Regulatory Decision Summary for Spravato

Spravato (esketamine) nasal spray was investigated in adults with Major Depressive Disorder (MDD) who did not respond to at least two separate courses of treatment in their current moderate to severe episode. The safety and efficacy assessment of Spravato was based primarily on five phase 3 studies, where Spravato was initiated with one of four antidepressants in the serotonin selective reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) class: 3 short-term (4-week) studies, a randomized withdrawal study and a 1-year, uncontrolled, open-label, long-term safety study. Between these, 1,601 subjects with MDD were treated with Spravato, including 479 for 6 months and 178 for 12 months. In addition, the interim report for an ongoing safety extension study was reviewed.

The primary efficacy outcome in the short-term studies was the change in the Montgomery-Asberg Depression Rating Scale (MADRS) total score from baseline to the end of the 4-week double-blind phase (Day 28). Two studies were conducted in adults aged 18 to 65 years - one using a fixed dose regimen (Spravato 56 mg or 84 mg) and the other a flexible dose regimen (Spravato 56 / 84 mg). The flexible dose study yielded a statistically significant and clinically meaningful result. In the fixed dose study, the magnitudes of differences in both dose arms were suggestive of a meaningful effect. However, because the 84 mg dose did not achieve statistical significance, subsequent endpoints could not be formally evaluated in accordance with the pre-defined testing sequence. A higher discontinuation rate in the 84 mg arm, performance of the 56 mg dose, comparable magnitudes of effect, baseline disease severity and study complexity were all considered in the overall assessment, which supported the efficacy of Spravato in combination with a SSRI or SNRI.

The overall results of the randomized withdrawal study, conducted in adults aged 18 to 65 years, were positive. In both remitters and responders, Spravato significantly prolonged time to relapse compared to placebo. Although uncertainties existed around potential unblinding and limited data to guide dosing, additional analyses and rationale were adequately supportive. A third short-term study was conducted in elderly patients (aged 65 years or older) using a flexible 28 / 56 / 84 mg dose regimen. Efficacy was not demonstrated in that study.

Across studies, the most common adverse events reported with Spravato were dissociation, dizziness, nausea, sedation, headache, vertigo, dysgeusia, hypoesthesia, anxiety, increased blood pressure and vomiting. There was a total of 7 deaths, all in patients exposed to Spravato: 3 suicides, 2 road accidents, myocardial infarction and sudden death. None were established to be related to Spravato. Serious adverse events potentially related to Spravato included suicidal ideation or behavior, elevated blood pressure and anxiety. Adverse events leading to Spravato discontinuation included anxiety, depression, blood pressure increased, dizziness, suicidal ideation, dissociation, nausea, vomiting, headache, muscular weakness, vertigo, hypertension, panic attack and sedation. Significant safety uncertainties with Spravato are risk of suicide, respiratory depression, cognitive decline, interstitial cystitis and abuse. Toxicological assessment was limited by lack of sustained exposure and minimal safety margins compared to expected human exposure. The results raised concerns for neuro-, juvenile and reproductive toxicities. These have all been labelled in the Canadian Product Monograph.

A Risk Management Plan was provided. Risk minimization measures included product labeling of safety concerns and uncertainties, and a Controlled Distribution Program (CDP). The CDP was designed to manage the acute risks of sedation, dissociation and hypertension, as well as the risks of abuse and diversion. Elements include enrollment of physicians, pharmacists and patients; supervised self-administration; post-administration observation; and delivery of Spravato directly to the site of care.

Considering the debilitating nature of the disease condition and limited treatment options, the benefit-harm-uncertainty profile of Spravato is positive, provided the risk minimization measures outlined are in place.