Intranasal esketamine for treatment-resistant depression faces an uncertain fate at an FDA advisory committee meeting Tuesday, as members ponder the drug’s mixed bag of clinical trial success.
Safety and efficacy of esketamine — the S-enantiomer of ketamine, an FDA-approved anesthetic as well as a street drug thanks to its dissociative and hallucinogenic effects — will be voted on by the agency’s Psychopharmacologic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee.
No regulatory agencies have approved esketamine or racemic ketamine for any psychiatric condition worldwide, although it’s not uncommon for ketamine to be used off-label in cases of severe depression. Unlike other antidepressants, its onset of action can be extremely rapid — hours to days, as opposed to several weeks for standard agents such as selective serotonin reuptake inhibitors.
Janssen Pharmaceutical brings five pivotal phase III studies of esketamine nasal spray to the meeting: three short-term randomized, double-blind, active-controlled studies (fixed dose, flexible dose, and flexible dose study in patients ≥65 years), one double-blind randomized withdrawal maintenance of effect study, and one open-label long-term safety study. The fixed dose trial of adults under 65 did not meet its primary endpoint, nor did the flexible-dose trial in patients 65 and older.
While most approved antidepressants have shown effectiveness data from at least two positive short-term trials and maintenance data in a post-marketing withdrawal trial, esketamine has only one positive short-term trial, the flexible dose trial in adults younger than 65. Its second positive trial is the randomized withdrawal trial.
“The Division of Psychiatry Products has not previously considered a randomized withdrawal trial as one of the two adequate and well-controlled trials comprising substantial evidence of effectiveness, but it is not unreasonable to do so,” FDA reviewers wrote in a report ahead of the meeting.
In sharp focus Tuesday will be the drug’s side effect profile. Besides dizziness, drowsiness, and rising blood pressure, patients in esketamine clinical trials experienced dissociative sensations, which are known effects of ketamine, a Schedule III drug with the street name of Special K.
During the trials, esketamine was administered under medical supervision, and no misuse or abuse was observed. But the potential for misuse or abuse is a concern, and Tuesday’s discussion will include a proposed Risk Evaluation and Mitigation Strategy (REMS) that would restrict esketamine to healthcare settings where patients are monitored for 2 hours, prohibit the drug from being dispensed directly to patients, and enroll patients in a registry to better characterize risks.
The esketamine development program received a Breakthrough Therapy Designation after preliminary evidence from an early study of IV esketamine suggested the drug could have a rapid effect, a substantial improvement over existing therapy for treatment-resistant depression.
Treatment-resistant depression is a serious, potentially life-threatening condition. For regulatory purposes, the FDA considers patients to have treatment-resistant depression if they have major depressive disorder and if despite at least two trials of antidepressants at adequate doses for an adequate duration, they have not responded. To date, the FDA has approved only one medication for treatment-resistant depression, a fixed-dose combination of fluoxetine and olanzapine (Symbyax).
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 proposes continuing treatment weekly for 4 more weeks, and then weekly or every other week in an ongoing maintenance phase.
On Tuesday, the FDA advisory committees will vote on whether esketamine is effective for treatment-resistant depression, whether its safety profile has been adequately characterized, and whether its benefits outweigh its risks. The committees also will discuss the proposed REMS and whether more pre- or post-approval data are needed.
While the FDA will consider input from the panel, it is not obliged to follow recommendations from its advisory committees.