A joint US Food and Drug Administration (FDA) advisory panel voted in favor of approval for brexanolone intravenous infusion (Zulresso, Sage Therapeutics) as the first-ever drug indicated for the treatment of postpartum depression.
The joint panel of the FDA's Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 17-1 that the benefits outweigh the risks of brexanolone for the treatment of moderate to severe postpartum depression.
However, because brexanolone is also associated with an increased risk for sedation-related events, including loss of consciousness, the panel strongly advised the FDA to establish strict guidance within the agency's Risk Evaluation and Mitigation Strategies (REMS) program, which would require that the drug be delivered by qualified staff in certified facilities.
Brexanolone's mechanism of action is different from that of currently available antidepressants. It is chemically identical to endogenous allopregnanolone, a hormone that drops following childbirth. Brexanolone acts as a positive allosteric modulator of gamma-aminobutyric acid-A (GABAA) receptors, which become dysregulated in the postpartum period.
Several panel members called the rapid-acting drug a "breakthrough" in the treatment of women who meet criteria for a major depressive episode during the third trimester or following childbirth, since current antidepressants take several weeks to work and aren't always effective in this patient population.
"I think it could be of tremendous help in changing the trajectory for postpartum depression," said panel chair Rajesh Narendran, MD, attending psychiatrist at the Resolve Crisis Network and associate professor in radiology and psychiatry at the University of Pittsburgh, Pennsylvania.
Unanimous Agreement on Efficacy
The panel unanimously agreed that the drug is effective, based on both study data provided by Sage and personal testimonies from patients who spoke at the meeting. Sage representatives reviewed data from three key phase 3 trials, which were presented earlier this year at the American Psychiatric Association annual meeting and subsequently published in The Lancet.
The three placebo-controlled, randomized studies enrolled a total of 247 patients diagnosed with postpartum depression from the third trimester through 4 weeks postpartum. Following delivery, 38 women were titrated to 60 µg/kg/hour of brexanolone and 102 women to 90 µg/kg/hour, and 107 women received placebo. The infusions were delivered continuously for 60 hours.
The primary efficacy endpoint, a significant difference from baseline on the 17-item Hamilton Depression (HAM-D) scale at hour 60, was met in all three studies. The improvement was maintained at 30 days post-infusion, and no significant differences were seen between the 60 and 90 µg/kg/hour dose groups.
Other endpoints were also significantly improved with brexanolone versus placebo, including the proportions achieving HAM-D remission at hour 60, up to 70% among 10 patients who received 90 µg/kg/hour in one of the studies versus just 9% with placebo (P = .008).
But in a second study, greater remission was seen with the 60 than the 90 µg/kg/hour, 51% and 31% (P = .083), respectively, versus 16% for placebo (P = .001).
Several clinical trial participants, whose travel expenses had been paid by Sage, gave emotional testimony about having been despondent prior to receiving the drug and credited it with saving their lives and their children's well-being.
The panel voted 18-0 that the evidence was substantial enough to support a claim of efficacy.
Panel member Felipe A. Jain, MD, assistant professor of psychiatry at Harvard Medical School, Boston, Massachusetts, commented: "The evidence presented today for moderate and severe postpartum depression was overwhelming, and remarkable for [brexanolone's] high effectiveness, rapidity of effect, and durability of response after the infusion."
Panelist Jess G. Fiedorowicz, MD, PhD, of the departments of psychiatry, epidemiology, and internal medicine at the University of Iowa, Iowa City, said, "These impressive results with a novel therapy are frankly groundbreaking."
Loss of Consciousness a Major Safety Concern
There were no deaths in the studies, but there were two events the FDA deemed serious: suicidal ideation 2 days after infusion in a patient given the 60 µg/kg/hour dose and syncope/altered consciousness in a patient in the 90 µg/kg/hour dose group.
In addition, "sedation-related events" occurred in more patients, including sedation/somnolence in 15% in the combined brexanolone groups versus 6% with placebo, dizziness/lightheadedness/presyncope/vertigo in 12% versus 7%, and syncope/loss of consciousness in 4% (6 of 140 patients receiving the drug) vs 0% with placebo. No dose–response pattern was seen for these adverse events.
The patients were closely monitored in the study and recovered, but panel members expressed concern about what might happen to both the mother and her baby if such side effects were to occur in the real world, and some also worried that the true risk couldn't be assessed with just 140 patients in the final safety cohort.
In anticipation of these concerns, FDA Risk Management Analyst Leah M. Hart, PharmD, outlined the agency's proposed REMS plan for brexanolone.
The treatment setting would be required to have overnight capabilities for patients for approximately 72 hours, intravenous infusion capabilities, and healthcare professionals onsite at all times who are trained to intervene if the patient experiences sedation or loss of consciousness.
And, Hart said, all patients treated with brexanolone would be enrolled in a registry to better characterize the risks.
Fiedorowicz commented, "I have concerns about safety that cannot be fully answered by the limited data...I'm concerned about loss of consciousness and sedation." But he added, "I think that in a highly supervised setting...a REMS could mitigate these safety concerns while awaiting further post-marketing study."
There was some disagreement on the panel as to what specific type of professional and/or facility would qualify, with some stating that only a hospital setting with a trained nurse would be sufficient, whereas others felt that alternative professionals could be trained and settings configured to perform the type of monitoring that was done in the trials.
Some advised that the FDA give brexanolone a Black Box warning in addition to the REMS.
Panel members also debated the type of interaction the mother should be allowed with her newborn while she receives the infusion, with suggestions ranging from no contact to supervised contact while she's seated.
The panel also spent time discussing the pros and cons of the two different target doses. Several panelists pointed out that it's easier to start by targeting the 90 µg/kg/hour dose and titrating down if an adverse event is detected than targeting the 60 µg/kg/hour dose and up-titrating if inefficacious.
But the panel agreed that the studies didn't provide sufficient data to determine which approach is optimal and that additional data should be collected post-marketing.
Overall, the general consensus was that the FDA could work out the details and brexanolone should be brought to market.
Jain commented, "As a clinician, I've seen patients with postpartum depression who have suffered with the shame it brings at this vulnerable point in their lives. Despite their best efforts, it has interfered with motherhood and their children's development. I believe that brexanolone may be a gamechanger in the treatment of postpartum depression. This is what hope looks like."
FDA advisory panels are vetted for conflicts of interest and special waivers are granted if necessary. No waivers were needed for this meeting.
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Cite this: FDA Panel Backs Novel Treatment for Postpartum Depression - Medscape - Nov 05, 2018.