Nancy A. Melville

June 05, 2017

MIAMI – An investigational formulation of allopregnanolone, a metabolite of progesterone, in which dosing replicates soaring levels of the hormone that occur during the height of pregnancy, appears to lead to rapid improvement of symptoms of severe postpartum depression.

Results of a double-blind phase 2 study show that following 60-hour intravenous administration of the drug, known as brexanolone, the majority of patients experienced significant improvement in depressive symptoms. The improvement began at 24 hours and was sustained at 30 days.

"The rapid onset of response, the robust treatment effect size and durability of the response we are seeing with this treatment are quite different from anything else available for postpartum depression," said Samantha Meltzer-Brody, MD, MPH, an associate professor in the Department of Psychiatry at the University of North Carolina (UNC) at Chapel Hill and director of the Perinatal Psychiatry Program at the UNC Center for Women's Mood Disorders.

The findings were presented here at the American Society of Clinical Pharmacology (ASCP) 2017 Annual Meeting, and the study was published online June 12 in the Lancet.

Rapid, Sustained Improvement

In preclinical studies, allopregnanolone, an endogenous neuroactive steroid, has been associated with rapid behavioral changes.

Following childbirth, levels of allopregnanolone plummet, leading to speculation that it plays a role in postpartum depression. To test the theory, the dose of brexanolone, an injectable agent, was designed to mimic the levels of exposure to allopregnanolone that are typical in the third trimester of pregnancy.

In testing the formulation in a previous proof-of-concept study involving four patients with severe postpartum depression, the authors found significant improvements in depression on the 17-item Hamilton Rating Scale for Depression (HAM-D).

The new double-blind phase 2 study tested the treatment against placebo. The study enrolled 21 women who were admitted to the UNC's Perinatal Psychiatric Inpatient Unit with severe postpartum depression (HAM-D scores >26) and who were less than 6 months post partum. They were randomly assigned in a 1:1 ratio to receive a 60-hour intravenous infusion either with brexanolone on an up- and down-titration cycle or a placebo.

In the brexanolone group, the study met its primary endpoint of a reduction of HAM-D scores of more than 20 points. The reduction in HAM-D scores in the brexanolone group was 12 points greater than the reduction in the placebo group (P = .008).

Improvement was sustained through the study's 30-day follow-up period.

Up to 70% of patients in the brexanolone group achieved remission from depression at 60 hours, defined as HAM-D scores of 7 or lower, compared to just 9% in the placebo group (P = .008). Remission was maintained through the 30-day follow-up (P = .03).

Similar improvement was also seen in scores on the Montgomery–Åsberg Depression Rating Scale, with significantly greater improvement in the brexanolone group (P = .01 at all follow-up time points).

There were no serious adverse events, deaths, or discontinuations, and the drug was generally well tolerated.

Dramatic Results

Dr Meltzer-Brody said the improvement she observed in one of the first women in the proof-of-concept study was dramatic.

"I can tell you, clinically, it was bizarre," she told meeting delegates. "Over the first 24 hours, the patient went from being profoundly depressed, withdrawn, not eating, and not interacting to making a complete state change. She perked up and was smiling and talking with other patients. I would have been skeptical if I hadn't seen it myself," she said.

Among existing treatments for postpartum depression, selective serotonin reuptake inhibitors (SSRIs) are the most common pharmacologic choices. However, inconsistent response rates underscore the need for improved options.

Administration via infusion is necessary because oral availability of allopregnanolone is poor.

Dr Meltzer-Brody noted that even the hospital's nurses were skeptical about whether women would be willing to receive a treatment requiring a 60-hour infusion, but she underscored the fact that the often dire nature of postpartum depression in many cases makes the decision easy.

"Any of us who takes care of this patient population knows that this can be an absolute crisis. Several of these patients had not responded to SSRIs and were even beginning to think that ending their life was an option, so most people in this position simply say 'sign me up' because they just want to make this go away," she said.

Recruitment has started for a phase 3 trial of brexanolone for postpartum depression. Known as the Hummingbird Study, the multicenter trial will be conducted in at least 50 sites across the United States. Brexanolone is also being investigated in a phase 3 study as an interventional treatment for super-refractory status epilepticus.

Compelling Findings

Commenting on the findings, discussant Lee Cohen, MD, professor of psychiatry and director of the Massachusetts Center for Women's Mental Health, in Boston, said the rapid nature of improvement that was observed is particularly compelling.

"For those of us who take care of this population, clinically, that really resonates," he said. "You want to get patients well and to get them well quickly."

He added going that forward, it will be important to study the role of anxiety in this patient population.

"In clinical trials in postpartum depression, the comingling of anxiety with depression is so great. So with this molecule, it will be interesting to see what's driving the improvement in mood and whether amelioration of anxiety is playing a role. It will also be interesting to see if the drug works as a stand-alone or as an adjunctive treatment," he said.

The study was supported by the National Institutes of Health and Sage Therapeutics. Dr Beltzer-Brody has relationships with Sage Therapeutics and J&J/Jansen. Dr Cohen has consulting relationships with Noven Pharmaceuticals and JDS Therapeutics LLC and has received research support from Alkermes Biopharmaceuticals, AstraZeneca Pharmaceuticals, Otsuka Pharmaceuticals, and others.

American Society of Clinical Psychopharmacology (ASCP) 2017 Annual Meeting. Presented May 31, 2017.

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