Brexanolone Passes Phase 3 Hurdle

Postpartum depression (PPD) is a common and serious complication following childbirth, affecting up to 20 percent of women by some estimates. Studies show that PPD not only negatively affects mothers, but also their children and families.

While conventional antidepressants can be effective at treating women with PPD, a therapeutic effect can take several weeks, and, as with other forms of depression, not every woman will respond to these medications. Additionally, some women may be hesitant to take antidepressants while breastfeeding, even though studies have suggested risks to a baby are minimal.

Women with PPD may soon have another treatment option: brexanolone, an intravenous formulation of the steroid hormone allopregnanolone. A pair of large, phase 3 clinical studies published in late-August found that a single, 60-hour infusion of brexanolone provides rapid and sustained mood improvement in women with PPD, without significant adverse effects.

“As the lead academic investigator who has been involved with brexanolone since the first open-label pilot study, this strong, compelling, and now peer-reviewed phase 3 data gives me a reason to be optimistic,” said Samantha Meltzer-Brody, M.D., M.P.H., director of the Perinatal Psychiatry Program at the University of North Carolina.

In April, Sage Therapeutics, developer of brexanolone, submitted a New Drug Application to the Food and Drug Administration for brexanolone. Meltzer-Brody told Psychiatric News that it is possible a decision on the medication will be reached before the end of the year.

As Meltzer-Brody and colleagues described in the Lancet, the two multisite trials enrolled 246 women who had developed depression within the first six months following childbirth. One trial included 138 women with severe PPD (scores of 26 or higher on the Hamilton Depression rating scale, or HAM-D); the other included 108 women with moderate PPD (HAM-D scores of 20 to 25). All participants were randomized to receive either a 60-hour infusion of brexanolone or placebo.

In both trials, the women receiving brexanolone showed greater improvements in their depressive symptoms than placebo after 60 hours. The effects of brexanolone were evident as early as 24 hours into the infusion protocol, and the symptom improvements were also maintained for up to 30 days.

Brexanolone was well-tolerated by the women; the rates of adverse side effects were the same in the brexanolone and placebo infusions (50 percent), with headache, dizziness and drowsiness reported as the most common side effects. Between both studies, only three women had to stop brexanolone infusions because of side effects (one woman in the placebo group also discontinued).

“The rapid onset of symptom improvement is especially encouraging,” noted Kristina Deligiannidis, M.D., an associate professor at the Feinstein Institute for Medical Research in Manhasset, New York, who was also involved in these trials. “With conventional antidepressants, we usually see our first small signal of improvement after two weeks, and then more robust effects after four, six, or eight weeks, depending on how fast we can titrate the medication to the optimal dose.”

The delay in response to antidepressants is particularly pertinent for postpartum depression, as any delays in treatment adversely impact a mother’s ability to care for her infant during a critical developmental period.

“I think this is exciting to see the first medication specifically addressing the problem of postpartum depression,” said Kimberly Yonkers, M.D., director of the Center for Wellbeing of Women and Mothers at Yale University. Yonkers was not involved with this trial. “Hopefully, we will see it developed in an oral form and at a price point that makes it affordable for a wide range of women. The current formulation is a bit constraining.”

“The treatment protocol is something we need to figure out,” Deligiannidis said, acknowledging that many new mothers may not have the time or resources to spend three days in a hospital receiving a brexanolone infusion, potentially every month (since long-term data is not yet available). “It’s possible that after an initial course of brexanolone, most women will have improved to the point we can switch them to oral antidepressants. That will minimize the number of prolonged infusion sessions.”

Another possibility, Deligiannidis said, is that women might be able to receive brexanolone in a non-hospital setting, similar to existing infusion centers for dialysis or chemotherapy, or even treatment at home. “Postpartum women already receive visiting nurse services in some situations,” she noted.

While Meltzer-Brody agrees that the long intravenous delivery of brexanolone is a hurdle she feels the benefits of the medication outweigh the potential challenges of a few days in the hospital. “So many women with postpartum depression have chronic symptoms that don’t respond well to current therapies,” she said. “If you were to tell them, ‘you have to give up three days but then you might be in remission,’ I think most would take that chance.”

These phase 3 trials were funded by Sage. Both Meltzer-Brody and Deligiannidis received support from Sage via grants to their respective academic institutions. Neither has received personal fees from the company or owns any stock options. ■