Efficacy and Safety of Zuranolone in Adults With Major Depressive Disorder With and Without Use of Standard-of-Care Antidepressants at Baseline in the LANDSCAPE Clinical Development Program

Abstract: Introduction 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 major depressive disorder (MDD). Efficacy and safety of zuranolone as an add-on to existing standard-of-care (SOC) antidepressant (ADT) is underexplored. Data for zuranolone as monotherapy or an add-on to existing SOC ADTs are reported from the LANDSCAPE trials MDD-201B (NCT03000530), MOUNTAIN (NCT03672175), WATERFALL (NCT04442490), and SHORELINE (NCT03864614). Methods Patients with MDD, 17-item Hamilton Rating Scale for Depression (HAMD-17) total score ≥20 (varied by study), and stable or no baseline SOC ADT use received zuranolone 20 mg (MOUNTAIN; not reported), 30 mg (ZRN30), or placebo (MDD-201B; MOUNTAIN); zuranolone 50 mg (ZRN50) or placebo (WATERFALL); or ZRN30 or interim ZRN50 (SHORELINE; open-label). Efficacy was evaluated using HAMD-17 change from baseline (CFB). Results For zuranolone monotherapy, mean Day (D)15 CFB HAMD-17 for zuranolone/placebo was −17.5/−11.6 (n=30/33; p=.0003), −11.6/−9.5 (n=120/115; p=.0301), and −14.3/−12.4 (n=173/174; p=.0165) in MDD-201B, MOUNTAIN (least squares mean [LSM]), and WATERFALL (LSM), respectively; and −15.0/−15.7 (n=394/110) for ZRN30/ZRN50 in SHORELINE. For zuranolone as an add-on to existing SOC ADTs, mean CFB HAMD-17 was −17.9/−7.7 (n=12/9; p=.0001), −11.4/−12.2 (n=56/57; p=.5979), and −13.8/−12.6 (n=75/77; p=.3552) for zuranolone/placebo in MDD-201B, MOUNTAIN (LSM), and WATERFALL (LSM), respectively; and −15.5/−16.5(n=293/75) for ZRN30/ZRN50 in SHORELINE. Zuranolone was generally well tolerated regardless of existing SOC ADT use. Conclusions Zuranolone demonstrated consistent depressive symptom improvement and safety profile regardless of existing SOC ADT use in adults with MDD.Short Description: In the LANDSCAPE clinical development program—designed to evaluate the efficacy and safety of zuranolone—adults with major depressive disorder (MDD) demonstrated improvements in depressive symptoms (measured by mean change from baseline in HAMD-17 total score at Day 15) following treatment with zuranolone as monotherapy or an add-on to standard-of-care (SOC) antidepressants (ADTs). Efficacy and safety of zuranolone in adults with MDD was generally consistent as monotherapy or as an add-on to existing SOC ADTs.Name of Sponsoring Organization(s): This study was sponsored by Sage Therapeutics, Inc., and Biogen Inc.