Regulatory Decision Summary for Rexulti

In treating patients with major depressive disorder (MDD), several sequential treatment steps are often needed to achieve remission and a return to pre-episode levels of functioning, which are the goals of treatment. For patients who have an inadequate response to antidepressants, which is defined in current clinical practice guidelines as a partial response (e.g., 25%-49% reduction in symptom scores) or no response (e.g., <25% reduction in symptom scores), the guidelines recommend switching treatment or using an adjunctive therapy.

To support the use brexpiprazole as adjunct to antidepressants for the treatment of MDD in patients who have had an inadequate response to 1 to 3 prior antidepressant trials, four pivotal Phase 3, randomized, double-blind, placebo controlled clinical trials of almost identical design were conducted to evaluate the efficacy and safety of brexpiprazole compared to placebo. Patients who completed 8 to 10 weeks of prospective antidepressant + placebo during the first phase of each study and had a persistent inadequate response to the antidepressant were eligible to enter the second phase of the study. All patients continued on the same antidepressant in the second phase and were randomized to 6 weeks of double-blind treatment with either adjunctive brexpiprazole or placebo. Three of the studies evaluated fixed doses of brexpiprazole of 1, 2 or 3 mg/day and 1 study evaluated flexible doses of 2-3 mg/day. The primary endpoint evaluated in all 4 studies was the mean change in the Montgomery Asberg Depression Rating Scale (MADRS) total score after 6 weeks of double-blind treatment (Week 8/10 to Week 14/16).

The Supplemental New Drug Submission (SNDS) was initially issued a Notice of Non-Compliance (NON) on May 3, 2018 because only one of these studies suggested a clinically meaningful effect of brexpiprazole after 6 weeks of treatment. The clinical significance of the statistically significant treatment effect with brexpiprazole on the primary efficacy endpoint in two of the other three pivotal clinical trials was uncertain. Also the secondary measures of efficacy had variable outcomes in the individual studies. Brexpiprazole as adjunct to antidepressants showed no effect on remission of depressive symptoms. In the context of considerable uncertainty about the clinical meaningfulness of the benefit, the benefit/harm/uncertainty was considered potentially less acceptable for MDD patients who are mostly antipsychotic naïve.

The analyses presented in the Response to NON focused on brexpiprazole 2 mg/day as adjunct to antidepressants. The studies that evaluated a fixed dose of 2 mg/day or a flexible dose of 2-3 mg/day brexpiprazole demonstrated that for patients with an inadequate response to 8 or 10 weeks of prospective antidepressant treatment (corresponding to the second trial of antidepressant with an inadequate response in the current depressive episode for most patients), there was statistically significant greater improvement in the MADRS total score with adjunctive brexpiprazole 2 mg/day compared to placebo. Some improvements were also observed in secondary measures of functional impairment, clinical global impression scores and response rates. No additional benefit was demonstrated at doses greater than 2 mg/day.

The safety profile of brexpiprazole in the clinical trials of patients with MDD was consistent with what can be expected for the class of atypical antipsychotic drugs. In the pivotal clinical trials, brexpiprazole was more frequently associated with extrapyramidal symptoms including akathisia, clinically significant weight gain and shifts from normal to high triglyceride values, somnolence, restlessness, and clinically significant prolactin elevations compared to placebo. Some adverse events were reported more frequently with the 3 mg/day dose. With respect to the types of adverse events (AEs) observed and other safety parameters (e.g., clinical laboratory) that can be affected during treatment with brexpiprazole, the safety profile of brexpiprazole in the MDD clinical trials was similar to what has been observed in clinical trials with schizophrenia patients, except that for some of these effects the difference in frequency between brexpiprazole and placebo was greater than what was observed in the schizophrenia clinical trials. Overall, the available safety data did not identify any new safety concerns with brexpiprazole used as an adjunct to antidepressants in patients with MDD.

The benefit/harm/uncertainty is only acceptable for brexpiprazole 2 mg/day (1.25 mg/day for patients with hepatic or renal impairment) as an adjunct to antidepressants for adult patients with MDD who have had inadequate responses to prior antidepressants during the current depressive episode. Because the efficacy and safety of brexpiprazole as an adjunct to antidepressants were demonstrated in 6-week, double-blind placebo controlled clinical trials the required length of adjunctive treatment with brexpiprazole, beyond 6 weeks, is not known. The Rexulti Product Monograph has been updated to reflect the efficacy and safety, as characterized in the clinical trials in patients with MDD.