Positive pivotal phase III results for zuranolone, an investigational two-week, once-daily, therapeutic for major depressive disorder.- Sage Therapeutics + Biogen

LS means (SE) change from baseline in HAMD-17 total score at Day 15 for patients who received zuranolone 50 mg was -14.1 (0.51) compared with -12.3 (0.50) for patients who received placebo (LS mean difference -1.7 points; p=0.0141). Monoamine-based antidepressants have been the standard of care for chronic treatment of MDD for the past 60 years. They are treatments administered daily, which require sufficient exposure and continuous use to maintain effect. Zuranolone is a two-week, once-daily oral drug under investigation for the treatment of MDD. It is a molecule that is designed to potentially provide a rapid-acting, sustainable treatment option, and could represent a breakthrough in the current management of depression. The WATERFALL Study was a pivotal, Phase III, double-blind, randomized, placebo-controlled study evaluating the efficacy and safety of zuranolone 50 mg in adults 18 to 64 years with MDD (N=543). The WATERFALL Study enrolled patients who had MDD with a HAMD-17 total score greater than 24 at screening and Day 1 prior to dosing. Zuranolone was generally well-tolerated in the WATERFALL Study and demonstrated a safety profile consistent with previous clinical studies. The rate of treatment emergent adverse events (TEAEs) in the zuranolone group was 60.1% (161/268) vs the placebo group at 44.6% (120/269). The majority of the TEAEs were mild to moderate. The most common TEAEs that were greater than 5% in patients treated with zuranolone (rates vs placebo) included somnolence 15.3% (vs 3.0%), dizziness 13.8% (vs 2.2%), headache 10.8% (vs 7.8%), and sedation 7.5% (vs 0.4%); these events predominantly occurred during the 14-day treatment period. Throughout the study, a total of two patients each (0.7%) reported serious adverse events (SAEs) in the zuranolone and placebo groups; no death occurred in the study. The percent of patients reporting TEAEs leading to drug discontinuation was 3.4% (9/268) and 1.5% (4/269), in the zuranolone and placebo groups, respectively. No signal for withdrawal symptoms as assessed by the 20-item Physician Withdrawal Checklist (PWC-20), or for increased suicidal ideation or behavior as per the Columbia-Suicide Severity Rating Scale (C-SSRS) were identified. Detailed Topline Results from the WATERFALL Study : i. The WATERFALL Study enrolled 543 patients with MDD. The patients were treated with zuranolone 50 mg or placebo once nightly for 14 days. ii. The primary endpoint of the study was the change from baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D) total score at Day 15; the first secondary endpoint was the change from baseline in the Clinical Global Impression-Severity of Illness (CGI-S) at Day 15. iii. The mean (SD) baseline HAMD-17 score at entry into the study was 26.8 (2.60) in the zuranolone 50 mg treatment group (n=268) and 26.9 (2.67) in the placebo group (n=269).iv. 90.3% of patients who received zuranolone, and 87.4% of patients who received placebo, completed the study. Patients with a response at Day 15 in the zuranolone group retained on average 86.1% of their HAMD-17 improvement at Day 42 (4 weeks after dosing ended). A similar maintenance of response was also observed with the MADRS scale, where people who responded to zuranolone at Day 15 maintained 87.6% of that response at Day 42. While not statistically significant, a numerical advantage in favor of zuranolone was demonstrated at Day 42.