The FDA has just made brexanolone (Zulresso) the first medicine approved specifically for post-partum depression, a potentially devastating disorder that afflicts roughly one in every seven new mothers in the U.S., according to the American Psychological Association.
Now the drug’s owner, Sage Therapeutics (NASDAQ: SAGE), of Cambridge, MA, must convince doctors to prescribe and new mothers to accept the treatment, which acts fast but requires a 60-hour continuous infusion in a health facility. The approval comes with other “black box” warnings about side effects.
Sage’s list price for brexanolone is $7,450 per vial, and it estimates a total course of therapy will cost $34,000.
While the approval is significant, there are caveats, especially the continuous 60-hour infusion that could limit its reach. The difficult logistics of the drug leave opportunities for better solutions. A rival treatment from Marinus Pharmaceuticals (NASDAQ: MRNS), also infusible, succeeded in a mid-stage study earlier this year. And Sage is developing a pill, SAGE-217, that works similarly to brexanolone. Sage reported successful late-stage data in January, and if approved, SAGE-217 could cannibalize brexanolone.
“We have to figure out the business side, how to make the two co-exist,” says Sage chief business officer Mike Cloonan. “But [before today] nothing was approved specifically for PPD. Multiple options for patients is a good thing.”
PPD 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 used off-label to treat PPD. But none are specifically approved for the condition or proven in clinical testing to be effective. They also take weeks to kick in, if they work at all.
The symptoms of PPD are similar to major depressive disorder—the most common type of depression—but the timing of the disease itself makes it a unique illness. In review documents, the FDA noted that PPD is a “life-threatening condition” due to the risk of suicide—the most common form of maternal death after childbirth in the developed world. Prolonged cases of PPD can also lead to behavioral development problems for the child.
Unlike typical antidepressant pills, Sage’s drug is an infusion of a chemical that is meant to normalize levels of the hormone allopregnanolone, which rise during pregnancy. The hypothesis is by doing so, PPD symptoms will dissipate—and much faster than they would with a typical antidepressant. Sage believes that one treatment should be enough to solve the problem.
Compared to a placebo in clinical testing, brexanolone led to a statistically significant reduction in a measure of depression symptoms known as the HAM-D scale 60 hours after they were treated. Those results prompted an FDA panel to vote overwhelmingly in favor of brexanolone in November.
The drug was largely well tolerated. Most commonly, patients experienced headaches, dizziness, and drowsiness. Yet the panel expressed concern about a particular side effect: Six of 140 women receiving brexanolone either were close to losing consciousness during the infusion or abruptly fell into a deep sleep. They didn’t experience major safety problems, but an abrupt loss of consciousness could be dangerous for mother and child. What’s more, the sleep or loss of consciousness was unpredictable, not apparently tied to any particular dose of brexanolone or other variable.
At the November advisory hearing, panelists debated whether brexanolone should only be administered as an in-patient procedure in a hospital, which would separate mother from child and family. The agency delayed approval of brexanolone by three months so it could review a plan, from Sage, to mitigate the potential risks of taking the drug.
The FDA says brexanolone patients must be monitored for loss of consciousness and a drop in oxygen levels, and cannot be left alone with their children.
Citing the sleep and consciousness issues, as well as the possibility of Sage’s own SAGE-217 offering a better solution in a year or two, SVB Leerink analyst Marc Goodman, in a research note, predicted that brexanolone would become a “niche product with sales below expectations.” Insurance coverage would be one hurdle, and another could be a difficult certification process for sites that would have to follow a strict, potentially complicated strategy to help contravene the unpredictable side effects.
Sage’s Cloonan acknowledges that the launch will be a learning experience. “We’re building the PPD market,” Cloonan says. Sage will “find out what’s really important to new moms,” he says. Until brexanolone rolls out, Sage can only guess which mothers will opt to be hooked up to an IV for two and a half days straight, instead of taking a pill, in order to have better odds of a faster remission.
Also unknown is how the 60-hour IV will impact breastfeeding. Data presented by Sage at a medical meeting earlier this year showed that it took an average of three days after the infusion for breast milk to clear any trace of brexanolone. The same presentation noted that breast milk output dropped 41 percent in seven days post-infusion, but a Sage spokesperson said the output data weren’t statistically significant because of study design and a small sample size of patients.
“I wouldn’t presume to say somebody wouldn’t necessarily want the infusion,” says Sage chief medical officer Stephen Kanes. “The unmet need is extraordinarily high, and the notion that they can get better that quickly is transformational.”