• The Food and Drug Administration would be making an unusual move if it greenlights Johnson & Johnson’s experimental depression treatment, according to a briefing document written by agency staff ahead of an upcoming regulatory meeting.
• Most approved antidepressants are backed by at least two positive, adequate and well-controlled short-term trials showcasing the drugs’ effectiveness, and then further supported with maintenance data from a post-marketing withdrawal trial, the FDA staff wrote. Yet the main evidence supporting approval of J&J’s esketamine comes from just one positive, short-term study, along with a successful withdrawal study.
• Agency staff noted that it wouldn’t be unreasonable for the FDA to consider a withdrawal study as one of the two adequate and well-controlled trials. Still, esketamine’s mixed bag of late-stage clinical data may come under question at next week’s joint advisory committee meeting.

Esketamine is a type of ketamine that J&J has been investigating in patients with treatment-resistant depression, which — by the FDA’s definition — means they have major depressive disorder and didn’t respond to at least two antidepressant treatments in their current episode.

Currently, there is only one FDA-approved therapy for treatment-resistant depression. J&J wants that to change with esketamine, but the drug’s late-stage track record is mixed. One Phase 3 study found esketamine significantly outperformed a control group at reducing depressive symptoms in patients aged 18 to 64, while a similar study of patients 65 and older found no significant difference between esketamine and a control arm.

And while FDA staff said the withdrawal study does support esketamine’s efficacy, the “enriched” population it enrolls is an important caveat.

“[These are individuals who have already tolerated the drug and have already experienced clinical benefit from treatment with the drug. Whether and how these details would be reflected in labeling has not yet been determined,” the staff wrote in their briefing document.

Like many sponsors, J&J maintained confidence in its drug — and has argued that regulators see value in the drug as well.

“Obviously the FDA, through their designation of breakthrough status for the drug, realizes the importance that this has for patients who suffer from treatment-resistant depression, who really haven’t had a new mechanism of action in [more] than a couple of decades now,” Joseph Wolk, J&J’s chief financial officer, said during the company’s latest earnings call on Jan. 22.

“We hope that that level of energy on both sides will carry” esketamine to approval, he added.

Esketamine has also risen some analysts’ eyebrows. Credit Suisse’s Vamil Divan called it a “potentially underappreciated depression drug in the company’s pipeline,” in a recent note.

The FDA is slated to make an approval decision on esketamine by March 4. Next week, the Psychopharmacologic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee will meet to evaluate esketamine and recommend whether the agency should give it a thumbs up or thumbs down.

The committees will vote on whether esketamine has a favorable risk-benefit profile, whether J&J has adequately characterized the drug’s safety profile in its intended indication, and whether additional safeguards beyond the FDA’s proposed Risk Evaluation and Mitigation Strategy will be needed.