Safety and Efficacy of Zuranolone 50 mg and Need for Repeat Treatment Courses in the Open-label, Phase 3 SHORELINE Study of Adult Patients With Major Depressive Disorder

Abstract: Introduction Zuranolone is a neuroactive steroid and positive allosteric modulator of both synaptic and extrasynaptic GABAA receptors in clinical development as an oral, once-daily, 14-day treatment course for adults with major depressive disorder (MDD). This is an interim analysis of the 50-mg Cohort from the ongoing, open-label, Phase 3 SHORELINE study (NCT03864614), evaluating (in a naturalistic manner) the safety and efficacy of 30-mg/50-mg zuranolone after initial/repeat treatment courses. Methods Adults (18-75 years) with MDD, HAMD-17 total score ≥20, and MADRS score ≥28 receive 30-mg/50-mg zuranolone. HAMD-17 responders (≥50% reduction from baseline) at Day (D) 15 after the first 14-day treatment course can continue in the study. The primary endpoint is safety/tolerability. Secondary endpoints include need for repeat treatment courses and change from baseline (CFB) in HAMD-17. Results As of November 2021, the 50-mg Cohort enrolled 199 patients (predominantly female [69.3%]; White [87.9%]). Baseline mean±SD HAMD-17 was 25.1±3.3. Most patients (146/199 [73.4%]) were D15 HAMD-17 responders and continued beyond D28. Mean±SD CFB in HAMD-17 was −16.0±6.0 at D15, −14.6±6.8 at D28, and −14.0±7.2 at D70 (among D15 responders). Of D15 responders, 80/146 (54.8%) received 1 and 116/146 (79.5%) received 1-2 treatment courses through ≤1 year. Most patients with TEAEs reported mild/moderate TEAEs (117/137 [85.4%]). Conclusions Interim data show 50-mg zuranolone was generally well tolerated, with sustained improvements in depressive symptoms through ≤1 year; ≈80% of D15 responders received ≤2 treatment courses. These results support further development of zuranolone for use as an episodic oral treatment for MDD.Short Description: In this interim analysis of the ongoing, open-label, Phase 3, 1-year longitudinal SHORELINE study—designed to evaluate the safety and efficacy of zuranolone in a naturalistic manner—≈80% of patients with MDD receiving a 14-day treatment course of 50-mg zuranolone achieved ≥50% reduction from baseline in HAMD-17 at Day 15, and ≈80% received ≤2 total treatments through ≤1 year. These results support development of zuranolone as an episodic oral treatment for patients with MDD.Name of Sponsoring Organization(s): This study was sponsored by Sage Therapeutics, Inc., and Biogen Inc.