Depressive Symptom Severity in Patients with Major Depressive Disorder (MDD) at Study Exit in the One-Year SHORELINE Study of Episodic Treatment with Zuranolone

Abstract: Introduction Zuranolone is an investigational neuroactive steroid and positive allosteric modulator of 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 analysis reports depressive symptom severity at study exit in patients who completed or prematurely withdrew from the ongoing, Phase 3, open-label, 1-year SHORELINE study, evaluating safety/efficacy of zuranolone 30 (ZRN30) and 50 mg (ZRN50) after initial/repeat treatment courses. Methods SHORELINE is enrolling adults (18–75 years) with MDD and Hamilton Rating Scale for Depression (HAMD-17) total score ≥20. HAMD-17 responders at Day (D)15 can continue the study. Patients with follow-up HAMD-17 ≥20 are eligible for repeat treatment from D70 (56 days after 14-day treatment). Results Patients receiving ZRN30/ZRN50 (n=924) were predominantly female (67.9%); baseline mean±SD HAMD-17 was 25.3±3.9 (severe). Among patients overall, 22.5% (n=208) were D15 non-responders, 33.4% (n=309) withdrew early, and 44.0% (n=407) completed the study (ZRN30/ZRN50, 43.0%/47.7%). For D15 responders who completed or discontinued after D28—most frequently due to patient withdrawal or loss-to-follow-up (70.7%)—overall/ZRN30/ZRN50 mean±SD HAMD-17 was 8.6±7.1/9.1±7.1/6.7±6.8 and 11.2±7.3/11.3±7.1/10.9±8.0, respectively; median (range) days since start of last treatment was 210.5 (27–414)/183.0 (28–414)/295.0 (27–407) and 94.0 (8–366)/84.5 (8–366)/131.0 (8–355), respectively. Most patients who completed or withdrew early had minimal/mild depressive symptoms at study exit (overall/ZRN30/ZRN50, 76.8%/75.2%/82.1% and 59.4%/57.9%/64.7%, respectively). Conclusions Most D15 responders had minimal/mild depressive symptoms at study exit regardless of premature withdrawal or one-year study completion. Median time since last zuranolone treatment at early termination was >90 days.Short Description: In this interim analysis of the Phase 3, open-label, 1-year SHORELINE Study (NCT03864614) evaluating the safety/efficacy of zuranolone in a naturalistic manner, the majority of patients had minimal/mild depressive symptoms at study exit, whether they completed or discontinued the study. Most patients who discontinued withdrew consent or were lost to follow-up and exited >90 days (median) since the start of their last zuranolone treatment, suggesting few patients left after an ineffective/poorly tolerated 14-day treatment.Name of Sponsoring Organization(s): Sage Therapeutics, Inc. and Biogen Inc.