With FDA Panel’s Nod, First Postpartum Depression Drug Nears Approval

Xconomy Boston — 

A panel of experts on Friday voted in favor of bringing what could be the first-ever drug approved specifically for postpartum depression to market. But should it get the expected green light from the FDA next month, how widely will the treatment, which requires a continuous, 60-hour intravenous infusion that a professional will have to monitor, be used?

By a 17 to 1 vote, the panel agreed that the benefits of the drug outweigh its risks for treating postpartum depression, or PPD—as long as patients are monitored in a healthcare facility and the treatment is administered under a risk mitigation plan that would need to be approved by the FDA.

Though the vote isn’t a guarantee of an approval for the drug’s developer, Cambridge, MA-based Sage Therapeutics (NASDAQ: SAGE), the FDA typically sides with its advisory panels. The agency will decide on the fate of the drug, known as brexanolone, by Dec. 19.

There was little debate at Friday’s hearing about the drug’s effectiveness. Panelists voted unanimously, 18 to 0, that the drug is an effective, and most importantly fast-acting treatment for PPD. Panel member Felipe Jain, a Harvard Medical School psychiatrist, described the evidence presented supporting the drug’s efficacy as “overwhelming.” He said he believes the Sage drug may be a “game changer” given the limited treatment options currently available to women who have the condition.

“This is what hope looks like,” Jain said.

Rather, the discussion primarily focused on how to get the treatment to the women who need it without risking their health. Administering the drug is a complex process: it is infused through a slow, 60-hour infusion that requires dialing up, and then down, doses of brexanolone by switching the IV bags along the way. And the FDA has highlighted the propensity of some patients on the drug, in testing, to abruptly lose consciousness or get sedated. Those issues were resolved in clinical testing by immediately switching off the infusion. As a result, no significant health problems, like a potentially dangerous slowing of breathing, occurred.

But the agency and panelists were concerned as to whether things would be the same in the real world, beyond the hyper-controlled environment of a clinical study.

“This administration…is guaranteed for medical errors. Even in an intensive care unit with experienced ICU nurses who do it all the time we still see errors with this type of thing,” said panelist Anne-Michelle Ruha, an associate professor of emergency medicine at the University of Arizona College of Medicine.

That’s why the agency has suggested implementing a risk management program in which a new mother is consistently monitored by a healthcare professional at a hospital or other professional setting—which may curtail its use, until Sage proves the drug is safe to use at home.

To have patients monitored in “a healthcare environment seems more sensible to us, at least to start,” said Mitchell Mathis, the deputy director of the FDA’s division of psychiatry products.

Even given the limitations, however, the need for a drug like brexanolone is significant. PPD is a very common medical issue. It affects some 12 percent of women giving birth every year in the U.S. and is characterized as a major depressive episode that begins either during pregnancy or within four weeks of delivery.

There are plenty of antidepressants on the market, and many are given off-label to treat PPD. None of them, however, are specifically approved for the condition or proven, in clinical testing, to be effective in doing so. They also take weeks to kick in if they work, and there is no telling which one will.

Indeed, though the symptoms of PPD are similar to major depressive disorder—the most common type of depression—timing of the disease itself makes it a unique illness. The disease is considered a “life-threatening condition” due to the risk of suicide—the most common form of maternal death after childbirth in the developed world, FDA reviewers wrote. Prolonged cases of PPD can also translate to behavioral development problems for the child.

Unlike typical antidepressant drugs, however, brexanolone isn’t a pill. It is an infusion of a chemical that is meant to bring levels of the hormone allopregnanolone, which rise during pregnancy, back to normal. The hypothesis is by doing so, PPD symptoms will dissipate—and much faster than they would with a typical antidepressant. The drug is being developed as a once-per episode of PPD treatment; the implication being that one treatment should be enough to solve the problem. With PPD, “you expect it to be episodic as opposed to a chronic condition like major depressive disorder” where the symptoms persist, said FDA reviewer Tiffany Farchione, the deputy director of the agency’s psychiatry products division.

In clinical testing, the Sage drug led to a statistically significant reduction, compared to a placebo, in a measure of patients’ depression symptoms known as the HAM-D scale 60 hours after they were treated. FDA reviewers appeared satisfied with brexanolone’s effectiveness, calling it “consistent with the efficacy results of other, approved antidepressants.”

The agency’s greater concern, and the focus of much of the panel’s discussion on Friday, was safety. The drug was largely well tolerated—the most common side effects were headaches, dizziness, and drowsiness. But FDA reviewers highlighted the fact that six of 140 women who got brexanolone in clinical testing either were close to losing consciousness during the infusion or abruptly fell into a deep sleep.

These events didn’t lead to major safety problems. But these reactions have been unpredictable—they don’t seem to be tied to any particular variable or dose of brexanolone, and an abrupt loss of consciousness would be dangerous for mother and child. Panelists raised such concerns in their discussion of the drug. Though the number of patients who lost consciousness in the study was small, the numbers of patients who experience that side effect would likely be amplified in real-world use of the drug.

Some panelists were satisfied that such concerns could be addressed with a risk mitigation plan that requires the drug be administered in a healthcare facility. But a few others said brexanolone might need a black box warning on its label—the strongest warning that the FDA can issue to notify physicians and patients about a drug’s risks.

All of which goes into Sage’s challenge going forward: turning brexanolone into a commercial success. FDA scientists stopped short of saying brexanolone should only be administered as an in-patient procedure in a hospital. Keeping new mothers in a hospital during the procedure would separate them from children and family. “It would be in the best interest of public health to have it widely available to the relevant patient population,” the FDA reviewers wrote.

But they weren’t comfortable with home infusions yet either, allowing a mother to be watched just by a family member, or even have a visiting nurse “police the infusion administration.” So they prefer, at least for now, a procedure done in a professional setting, like an infusion clinic.

“We still expect the brexanolone launch to be difficult,” Stifel analyst Paul Matteis wrote after reading through the briefing documents.

Even so, Sage has another way to solve this issue, and it isn’t brexanolone. A much more convenient, experimental pill it’s been developing, SAGE-217, is meant to work the same way as brexanolone—it targets a neurotransmitter called GABA. The drug is being tested in a variety of neurological diseases, among them PPD. It has already succeeded in a mid-stage trial in major depressive disorder, and a Phase 3 study in PPD is currently underway, with results expected later this year.

Frank Vinluan contributed to this report.