Long-Term Safety and Efficacy of Initial and Repeat Treatment Courses With Zuranolone in Adult Patients With Major Depressive Disorder: Interim Results From the Open-Label, Phase 3 SHORELINE Study.

Objective: Zuranolone is a positive allosteric modulator of both synaptic and extrasynaptic γ-aminobutyric acid (GABA) type A receptors and a neuroactive steroid approved in the United States as an oral, once-daily, 14-day treatment course for adults with postpartum depression and under investigation for adults with major depressive disorder (MDD). Interim results from the open-label, longitudinal, phase 3 SHORELINE Study (NCT03864614) that evaluated the long-term safety and efficacy of zuranolone in adults with MDD are reported.Methods: This interim report includes patients who were enrolled and had the opportunity to be on study for up to 1 year between February 2019 and September 2021. Adults aged 18-75 years with MDD diagnosed per DSM-5 criteria and a 17-item Hamilton Rating Scale for Depression (HAMD-17) total score ≥ 20 received an initial 30-mg or 50-mg 14-day zuranolone course. HAMD-17 responders (≥ 50% reduction from baseline) at Day (D)15 of the initial treatment period were allowed to continue in the study beyond D28 and were followed up for ≤ 1 year, during which repeat treatment courses were permitted. The primary endpoint was safety and tolerability of the initial and repeat treatment courses through 1 year. Secondary endpoints included change from baseline (CFB) in HAMD-17 total score and need for repeat treatment course(s).Results: As of September 2021, among patients in the 30-mg (n = 725) and 50-mg (n = 199) Cohorts who received a zuranolone dose, 493 (68.0%) and 137 (68.8%), respectively, reported a treatment-emergent adverse event (TEAE); most patients who experienced TEAEs reported mild/moderate events (30-mg Cohort, 90.9% [448/493]; 50-mg Cohort, 85.4% [117/137]). Mean (standard deviation) CFB HAMD-17 total score at D15 of the initial treatment period was -15.2 (7.1) and -16.0 (6.0) for the 30-mg and 50-mg Cohorts, respectively; similar improvements were observed after repeat treatment courses. The proportion of patients who received only 1 treatment course during their time on study was 42.9% (210/489) in the 30-mg Cohort and 54.8% (80/146) in the 50-mg Cohort; 57.1% (279/489) and 45.2% (66/146) patients, respectively, received 2-5 total treatment courses. The majority of patients who initially responded to zuranolone received ≤ 2 total treatment courses (30-mg Cohort, 68.5% [335/489]; 50-mg Cohort, 79.5% [116/146]).Conclusions: Of patients who experienced TEAEs, most reported mild or moderately severe events, and responders to zuranolone experienced improvements in depressive symptoms with initial and repeat treatment courses.Trial Registration: ClinicalTrials.gov identifier: NCT03864614.

Zuranolone for the Treatment of Postpartum Depression.

OBJECTIVE: Postpartum depression (PPD) is a common perinatal complication with adverse maternal and infant outcomes. This study investigated the efficacy and safety of zuranolone, a positive allosteric modulator of synaptic and extrasynaptic GABAA receptors and neuroactive steroid, as an oral, once-daily, 14-day treatment course for patients with severe PPD. METHODS: In this double-blind phase 3 trial, women with severe PPD were randomized in a 1:1 ratio to receive zuranolone 50 mg/day or placebo for 14 days. The primary endpoint was change from baseline in total score on the 17-item Hamilton Depression Rating Scale (HAM-D) at day 15; key secondary endpoints were change from baseline in HAM-D score at days 3, 28, and 45 and change from baseline in Clinical Global Impressions severity (CGI-S) score at day 15. Adverse events were monitored. RESULTS: Among 196 patients randomized (zuranolone, N=98; placebo, N=98), 170 (86.7%) completed the 45-day study. Treatment with zuranolone compared with placebo resulted in statistically significant improvement in depressive symptoms at day 15 (least squares mean [LSM] change from baseline in HAM-D score, -15.6 vs. -11.6; LSM difference, -4.0, 95% CI=-6.3, -1.7); significant improvement in depressive symptoms was also reported at days 3, 28, and 45. CGI-S score at day 15 significantly improved with zuranolone compared with placebo. The most common adverse events (≥10%) with zuranolone were somnolence, dizziness, and sedation. No loss of consciousness, withdrawal symptoms, or increased suicidal ideation or behavior were observed. CONCLUSIONS: In this trial, zuranolone demonstrated significant improvements in depressive symptoms and was generally well tolerated, supporting the potential of zuranolone as a novel, rapid-acting oral treatment for PPD.