Regulatory Decision Summary for Spravato

The efficacy and safety of Spravato (esketamine hydrochloride) for the treatment of patients with an episode of major depressive disorder (MDD) requiring urgent psychiatric care were primarily supported by the results of two identically designed pivotal phase III studies. The two phase III clinical trials were randomized, double-blind, placebo-controlled, multicenter studies. The primary objective of these studies was to evaluate the efficacy of Spravato 84 milligram (mg), twice-weekly for four weeks, as an add-on therapy to comprehensive standard of care, in reducing the symptoms of MDD, including suicidal ideation, in subjects who are assessed to be at imminent risk for suicide.

The primary efficacy endpoint was change from baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score at 24 hours post-first dose. The key secondary endpoint was change from baseline Clinical Global Impression – Severity of Suicidality – Revised (CGI-SS-R) scores also at 24 hours post-first dose. While the primary endpoint reached clinical and statistical significance, the key secondary endpoint did not. Therefore, the observed rapid reduction in depressive symptoms did not translate into decreased suicidality. Subsequent endpoints were generally in line with the conclusion that Spravato alleviated depressive symptoms, but not suicidality.

The safety profile of Spravato was comparable to what has been previously observed: transient increase in blood pressure, dizziness, and dissociative symptoms following administration. Other adverse events (AEs) included nausea, vomiting, constipation, paresthesia oral, hypoesthesia, somnolence, sedation, blurred vision, anxiety, and dysgeusia. Most AEs were reported post-dose on the day of intranasal Spravato administration and resolved within the same day. Suicidality-related events were noted in both groups, with one completed suicide during the follow-up phase of one of the pivotal studies in the Spravato group. Causal factors relating to suicidality-related AEs are difficult to establish in this population. Overall, the known risks and AEs are adequately mitigated by the warnings found in the product monograph as well as by the controlled distribution program.

Although no improvements were observed on suicidality-related endpoints, the fast-acting properties of Spravato administered over a 4-week period may benefit patients with severe depressive symptoms. The indication was revised to better align with the data and the population studied.

In addition, the sponsor provided a Phase II study that demonstrated a lack of efficacy of Spravato in Japanese subjects with treatment-resistant depression. The results of this study led to the deletion of the dosing recommendations for patients of Japanese ancestry and to the addition of information to warn prescribers and patients of the lack of efficacy of Spravato in Japanese patients.

An updated risk management plan was provided and found acceptable. The controlled distribution program did not require any substantial revisions and was deemed applicable to the use for the extended indication.