Johnson & Johnson preps for esketamine filing in resistant depression, despite a missed trial

J&J
Current drugs don't work in around a third of people with depression, Johnson & Johnson says. (Raysonho/CC0)

A new type of drug for depression has been a long time coming, and Johnson & Johnson is looking increasingly likely to end the drought with esketamine—even though one of its late-stage trials missed the mark.

Two studies reported at the American Psychiatric Association (APA) over the weekend indicated the drug improved the efficacy of conventional oral antidepressants, and J&J remains confident it is on course to file the nasal spray formulation for approval in treatment-resistant depression in the second half of the year.

If approved by the FDA, esketamine would become one of the first new approaches to treat refractory major depressive disorder (MDD) in the last 50 years, and provide a new option for people—estimated to be in the millions worldwide—who struggle to control symptoms despite drug therapy.

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The first of the two studies presented at APA showed that in adults with treatment-resistant depression, esketamine was more effective than placebo in relieving symptoms when given on top of newly prescribed oral antidepressant drugs—the first time any drug has been shown to do so in trials, according to J&J. This was a patient group that had been unable to control symptoms despite trying out two or more current drugs.

The second study zeroed in on an older patient group—people aged 65 or older—and in this case esketamine achieved a “clinically meaningful” improvement over placebo when added to oral therapy, but didn’t meet the threshold for statistical significance. J&J said that this patient group often has lower response rates to antidepressants, which could explain the result.

The pressing need for new treatment options means esketamine has picked up a pair of breakthrough designations from the FDA, one of treatment-resistant depression and the other for suicidal ideation, and the company has previously said it expects the drug to be among a crop of new products with $1 billion-plus sales potential.

“With about 30% of patients with major depression failing to respond to currently available antidepressants, treatment-resistant depression represents a major public health need,” said Husseini Manji, M.D., the company’s head of neuroscience R&D.

“What makes this even more significant is that the response was rapid and this milestone was achieved in patients deemed to be treatment-resistant,” he added.

J&J isn’t the only company trying to bring a new drug to market that aims to tackle treatment-resistant depression, although its closest rival—Alkermes—recently hit a bump when the FDA asked for more clinical trials before it could review ALKS 5461, a once-daily pill opioid system modulator combining samidorphan and buprenorphine. The regulator has however since accepted the application and has set a PDUFA date of January 31, 2019 for its review.

Esketamine is thought to work as an N-methyl-D-aspartate (NMDA) receptor antagonist, a new mechanism of action in depression. It’s closely related to anesthetic and notorious party drug ketamine, which is already being used off-label to treat resistant depression to the alarm of some psychiatric specialists who say there is still not enough evidence for its safety and efficacy. Esketamine is designed to sidestep some of the negative characteristics of ketamine, such as hepatotoxicity, cognitive deficits and addiction with protracted use.

Meanwhile, Allergan has also been developing an NMDA-acting drug called rapastinel, with phase 3 data due early next year, and has said it thinks this could have a more benign tolerability profile to other NMDA drugs as it works as a partial agonist rather than an antagonist at the NMDA receptor.

A report published by Informa Pharma Intelligence last year suggested that NMDA-acting drugs will drive an increase in U.S. antidepressant sales from around $4.6 billion a year in 2016 to more than $7 billion in 2024.

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