The journey to FDA approval of esketamine
After significant preclinical research on esketamine, and the successful development of an intranasal spray delivery system, five phase 3 clinical trials (three short term; two long term) were completed investigating the efficacy of esketamine in patients with TRD. The esketamine doses that demonstrated efficacy were 56 mg and 84 mg. The primary short-term, randomized, double-blind, placebo controlled 4-week clinical trial required that patients with established treatment resistant MDD, with at least 2 failed adequate antidepressant treatments in the current episode, would be started on a novel antidepressant (sertraline, escitalopram, venlafaxine XR, or duloxetine) simultaneously with the onset of treatment with either intranasal ketamine or intranasal placebo.
The subjects in this trial were quite depressed, with a mean Montgomery-Asberg Depression Rating Scale (MADRS) score of 37 at the time of randomization. Moreover, one-third of the study participants had a history of suicidal ideation. The primary endpoint of this study was the change in the total MADRS score from baseline to study end at day 28. On day 1 of the study, subjects were started on a new oral antidepressant, which they continued daily throughout the study. Simultaneously, they received either esketamine spray or placebo spray twice weekly for the 4 weeks. By 24 hours after the first dose of esketamine, most of the treatment difference from placebo was seen. From 24 hours post-dose through day 28 both esketamine and placebo groups continued to improve. At day 28 esketamine spray/oral antidepressant had improved the MADRS score by an average of 4 points (P = .02) compared with placebo spray/oral antidepressant.
The second study was a long-term maintenance study in patients with TRD that began with 16 weeks of open-label treatment with a new oral antidepressant along with esketamine. Esketamine was administered twice weekly for the first 4 weeks (the Induction Phase), weekly for the next 4 weeks, and then weekly or biweekly for the remaining 8 weeks (the 12-week Optimization Phase).
At week 16, two sub-groups were identified: stable remitters (a MADRS ≤ 12) or stable responders (≥ 50% reduction in the baseline MADRS score). At that point, after 16 weeks of open-label esketamine spray/oral antidepressant, remitters and responders entered into separate maintenance phases, which involved double-blind, placebo spray-controlled randomization for up to 80 weeks. All patients were treated with either flexibly dosed esketamine spray (56 mg or 84 mg) weekly or every other week, or placebo spray weekly or every other week, as well as continuing on their original open label oral antidepressant.
The stable remitters on esketamine spray/oral antidepressant relapsed 51% less than placebo spray/oral antidepressant. The stable responders on esketamine spray/oral antidepressant relapsed 70% less than placebo spray/oral antidepressant.
Dr Miller reports that he is on Janssen’s Advisory Board and on the Speaker’s Bureau for Spravato.
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