Studies

This work was sponsored by Sage Therapeutics, Inc., and Biogen Inc. Zuranolone is in clinical development as a once-daily, oral, 14-day treatment course for adults with major depressive disorder (MDD). Patients initiated 50-mg zuranolone/placebo alone (WATERFALL Study; NCT04442490) or co-initiated with antidepressant (ADT; CORAL Study; NCT04476030). In WATERFALL (zuranolone, n=268; placebo, n=269), treatment-emergent adverse events (TEAEs) were reported in 60.1% zuranolone-treated and 44.6% placebo-treated patients; of these, most reported mild/moderate TEAEs (zuranolone, 95.0%; placebo, 97.5%). The most common TEAEs with zuranolone (≥5% and greater than placebo) were somnolence (15.3%), dizziness (13.8%), headache (10.8%), and sedation (7.5%). TEAE-related dose reduction occurred in 8.6% zuranolone-treated and 0.4% placebo-treated patients; 3.4% discontinued zuranolone and 1.5% discontinued placebo. Of two zuranolone-treated patients with serious adverse events (SAEs), one experienced psychotic disorder and slow speech assessed as possibly zuranolone-related. No sexual dysfunction-related TEAEs or signals for weight gain were identified. In CORAL (zuranolone+ADT, n=212; placebo+ADT, n=218), TEAEs were reported in 74.1% zuranolone+ADT-treated and 65.6% placebo+ADT-treated patients; of these, most reported mild/moderate TEAEs (zuranolone+ADT, 94.9%; placebo+ADT, 96.5%). The most common TEAEs with zuranolone+ADT (≥5% and greater than placebo+ADT) were somnolence (18.4%), dizziness (13.2%), insomnia (9.9%), dry mouth (9.4%), fatigue (8.5%), sedation (5.7%), decreased appetite (5.7%), and tremor (5.2%). TEAE-related dose reduction occurred in 9.4% of zuranolone+ADT-treated and 2.8% placebo+ADT-treated patients; 6.6% discontinued zuranolone+ADT and 3.7% discontinued placebo+ADT. Of two zuranolone+ADT-treated patients with SAEs, one experienced seizure-like phenomena assessed as related to zuranolone. Rates of sexual dysfunction-related TEAEs were similar (zuranolone+ADT, 4.7%; placebo+ADT, 4.1%); no signals for weight gain were identified. Overall, 50-mg zuranolone was generally well tolerated.