Should the FDA ignore its gold standard and approve J&J’s top drug prospect esketamine without solid supporting evidence from two well-controlled studies? Even after it failed in other studies and presents some serious safety issues to deal with?
In an internal review posted online this morning, regulators posed those questions to an expert committee this morning picking up the pharma giant’s pitch for their version of the party drug ketamine. Their answer may well influence the entire field of depression drug research, where failures are far more common than success.
J&J has a lot riding on this one. The pharma giant has tapped esketamine as one of its top late-stage efforts, putting it in a lineup of potential blockbusters the company is pushing to beef up revenue.
The agency has already blessed J&J with its breakthrough therapy designation for esketamine, impressed by the mid-stage data that was produced to show how its intranasal therapy brought swift relief to patients suffering from deep depression.
That aspect of the drug is well known. Ketamine — known in party circles as Special K — is a horse tranquilizer that also has produced a fast effect in a long range of academic studies over the years. In coming up with its own version, J&J is looking to keep the swift impact and lose the hallucinogenic qualities that make it a controlled substance.
Depression, though, is a mass market, and the bar on an approval is high, as Richard Pops could tell you after Alkermes was repeatedly slapped down on ‘5461. Antidepressants on the market, though, are often used randomly, in sequence, to find one that can produce an effect — often taking weeks to begin working.
For its studies, J&J researchers recruited heavily pre-treated patients in desperate need of a therapy. They were started on a new antidepressant plus esketamine, figuring that antidepressants usually act so slowly it wouldn’t interfere with esketamine’s fast action.
As the review notes, J&J has positive results from “the flexible-dose trial in adults younger than 65 years of age and the randomized withdrawal study.” Withdrawal studies, though, are generally not recognized as a well controlled study that qualifies as one of the 2 typically needed studies for an approval.
Then there were the failures — which, by the way, are quite common in depression. One reason why J&J ran 5 studies is to give themselves better odds at success, rather than restricting themselves to 2 pivotals.
In the fixed-dose study of adults younger than 65 years of age, the prespecified analysis plan dictated that efficacy of the 84-mg dose would be evaluated first, followed by evaluation of the 56-mg dose. However, the 84-mg dose did not separate from placebo and the testing sequence ended there. The geriatric study included flexible doses ranging from 28 to 84 mg; the effect of esketamine in the combined dose group was not statistically superior to placebo (1-sided p = 0.029).
The safety profile is also far from benign, including sedation, dissociative behavior and increased blood pressure as primary concerns. And none of that was new to the R&D team when they started the work.
To get an OK here will also clearly require a detailed risk mitigation plan, and the FDA wants its experts to weigh in on that as well. The proposed REMS includes 2 hours of monitoring after the drug is given to the patient. There will be no distribution of the drug to patients — to avoid abuse — and the plan now is to include a patient registry to track risks.
The FDA’s internal review neither suggests an approval is warranted or that the panel should vote no. The agency has already proved its willingness to forego the 2-trial standard, at least in other diseases. The big question is whether the experts will go for a new and clearly imperfect drug to add for a group of patients with nowhere else to turn. Under those circumstances, J&J seems to have pretty good odds of success in a field better known for repeated setbacks.
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