Two FDA advisory committees have voted 14-2 in favour of the use of esketamine for treatment-resistant depression (TRD). The advisors found that the intranasal drug is effective in TRD, and that the benefits outweigh the risks. The esketamine program received a Breakthrough Therapy Designation (BTD) in 2013 based on a phase II study of an intravenous formulation in treatment-resistant depression (Singh et al. Biol Psychiatry 2016;80:424-431).
Esketamine is the S-enantiomer of ketamine, an NMDA receptor antagonist that enhances glutamine release in the brain. The drug is currently approved in Europe and South America as an anesthetic. No country has approved ketamine or its enantiomers (S, R) for any psychiatric indication.
Esketamine is administered as two sprays of intranasal esketamine 14 mg (total dose 28 mg). The proposed dosing is twice a week (28-56 mg at each dose, titrated to 84 mg in week 2) for an initial 4 weeks; followed by weekly dosing for an additional 4 weeks; and then weekly or every other week dosing during the maintenance phase. The drug would be used as an adjunct to an oral antidepressant.
The committees reviewed data from four phase II and four phase III studies of intranasal esketamine. For all phase III studies, TRD was defined as a lack of clinically meaningful improvement (≤25%) in depression after treatment with at least two different antidepressants for an adequate duration (at least 6 weeks). All of the phase III studies are unpublished but results were made available in the FDA briefing document (February 12, 2019). Results from the phase III program have been mixed, with two of three pivotal trials failing to meet their primary endpoints.
TRANSFORM-1 (study 3001) was a fixed-dose study of esketamine 84 mg or 56 mg versus placebo in 342 patients on an oral antidepressant. There was no significant difference in change from baseline in MADRS score with esketamine 84 mg versus placebo add-on (-18.2 vs. -14.9); data for the lower-dose group were not formally analysed.
TRANSFORM-2 (study 3002) compared esketamine 56 mg or 84 mg or placebo in 223 patients receiving an oral antidepressant. Least-square mean change from baseline in MADRS total score was -19.8 with esketamine + antidepressant versus -15.8 with placebo + antidepressant at day 28.
SUSTAIN-1 (study 3003) was a continuation trial and included responders (>50% reduction in MADRS total score at 4 weeks) in studies 3001 (n=151) and 3002 (n=125); additional subjects (n=273) were enrolled if they were responders to open-label esketamine. Following a 12-week optimization phase, subjects entered a double-blind maintenance phase if they had a stable response (≥50% reduction in MADRS total score) or remission (MADRS total score <12 for at least 3 of 4 weeks). During the maintenance phase, patients were re-randomized to esketamine or placebo; all continued on oral antidepressant. There was a significant difference in time to relapse of depression in favour of esketamine versus placebo both in the remission group (primary endpoint; hazard ratio 0.49) and in the stable response group (secondary endpoint; HR 0.30). The proportion of patients who relapsed was 27% and 45% with esketamine and placebo, respectively, in the remission group; and 26% and 58%, respectively, in the stable response group. A concern raised by the FDA reviewer was that results were driven by a single site, which reported a 100% relapse rate with placebo add-on in both the remission and stable response groups.
TRANSFORM-3 (study 3005) was a geriatric study (mean age 70 years) in patients who had failed to respond to at least one prior antidepressant. Patients received esketamine 28 mg, 56 mg or 84 mg, or placebo add-on; all subjects received an oral antidepressant. There was no significant difference in change from baseline to day 28 on MADRS total score with esketamine versus placebo (-10.1 vs. -6.5).
The FDA committees also reviewed safety issues with esketamine, notably sedation, dissociation and hypertension. In study 3001, the most common adverse events with esketamine 84 mg were dissociation (46.6% vs. 19.5% with placebo), nausea (31.9% vs. 10.6%), dizziness (27.6% vs. 9.7%), sedation (25.0% vs. 11.5%), vertigo (20.7% vs. 1.8%), hypoaesthesia (14.7% vs. 1.8%) and increased blood pressure (12.1% vs. 4.4%). During the study, 72% of patients receiving esketamine 84 mg experienced dissociation, defined as >4-point change in Clinician-Administered Dissociative States Scale (CADSS) score. The mean change in systolic BP was 20 mmHg (vs. 12 with placebo); mean change in diastolic BP was 14 mmHg (vs. 10).
In the product briefing, the risk of ketamine abuse was also noted although the lifetime prevalence of ketamine abuse in the U.S. is reportedly low (1.3%).
While efficacy claims were only supported by one short-term study (TRANSFORM-2) and a maintenance trial (SUSTAIN-1), the FDA advisors determined that the benefits outweighed the risks in this difficult-to-treat study population. Also working in the drug’s favour were its rapid onset of action, and a lack of alternatives for TRD.
The committees’ recommendation for approval will now be forwarded to the FDA, which is expected to grant approval to esketamine for TRD later this year.