Zuranolone reduces symptoms of major depression

Zuranolone is a novel, oral, neuroactive steroid and GABAA receptor positive allosteric modulator. Results from the pivotal WATERFALL study of zuranolone in patients with major depressive disorder (MDD) showed a statistically significant and clinically meaningful reduction in depressive symptoms after 15 days [1].

Dr Anita Clayton (University of Virginia, VA, USA) presented the results of the multicentre, phase 3 WATERFALL study (NCT04442490). The WATERFALL study evaluated the efficacy and safety of zuranolone compared with placebo in 543 adults with MDD with a total score of ≥24 on the 17-item Hamilton Rating Scale for Depression (HAMD-17). Participants were randomised 1:1 to zuranolone 50 mg or placebo, once daily for 2 weeks. Pre-existing antidepressants could be continued.

The primary endpoint was a statistically significant change from baseline in HAMD-17 at day 15. This endpoint was met, with a difference of -1.7 points in favour of zuranolone versus placebo (least-squares mean change from baseline [SE] -14.1 [0.51] vs -12.3 [0.50]; P=0.0141). At all measured time points through day 42, HAMD-17 results demonstrated a numerical improvement in depressive symptoms versus placebo. The difference reached nominal significance at days 3, 8, and 12 (all P<0.001). The SF-36 Health Survey (v2) patient-reported outcome measure, collected during the double-blind period, demonstrated that zuranolone improved quality of life and overall health across nearly all functioning and well-being domains at day 15, and continued to do so after completion of treatment at day 42. The rate of treatment-emergent adverse events (TEAEs) was 60.1% versus 44.6% in the placebo group. The severity of almost all observed TEAEs was mild to moderate: 95.0% versus 97.5%. The most common TEAEs in the zuranolone versus placebo group were somnolence (15.3% and 3.0%), dizziness (13.8% and 2.2%), headache (10.8% and 7.8%), and sedation (7.5% and 0.4%).

Zuranolone was generally well-tolerated and demonstrated a safety profile consistent across the clinical development programme.

1. Clayton A. Zuranolone in major depressive disorder: topline results from the phase 3, multicenter, randomized, double-blind, placebo-controlled WATERFALL study. S.09.02, ECNP 2021 Congress, 2–5 October.

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Posted on 26 November 202117 May 2024