Sustained Benefits of Zuranolone in Patients With Major Depressive Disorder: Results From the LANDSCAPE Clinical Development Program

Abstract: Introduction Many patients with major depressive disorder (MDD) experience relapse after responding to standard-of-care antidepressants. Zuranolone is a 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 MDD. This analysis describes the sustained effects of zuranolone across 4 randomized trials in the LANDSCAPE program. Methods Patients with MDD received zuranolone 30 mg or placebo in MDD-201B (NCT03000530) and MOUNTAIN (NCT03672175; 20-mg data not reported), zuranolone 50 mg or placebo in WATERFALL (NCT04442490), and zuranolone 30 mg or interim 50 mg in open-label SHORELINE (NCT03864614). Sustained improvement in depressive symptoms was assessed in Day (D)15 Hamilton Rating Scale for Depression total score (HAMD-17) responders (≥50% reduction from baseline) using percent retention of D15 HAMD-17 improvement among all pooled zuranolone-treated patients and number of repeat treatment courses and Kaplan-Meier estimate of time-to-first repeat treatment in SHORELINE. Results Among pooled zuranolone D15 HAMD-17 responders (n=903), mean percent retention of D15 HAMD-17 improvement was 89.9%/84.9%/84.2%/85.8% at D21/D28/D35/D42. In the SHORELINE 30/50-mg Cohorts (n=489/146), 42.9%/54.8% of patients received only the initial 14-day treatment course and 68.5%/79.5% received ≤2 total treatment courses during ≤1 year; estimated median time-to-first repeat treatment course was 135/249 days. Zuranolone was generally well tolerated in all 4 trials. Conclusions In adults with MDD, improvements in depressive symptoms with a 14-day zuranolone treatment course were sustained through ≥4 weeks posttreatment in 4 studies, with most SHORELINE patients receiving ≤2 treatment courses within 1 year.Short Description: In the LANDSCAPE clinical development program—designed to evaluate the efficacy and safety of zuranolone—the mean percent retention of HAMD-17 improvement at all off-treatment timepoints was >80% in adults with MDD who achieved ≥50% reduction from baseline in HAMD-17 at Day 15 with zuranolone treatment. At Days 21 and 42, pooled mean percent retention among Day 15 responders was 89.9% and 85.8%. Zuranolone treatment demonstrates sustained improvement in depressive symptoms in adults with MDD.Name of Sponsoring Organization(s): This study was sponsored by Sage Therapeutics, Inc., and Biogen Inc.