Zuranolone Safety and Tolerability in Adults with Postpartum Depression: Analyses from SKYLARK, a 50 mg Placebo-Controlled Study

This study was sponsored by Sage Therapeutics, Inc., and Biogen Inc. Zuranolone is an investigational positive allosteric modulator of synaptic and extrasynaptic GABAA receptors and a neuroactive steroid in clinical development as a once-daily, oral, 14-day treatment course for adults with major depressive disorder or postpartum depression (PPD). The placebo-controlled SKYLARK Study (NCT04442503) met its primary endpoint (improvement in depressive symptoms at Day 15) and zuranolone was generally well tolerated in adults with PPD. In SKYLARK (zuranolone 50 mg, n=98; placebo, n=98), treatment-emergent adverse events (TEAEs) were reported in 66.3% of zuranolone-treated and 53.1% of placebo-treated patients. In patients that experienced TEAEs, most reported mild (zuranolone, 50.8%; placebo, 75%) or moderate (zuranolone, 44.6%; placebo, 23.1%) events. Common (≥5%) TEAEs were somnolence (26.5%), dizziness (13.3%), sedation (11.2%), headache (9.2%), diarrhea (6.1%), nausea (5.1%), urinary tract infection (5.1%), and COVID-19 (5.1%) with zuranolone, and headache (13.3%), dizziness (10.2%), nausea (6.1%), and somnolence (5.1%) with placebo. Dose reduction due to TEAEs was 16.3% with zuranolone vs 1.0% with placebo; TEAEs (>1 patient) leading to zuranolone dose reduction were somnolence (7.1%), dizziness (6.1%), and sedation (3.1%). Treatment discontinuation due to TEAEs was 4.1% with zuranolone vs 2.0% with placebo; TEAEs (>1 patient) leading to zuranolone discontinuation included somnolence (2.0%). Serious TEAEs were reported in 2.0% of zuranolone-treated and 0% of placebo-treated patients; per investigators, none were related to zuranolone. No signals for weight gain or sexual dysfunction were identified. Zuranolone 50 mg was generally well tolerated in adults with PPD. Dose reduction mainly resulted from somnolence, dizziness, and sedation; treatment discontinuation was low.