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Brexpiprazole Shows Promise in Adults With Acute Schizophrenia

Phase III data reported at neuropsychopharmacology meeting

Positive results have been reported from two pivotal phase III trials that evaluated the effects of an investigational compound, brexpiprazole (Otsuka/Lundbeck), as monotherapy in adult patients with schizophrenia. The new data were presented at the 53rd annual meeting of the American College of Neuropsychopharmacology, held in Phoenix, Arizona.

Brexpiprazole is a serotonin–dopamine activity modulator (SDAM) that acts as a partial agonist at 5-HT1A and dopamine D2 receptors, and as an antagonist at 5-HT2A and noradrenaline alpha1B/2C receptors, all with similar high potency (greater than 1 nM). A new drug application for brexpiprazole has been filed with the FDA, and the Prescription Drug User Fee Act goal date is July 2015.

In the first study, 636 adults with acute schizophrenia were treated with brexpiprazole (0.25 mg, 2 mg, or 4 mg) or placebo for 6 weeks.

Brexpiprazole 2.0 mg and 4.0 mg demonstrated greater improvement than placebo in the primary endpoint of the change from baseline to week 6 in the Positive and Negative Syndrome Scale (PANSS) total score (2 mg: –20.73 [P < 0.0001] and 4 mg: –19.65 [P = 0.0006] vs. placebo: –12.01; 0.25 mg was similar to placebo [–14.90]). Key secondary endpoint results –– changes in the Clinical Global Impression–Severity Scale (CGI-S) score at week 6 –– supported the primary results (2 mg: –1.15 [P = 0.0056] and 4 mg: –1.20 [P = 0.0012]; vs. placebo: –0.82).

Overall, approximately 65% of patients completed the 6-week study. Discontinuation rates due to adverse events were 13.3%, 8.2%, 9.4%, and 17.4% for brexpiprazole 0.25 mg, brexpiprazole 2 mg, brexpiprazole 4 mg, and placebo, respectively, whereas the corresponding discontinuation rates due to lack of efficacy were 7.8%, 9.3%, 3.9%, and 9.8%.

The most frequently reported treatment-emergent adverse events (TEAEs) included diarrhea (5.6%, 1.6%, and 3.9% vs. 1.6%); nausea (1.1%, 5.5%, and 3.3% vs. 4.3%); akathisia (0%, 4.4%, and 7.2% vs. 2.2%); and headache (10.0%, 9.3%, and 12.2% vs. 8.2%) in the brexpiprazole 0.25-mg, 2-mg, and 4-mg groups compared with the placebo group, respectively.

In the second study, 674 adults with acute schizophrenia were treated with fixed doses of brexpiprazole (1mg, 2 mg, or 4 mg) or placebo for 6 weeks.

Brexpiprazole 4 mg showed significant improvement over placebo in the primary endpoint of PANSS total score from baseline to week 6 (–20.0 vs. –13.5; P = 0.0022), whereas the 1-mg (–16.9) and 2-mg (–16.6) doses showed only numeric improvement versus placebo (–13.5; P > 0.05).

Key secondary endpoint results –– changes in the CGI-S score versus placebo at week 6 –– supported the primary results (1 mg: –0.9 [P > 0.05], 2 mg: –1.0 [P > 0.05]; and 4 mg: –1.2 [P = 0.0015] vs. placebo: –0.8).

Overall, approximately 68% of patients completed the 6-week study. Discontinuation rates due to adverse events were 9.2%, 5.9%, 7.1%, and 12.0% in the brexpiprazole 1 mg, brexpiprazole 2 mg, brexpiprazole 4 mg, and placebo groups, respectively, whereas the corresponding discontinuation rates due to lack of efficacy were 7.5%, 10.8%, 8.7%, and 11.4%.

The most frequently reported TEAEs included dyspepsia (5.8%, 3.8%, and 3.3% vs. 3.3%); insomnia (12.5%, 13.4%, and 15.2% vs. 14.7%); and agitation (8.3%, 8.6%, and 7.1% vs. 7.1%) for brexpiprazol 1 mg, brexpiprazol 2 mg, and brexpiprazole 4 mg versus placebo, respectively.

Source: Otsuka; December 11, 2014.

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