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FDA panels back brexanolone infusion for postpartum depression


 

A joint panel of the Food and Drug Administration voted Nov. 2 in support of brexanolone infusion as a treatment for postpartum depression.

The 17-1 vote by members of the Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee was based primarily on data from three studies, including 247 women aged 18-44 years with postpartum depression; 140 received brexanolone and 107 received placebo. Effectiveness was assessed based on the Hamilton Depression Scale (HAM-D) at the end of the infusion (hour 60).

In all three studies, patients given brexanolone showed significantly improved HAM-D scores, compared with placebo. The patients experienced significant differences at hour 24, which illustrated the rapid response. “The individual item scores of the HAM-D consistently favored brexanolone IV over placebo, confirming an overall antidepressant effect of the drug,” according to the briefing document of Sage Therapeutics, developer of the drug. In addition, more than 80% of the patients in the treatment and placebo groups sustained their improvement in symptoms at 30 days after the end of the infusion.

“[Postpartum depression] is symptomatically indistinguishable from an episode of major depression,” the FDA briefing document said. “However, the timing of its onset has led to its recognition as a potentially unique illness. There are no drugs specifically approved to treat [postpartum depression].”

Some clinicians use drugs approved for major depression to treat postpartum depression, but the effectiveness of these drugs is limited, the agency said. Other interventions, such as electroconvulsive therapy, repetitive transcranial magnetic stimulation, and psychotherapy also are used, but they can take several weeks to show results.

Recent estimates of postpartum depression in the United States range from about 8% to 20%, according to the FDA document. and both the FDA and Sage Therapeutics agreed on the need for additional treatment options for women with postpartum depression. Potential advantages of brexanolone include a rapid onset of action and significant improvement of depressive symptoms, according to Sage.

The treatment protocol for brexanolone involves a single 60-hour continuous infusion with a recommended maximum dose of 90 µg/kg/h, referred to as a “90 dose regimen.” The patient receives a single infusion per episode of postpartum depression. The infusion includes three dosing phases: titration at 30 μg/kg/h for 4 hours followed by 60 μg/kg/h for 20 hours (hour 0-24), maintenance at 90 μg/kg/h for 28 hours (hour 24-52), and taper at 60 μg/kg/h for 4 hours – followed by 30 μg/kg/h for 4 hours (hour 52-60).

Brexanolone is an allosteric modulator of GABAA receptors and “a new molecular entity not currently marketed anywhere in the world for any indication,” according to the FDA document. The drug originally was studied as a treatment for seizure patients before its antidepressant properties were discovered.

Adverse reactions observed in 3% or more of the brexanolone patients during the 60-hour treatment and 4-week follow-up included dry mouth, infusion site pain, fatigue, headache, sedation/somnolence, dizziness/vertigo, and loss of consciousness.

Of those reactions, loss of consciousness was the issue of greatest concern to the committee members and informed their discussion of the strict Risk Evaluation and Mitigation Strategy protocol that would be needed to accompany approval of the drug. The details of the REMS will be determined, but the basics of the FDA’s proposed REMS to mitigate the risk of loss of consciousness include administration of the drug only in medically supervised settings by an authorized representative.

In addition, the proposed REMS states that the authorized representative must “establish policies and procedures to ensure that 1) all staff are trained on the risks and 2) the product is not dispensed for use outside the health care setting.”

The proposed REMS also stated that, “Patients must be continuously monitored for the duration of the infusion and 12 hours after, by health care provider who can intervene if the patient experiences excessive sedation or loss of consciousness.”

Despite those concerns, which most committee members thought could be addressed by the REMS, the overall impression of the committees’ members was that brexanolone could have a significant impact on postpartum depression. According to one member, brexanolone is mechanistically “groundbreaking” and “could be a tremendous help in changing the trajectory of postpartum depression.”

The FDA usually follows its panels’ recommendations, which are not binding.

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