- The Food and Drug Administration on Tuesday approved Johnson & Johnson's depression drug esketamine, clearing the first therapy in decades that works differently than existing treatments for the debilitating mood disorder.
- Approval of the drug, which will be sold by J&J as Spravato, gives a new treatment option for individuals who have previously failed two or more antidepressants, a population that is estimated to account for roughly a third of the 16 million adults in the U.S. who have had an episode of major depressive disorder.
- Esketamine is closely related to ketamine, an anesthetic approved in 1970 that's more commonly known for its recreational use. Due to the risk of potentially serious side effects like sedation and disassociation, Spravato will only be available commercially though a restricted distribution system.
Patients with depression who have failed existing antidepressants have had few other treatment options.
Only one other drug, a combination of olanzapine and fluoxetine, is approved for treatment-resistant depression, although there are several drugs used off-label.
"The fact that esketamine works differently than our current medications for the treatment-resistant population offers more hope," Walter Dunn, staff psychiatrist and assistant clinical professor at the University of California, Los Angeles, said in an interview with BioPharma Dive.
"We know that for someone who has failed two traditional antidepressants, if you try a third of the currently approved medications, there's a [small] chance to achieve remission," said Dunn, who served on an FDA advisory panel which recommended approval of Spravato last month by a vote of 14-2. Dunn voted in favor of the drug.
Spravato works by inhibiting the N-methyl-D-asparate glutamate receptor, a mechanism of action that's thought to help restore links between nerve cells in the brain. Unlike ketamine, which is typically administered intravenously, Spravato is given via a nasal spray.
Clinical testing of Spravato yielded mixed results, with only one of three four-week clinical trials demonstrating a statistically significant benefit in favor of J&J's drug. In all three, patients were started on a new oral antidepressant and randomized to receive Spravato or placebo in addition — a design that experts on the advisory committee indicated better reflected how the drug would be used in the real world.
The FDA's approval clears Spravato for use in conjunction with an oral antidepressant.
In the short-term trial that succeeded, treatment with Spravato resulted in a significantly greater reduction from baseline than placebo on a scale measuring the severity of depression symptoms.
Typically, the FDA requires two randomized, short-term studies for approval of a new antidepressant. For Spravato, however, the agency agreed to consider a withdrawal, or maintenance, study as one of the two positive trials supporting J&J's application.
In that trial, patients in stable remission on Spravato were 51% less likely to relapse compared to those who continued on a regimen of placebo plus oral antidepressant.
UCLA's Dunn noted the maintenance study gave the FDA a chance to assess Spravato's longer-term effects, which have been less well-documented in previous studies of ketamine.
"The ability [of esketamine] to sustain mood benefits, i.e. in maintenance treatment, was less clear," Dunn said. "I suspect that is why the FDA was OK or possibly even more interested in looking at this maintenance trial as one of the confirmatory trials for approval."
Yet Spravato's mixed results, and the FDA's willingness to accept them, does add caveats to the drug's approval.
"I think we need to be cognizant of not positioning [Spravato] as a wonder drug or as a panacea, because it's not," said Steven Meisel, system director of medication safety at Fairview Health Services in Minneapolis, Minnesota, in an interview with BioPharma Dive.
"For those people for whom it does work, it could be life-saving and life-changing," he added. "I think that's why the FDA approved it." Meisel served on the advisory committee that recommended Spravato and voted in favor of the drug.
Spravato will be sold through a restricted distribution system under a Risk Evaluation and Mitigation Strategy (REMS), due to the FDA's concerns for the potential of abuse and misuse of the drug. The REMS program also provides for monitoring of Spravato's side effects.
Patients can only receive Spravato under the supervision of a health care provider at a certified clinic, who is required to monitor treated individuals for at least two hours after administration. Individuals taking Spravato are cautioned against driving or operating heavy machinery after taking the drug. Spravato can't be taken at home.
Treatment also raised blood pressure more frequently than observed in the placebo group — a risk that presents questions on long-term use of Spravato, Meisel said.
Kim Witczak, a consumer representative on the FDA's panel and voted against recommending Spravto, also cited worries the FDA relied too heavily on REMS to ease concerns on Spravato's safety.
"We really don't know the long-term safety of this drug," Witczak said in an interview with BioPharma Dive.
For J&J, Spravato's approval represents a significant addition to its portfolio of neuroscience drugs, which includes Concerta (methylphenidate) and Risperdal (risperidone).
The pharma said it was working to educate and certify treatment centers for Spravato. J&J priced the drug at a wholesale acquisition cost of $590 to $885 per treatment session, depending on which dose patients receive.
During the one-month induction phase, treatment with Spravato would cost between $4,720 to $6,785. If a patient responds, dosing would change in the maintenance phase, putting the subsequent monthly list price for the drug between $2,360 and $3,540.
In an emailed statement, J&J said Spravato's list price is "generally comparable" with other specialty mental health drugs.