By a wide margin -- 14 yes votes, 2 no, and 1 abstention -- FDA advisory committee members voted Tuesday that the benefits of esketamine nasal spray for treatment-resistant depression outweighed its risks.
They also overwhelmingly supported -- again with votes of 14-2-1 -- that drugmaker Janssen Pharmaceuticals provided sufficient evidence to support the effectiveness of esketamine nasal spray for treatment-resistant depression, and 15-2 in favor of its safety profile.
The recommendation brings intranasal esketamine a step closer to approval, despite the fact that the drug had only one positive short-term phase III trial.
Esketamine is the S-enantiomer of ketamine, an FDA-approved anesthetic and street drug known for its dissociative and hallucinogenic effects. While ketamine has not been approved for depression in the U.S. or any other country, it has been used off-label in cases of severe depression. Unlike other antidepressants, its can be extremely rapid -- -- as opposed to several weeks for standard agents such as selective serotonin reuptake inhibitors.
Janssen brought five pivotal phase III studies of the drug to the meeting: three short-term randomized, double-blind, active-controlled studies (fixed and flexible dose studies in adults younger than 65, and a flexible dose study in patients 65 and older), one double-blind randomized withdrawal maintenance of effect study, and one open-label long-term safety study. Two of the three short-term studies did not meet their primary endpoint, but the flexible dose trial in adults younger than 65 and the maintenance study were positive.
"I believe there is compelling evidence that esketamine is an effective treatment for this highly treatment resistant population," said panel member Walter Dunn, MD, PhD, of the University of California, Los Angeles. "I really commend the FDA for considering [the maintenance trial] to be one of the pivotal trials."
"From our experience with ketamine off-label use for the last 10-plus years, we know it works and we know it works fast," Dunn continued. "The question is, will that effect last? And I think the maintenance trial really demonstrated there is potential for a long-term benefit for this patient population."
"There may be some people who would substantially benefit from this medication and that's important," added panelist Steve Meisel, PharmD, of Fairview Health Services in Minneapolis.
But the long-term implications of supporting drugs with only one short-term positive trial is concerning, Meisel noted: "What precedent is set when two of three shorter efficacy studies didn't meet the primary endpoint? Do we set a precedent that may be hard to step back from?"
The drug's side effect profile was of concern: in trials, patients experienced sedation, rising blood pressure, and dissociative sensations, which are known effects of ketamine. The latter effect, in fact, has made ketamine a popular street drug known as Special K.
In the end, the need for effective therapy for treatment-resistant depression and a well-planned Risk Evaluation and Mitigation Strategy (REMS) helped sway the panel's decision. Under the REMS, esketamine would be restricted to healthcare settings, the drug would not be dispensed directly to patients, and patients would enroll in a registry to better characterize risks.
Esketamine is designed to be administered intranasally twice a week for an initial 4 weeks, in conjunction with a newly initiated oral antidepressant. The proposed initial adult esketamine dose is 28-56 mg at each administration, which can be titrated to 84 mg by week 2. The drugmaker proposed continuing treatment weekly for 4 more weeks, and then weekly or every other week in an ongoing maintenance phase.
In a issued immediately after the advisory committee meeting, Janssen announced that esketamine nasal spray will be known as Spravato. An FDA decision is expected by March 4; while the agency will consider input from the panel, it is not obliged to follow recommendations from its advisory committees.