J&J may have a deeply flawed application for its new/old drug to treat major depression, but the researchers who turned out to present the case for esketamine encountered a receptive audience of FDA experts on Tuesday.
By a wide margin — 14 yes, 2 no and 1 abstention — the panel concluded that J&J had offered “substantial evidence of the effectiveness of esketamine,” an intranasal version of a powerful anesthetic called ketamine, better known in party circles as ‘Special K.’
The key safety issue is the known link between the longtime use of ketamine and neurotoxicity. The researchers relied on preclinical dog and rat studies to make their case — hardly the gold standard on safety data. But the panel seemed content that a long-term safety study on a postmarketing basis would be enough to warrant an OK now, with 15 voting that J&J had successfully outlined the safety profile for an initial approval. And at least one of the authorities noted that currently used depression drugs also have safety issues with longtime use.
The money question:
Do the benefits outweigh the risks? Yes: 14. No: 2. Abstain: 1.
J&J calls esketamine — which they plan to market as Spravato — the first drug with a new mechanism of action in depression for some 30 years. Of course, ketamine has also been used off-label for depression for years. It’s an NMDA drug, with rivals in the clinic from various biopharma companies, including Allergan.
“Ketamine is a nasty drug,” noted panel member Steven Meisel, system director of medication safety at Fairview Health Services/Healtheast Care System. “It’s been around for 50 years….But obviously we’re using lower doses.” Meisel, though, was impressed by a survey researchers completed that highlighted just how much these patients needed a new therapy.
“You don’t take that patient’s voice as often as you should in this space.”
“The vast majority of these patients will take the risks,” he added. “I think that’s very important….”
Two of the studies failed to meet the primary outcome, and that raised concerns.
“What precedent is set when 2 of 3 shorter efficacy studies didn’t meet the primary endpoint?” Meisel asked. “That’s something the agency has to wrestle with. “Do we set a precedent that may be hard to step back from.”
If the FDA goes ahead and offers a formal approval, which looks increasingly likely in view of the neutral internal review, they’ll be once again overlooking the agency’s gold standard on 2 positive, well controlled studies. But that’s increasingly common, especially under commissioner Scott Gottlieb.
J&J experienced significant failures with this program, and has promising data from one late-stage study and a withdrawal study, which the experts and insiders seemed willing to accept in lieu of a second well-controlled trial.
Esketamine is one of J&J’s top late-stage drugs, which the pharma giant believes has blockbuster market potential. By all appearances, they’ll soon be able to explore just how big this drug can be.
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