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A 2-week oral treatment for major depressive disorder was both safe and effective, according to the phase III WATERFALL study.

Compared with placebo, adults treated with zuranolone, an investigational neuroactive steroid and GABA type A receptor-positive allosteric modulator, saw a significant improvement in depressive symptoms by day 15, reported Anita H. Clayton, MD, of the University of Virginia School of Medicine in Charlottesville.

Measured with the 17-item Hamilton Rating Scale for Depression (HAMD-17), those on zuranolone 50 mg once daily saw a 1.7-point greater drop in total score versus placebo (least squares mean change from baseline -14.1 vs -12.3, P=0.0141) -- meeting the study's primary endpoint.

And by day 42, those who had received zuranolone were able to maintain this significant improvement in depression, Clayton reported in a poster presentation at the Psych Congress, held virtually and in San Antonio.

"Rapid onset of improvement in depressive symptoms was observed starting at day 3 and continuing through day 42," she noted.

At all measured time points -- days 3, 8, and 12 of the treatment period, as well as days 15, 21, 28, 35, and 42 -- Clinical Global Impression (CGI)-Improvement response rates favored zuranolone over placebo. While change from baseline CGI-Severity scores also favored zuranolone at all time points, day 15 scores were not statistically significantly better than placebo (-1.8 vs -1.6 with placebo, P=0.12).

By day 15, anxiety symptoms also improved with zuranolone as measured by the Hamilton Rating Scale for Anxiety (-10.4 vs -9.1, P=0.02).

The study included 271 patients who were randomized to receive zuranolone compared with 272 who received placebo. All participants were 18 to 64 years old, with a diagnosis of major depressive disorder. All had a HAMD-17 total score of 24 or higher at screening; the average total score at baseline was 27 in both groups, and the average baseline Montgomery-Åsberg Depression Rating Scale total score was 35.

Those who received 50 mg of zuranolone took it once daily in the evening for 14 days, and were then followed for an additional 28-day period. Pre-existing use of antidepressant medications was allowed if the patient was on a stable dose for at least 60 days prior to the first day of study treatment. About 30% of both study groups were using antidepressants at baseline.

More than 90% of participants on zuranolone, and 87% of those on placebo, completed the study.

Zuranolone was well tolerated, with 60% of patients experiencing at least one treatment-emergent adverse event -- 32% of which were mild and 25% were moderate -- compared with 45% of those on placebo. The most common adverse events seen in the zuranolone group were somnolence, dizziness, headache, sedation, and diarrhea. No patients died in either group.

The WATERFALL trial is part of the greater Landscape clinical development program for patients with major depressive disorder -- also comprised of the MDD-201B, SHORELINE, and MOUNTAIN studies -- which tested the efficacy of 30-mg zuranolone. Paired with the Landscape program, the developer Sage Therapeutics also tested the 30-mg dose for postpartum depression in the ROBIN and SKYLARK studies, which are part of the Nest clinical development program.

Sage also announced the upcoming CORAL study, with topline data expected in early 2022, testing zuranolone in combination with standard treatment for depression relief.

Zuranolone was granted fast track designation by the FDA in 2017 and breakthrough therapy designation in 2018 for the treatment of major depressive disorder. A few weeks ago, for the drug in the second half of 2022.

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