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NEW YORK CITY -- Brexanolone IV achieved rapid and durable relief of moderate-severe postpartum depression (PPD) in two randomized, double-blind, placebo-controlled phase III studies reported here.

With change in 17-item Hamilton Rating Scale for Depression (HAM-D) score from baseline at 60 hours as the primary endpoint in both trials, patients receiving the drug showed double-digit declines in scores that persisted for 30 days, according to Samantha E. Meltzer-Brody, MD, of the University of North Carolina in Chapel Hill, and colleagues whose reports appeared as posters at the .

Developer Sage Therapeutics submitted a marketing application to the FDA last month. If successful, brexanolone will be the first antidepressant approved specifically for PPD, which affects an estimated 11.5% of new mothers in the perinatal period.

Brexanolone is a proprietary formulation of allopregnanolone, a neurosteroid that the study authors described as "a positive allosteric modulator of gamma-aminobutyric acid A (GABA_A) receptors." This is a relatively novel target in depressive syndromes; current drugs mostly address serotonin and/or norepinephrine pathways. However, a number of studies in humans and animals have tied low GABA levels to depression, suggesting that a carefully designed GABA-active agent might be an effective treatment.

One of the trials, dubbed Hummingbird 202B, involved patients with severe PPD, defined as HAM-D score of at least 26; the other, Hummingbird 202C, tested the drug in patients with moderate PPD, with HAM-D scores of 20-25.

Study 202B randomized patients to two doses of the drug -- 60 or 90 μg/kg/hour -- or placebo delivered by infusion over 60 hours. Study 202C only tested the 90-μg/kg/hour dose versus placebo, also as a 60-hour infusion.

Participants were ≤6 months postpartum at screening. Enrollment required a diagnosis of PPD based on a major depressive episode diagnosis no earlier than the third trimester and no later than the first 4 weeks following delivery.

The group with moderate PPD (study 202C) included 104 women. HAM-D total score from baseline of 14.2 points at 60 hours in the brexanolone 90 mg/kg/hour group compared with a 12.0-point reduction in the group who received the placebo (P=0.0160).

Statistical significance was first observed at hour 48 and sustained through day 7, and the mean reduction from baseline in HAM-D score seen at hour 60 in the brexanolone group was maintained at day 30. Clinical Global Impression-Improvement (CGI-I) scales also improved in brexanolone patients (P=0.0005 versus placebo).

The severe PPD group (study 202B) included 122 patients. At hour 60, the 90-μg/kg/hour group showed a mean reduction in HAM-D total score of 17.7 points from baseline compared with 14.0 points with placebo (P=0.0252). Treatment with 60 μg/kg/hour brexanolone produced a significant mean reduction in HAM-D total score of 19.9 points versus placebo (P=0.0013). In the brexanolone groups, reductions in HAM-D total score were first observed at 48 hours, and the effect at 60 hours was maintained at the 30-day follow-up. Additionally, there were significant improvements in the CGI-I at hour 60 at both doses relative to placebo.

Study authors offered no explanation for the numerically greater response with the lower brexanolone dose. Although HAM-D reductions with the higher dose were significantly greater than with placebo at the 60-hour and 30-day points, it showed no advantage at any other evaluation. The lower dose, on the other hand, was consistently superior to placebo. The high dose also did not produce greater rates of HAM-D remission (score of 7 or less) versus placebo, whereas the 60-μg/kg/hour dose did.

Brexanolone was well-tolerated, with common adverse events including headache, dizziness, and somnolence. One patient in each group had a serious adverse event. Neither required hospitalization.

Stephen Kanes, MD, PhD, Sage's chief medical officer and a study co-author, called brexanolone "game-changing" in an interview with MedPage Today. "If approved, it will entirely change the paradigm within which these patients are treated," he asserted.

Kanes said PPD is now treated with conventional antidepressants and therapy that take weeks to months to become effective. In addition to the rapid onset of treatment effect with brexanolone, he noted that the single 60-hour infusion appears to be all that is needed in this population.