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FDA Approves Brexpiprazole (Rexulti) as Adjunctive Treatment for Adults With Depression or Schizophrenia

U.S. launch planned for early August

The FDA has approved brexpiprazole (Rexulti, Otsuka/Lundbeck) as an adjunctive therapy for adults with major depressive disorder (MDD) and as a treatment for adults with schizophrenia.

The mechanism of action of brexpiprazole in the treatment of MDD or schizophrenia is unknown. However, the drug’s efficacy may be mediated through a combination of partial agonist activity at serotonin 5-HT1A and dopamine D2 receptors, and antagonist activity at serotonin 5-HT2A receptors. In addition, brexpiprazole exhibits high affinity for these receptors, as well as for noradrenaline alpha1B/2C receptors.

The FDA’s approval was supported by four completed placebo-controlled, phase III studies in the newly approved indications –– two studies as adjunctive therapy to antidepressants in MDD and two studies in schizophrenia.

As adjunctive therapy for MDD, the efficacy of brexpiprazole was evaluated in two 6-week, placebo-controlled studies of adult patients, with or without symptoms of anxiety, who had failed to achieve an adequate response during one to three treatment attempts with antidepressant therapy (ADT), and who had also failed to achieve an adequate response in a single-blind ADT phase for 8 weeks. The primary endpoint for both studies was the change in the Montgomery–Åsberg Depression Rating Scale (MADRS).

Brexpiprazole (2 mg or 3 mg) plus ADT was superior to placebo; the mean baseline MADRS score decreased by 8.36 (2 mg) and 8.29 (3 mg) points from 27.0 points at randomization compared with reductions of 5.15 and 6.33 points with placebo plus ADT in the respective studies.

The discontinuation rate due to adverse events (AEs) was 3% for brexpiprazole plus ADT compared with 1% for placebo plus ADT. The most common AEs for the pooled doses of adjunctive brexpiprazole plus ADT included akathisia (9% vs. 2% for placebo), and weight increase (7% vs. 2%).

The efficacy of brexpiprazole in adults with schizophrenia was established in two 6-week, phase III, randomized, placebo-controlled studies that compared fixed doses of brexpiprazole with placebo.

Brexpiprazole demonstrated statistically significant efficacy for the primary endpoint of the Positive and Negative Syndrome Scale (PANSS). In one study, the change from baseline in the PANSS total score for brexpiprazole at both 2 mg/day and 4 mg/day (–20.73 points and –19.65 points) was superior to placebo (–12.01 points); in the other study, the change from baseline in the PANSS total score for brexpiprazole at a dosage of 4 mg/day was superior to placebo (–20.00 points vs. –13.53 points, respectively), but the change from baseline in the PANSS total score with brexpiprazole 2 mg/day was not superior.

The most common AEs associated with brexpiprazole (1, 2, and 4 mg) versus placebo included weight gain (4% vs. 2%, respectively). The incidence of somnolence (also including sedation and hypersomnia) in all patients with schizophrenia who received brexpiprazole (n = 1,256) was 5% compared with 3% for patients receiving placebo (n = 463).

Brexpiprazole will become available in the U.S. in early August 2015.

Source: Lundbeck; July 13, 2015.

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