- An advisory panel of experts on Tuesday recommended the Food and Drug Administration approve Johnson & Johnson's experimental depression drug esketamine, lending support for the agency to clear the treatment despite a mixed record in clinical testing.
- Asked whether the benefits of esketamine outweigh its risks, the committee voted 14 to 2 in favor, with one abstention. Panel members generally were comfortable with J&J's demonstration of the drug's efficacy and safety, although several raised concerns over long-term use. The FDA is not required to follow the panel's advice, but it usually does so.
- Esketamine is designed for patients with treatment-resistant depression who have failed at least two previous antidepressants. Only one other drug is approved by the FDA for this condition, making the need for new treatment particularly acute. J&J's evidence for esketamine, though, includes several failed studies, making the decision facing the FDA a test case of the regulator's standards.
Approval of esketamine would mark a milestone both for a field that's seen few new treatments emerge and for a regulator perceived to have adopted a more flexible approach to drug approvals.
J&J's drug is chemically related to ketamine, a decades-old club drug that's been studied and used off-label for psychiatric conditions in the past.
Similarly to its better known analogue, esketamine inhibits the N-methyl-D-asparate glutamate receptor, a mechanism of action thought to restore links between nerve cells in the brains of people with major depressive disorder. J&J developed esketamine as a nasal spray, rather than as an intravenous treatment.
To support an application for approval, J&J launched a broad clinical program of seven Phase 3 studies, three of which studied the drug over short 4-week time periods. Two of those three trials failed to reach the statistical threshold for success, however, weakening J&J's case for approval.
The drugmaker did secure positive results in a longer-term, randomized maintenance study which tested the effects of withdrawing esketamine treatment.
Usually, the FDA requires evidence showing an experimental antidepressant succeeded in two randomized short-term studies. In reviewing esketamine, however, agency staff indicated it would not be "unreasonable" to count the withdrawal study toward that two-study standard.
In debating the drug's profile Tuesday, panel experts largely agreed with the FDA, signaling J&J had provided sufficient evidence of esketamine's safety and efficacy.
Committee members were more hesitant, however, in judging the long-term effects of esketamine use.
"I don't think we really understand what happens when you take this week after week for months and years," said Steven Meisel, system director of medication safety at Fairview Health Services in Minneapolis, during the panel's discussion of esketamine's safety on Tuesday.
Treatment with esketamine comes with serious side effects, including sedation, disassociation and heightened blood pressure. Three patients in J&J's clinical program died by suicide, although FDA staff noted "it is difficult to consider these deaths as drug-related."
Most treatment-emergent adverse events occurred shortly after dosing and were transient, J&J said.
Both J&J and the FDA have proposed a Risk Evaluation and Mitigation Strategy program to help balance these risks — something that appeared to lessen some of the concerns held by panel experts. Under the FDA's proposed structure, patients given esketamine would be monitored directly after administration, and pharmacies would be required to get certified to prevent direct dispensation of the drug.
The FDA is set to make its decision by early March. Clear support from the advisory committee makes an approval more likely but not assured.
Granting a green light, though, would create a precedent for how the regulator considers drugs in the future, several committee members noted.
"If some other drug has the same pattern, do we set a precedent that's hard to step back from?" cautioned Fairview's Meisel.
For some on Wall Street, the answer is already clear.
"Today's favorable FDA panel on JNJ's antidepressant esketamine provides additional evidence of regulatory comfort in viewing psychiatric drugs favorably despite mixed efficacy data," wrote RBC Capital Markets analyst Brian Abrahams in a Feb. 12 note to investors.
That comfort has limits, though. The FDA recently rejected an experimental depression drug from Alkermes that had failed in two late-stage studies. The company had argued for flexibility, but both an advisory panel and the agency were unmoved.
Shares in J&J rose by nearly 2% in Tuesday trading, as did shares in other drugmakers developing antidepressants like Sage and Alkermes.