The Food and Drug Administration on Friday granted approval to a new kind of antidepressant, clearing an oral medicine developed by partners Sage Therapeutics and Biogen for postpartum depression.
But, in a decision that will restrict how widely it’s used and the amount of revenue it generates, the agency rejected the companies’ attempt to also win approval for major depressive disorder, or MDD.
According to Biogen, the FDA found the companies’ clinical trial evidence insufficient proof that the medicine, known scientifically as zuranolone, is effective for MDD and asked for further testing.
Both Sage and Biogen have identified zuranolone, which will be sold under the brand name Zurzuvae, as a key product for their near-term growth, with an approval in MDD a core part of their calculus. That’s because, while estimates vary, health authorities believe tens of millions of people in the U.S. experience MDD, making it one of the most common mental disorders.
Yet, mixed results from studies in MDD appear to have driven the FDA’s decision to approve zuranolone only for postpartum depression, or PPD. Around 500,000 women experience postpartum symptoms in the U.S. each year, per an estimate cited by the companies.
“We believe that Zurzuvae will be an important option to treat PPD and we will thoroughly review the feedback from the FDA on the use of zuranolone in MDD to determine next steps,” Biogen CEO Chris Viehbacher said in a statement.
For the past three decades, doctors often prescribed so-called SSRI drugs like Prozac, Lexapro and Zoloft to treat depression. But those medications don’t work for everyone, and they can cause a variety of side effects, from weight gain and impaired cognitive function to aggression and suicidal thoughts.
Zuranolone acts differently than SSRIs; it amplifies proteins that regulate a kind of chemical messenger found in the central nervous system. Clinical trials have shown the drug doesn’t have the more worrisome side effects seen with other antidepressants.
It also appears to provide rapid relief, though in MDD its degree of benefit remains unclear. A large study of zuranolone in that indication failed in 2019. And since then, further late-stage testing has raised questions about how substantial and long-lasting its effects are.
Sage and Biogen have maintained their drug has the ability to quickly rebalance “dysregulated neuronal networks to help reset brain function.”
The FDA based its approval decision in PPD on two clinical trials. One, named SKYLARK, found zuranolone to be significantly better than a placebo when tested in postpartum patients, as measured by a widely used scale that evaluates symptoms of depression. These improvements were seen as early as three days into treatment and sustained throughout 45 days of follow-up.
Other antidepressants can take weeks to show an effect.
“Postpartum depression is a serious and potentially life-threatening condition in which women experience sadness, guilt, worthlessness — even, in severe cases, thoughts of harming themselves or their child,” said Tiffany Farchione, director of the psychiatry division in the FDA’s main drug review office, in a statement.
“Having access to an oral medication will be a beneficial option for many of these women coping with extreme, and sometimes life-threatening, feelings,” Farchione added.
Against MDD, results with zuranolone weren’t as clear-cut. The failed trial, for example, showed zuranolone to be better than a placebo in the initial days following treatment. But its effects appeared to wane, and by day 15 the difference between the drug and control groups had narrowed enough that the study missed its primary goal.
Sage redrew development plans for zuranolone shortly after that setback, announcing in March 2020 how it would conduct three additional late-stage trials in MDD, with the hope of generating enough positive data to support an FDA approval application. A month later, the company said it would lay off a little over half of its workforce to help reduce costs.
Later that year, though, Sage agreed to sell some of the rights to zuranolone and a separate, experimental drug for tremors to Biogen. In exchange, Biogen gave its new partner an upfront cash payment and equity investment that, together, were worth $1.5 billion.
Data from those three additional studies, dubbed WATERFALL, SHORELINE and CORAL, were released between mid-2021 and early 2022. Each had a slightly different design; SHORELINE followed participants for a year after treatment, while CORAL administered zuranolone along with a standard-of-care antidepressant. All tested a higher dose of zuranolone than the failed trial, and all hit their main goals.
The studies weren’t completely positive, however. Zuranolone didn’t meet some of their “secondary” aims, and the drug’s effects still seemed to diminish over time.
Barry Greene, Sage’s CEO, said in a statement that the company was “highly disappointed” in the FDA’s rejection of the drug for MDD.
For postpartum use, Zurzuvae will carry a boxed warning advising doctors to instruct their patients not to drive a motor vehicle or engage in other complex tasks due to the drug’s depressant effects.
The companies don’t expect to make the drug commercially available until the fourth quarter of this year, as the Drug Enforcement Administration has to first classify it as a controlled substance.
Sage already sells a drug, Zulresso, for postpartum depression. However, it’s given as a continuous intravenous infusion over 60 hours, and carries an FDA warning for excessive sleepiness and sudden loss of consciousness. Sales have been minimal since its 2019 approval.
Ahead of the FDA’s approval decision, analysts at Jefferies forecast annual sales of zuranolone would reach more than $1 billion a year, provided the drug secured an MDD indication. They modeled peak sales from PDD somewhere in the range of $300 million to $500 million.