Otsuka Pharmaceutical. a global healthcare company, and H. Lundbeck A/S, a global pharmaceutical company, announce top-line results from two phase III clinical trials evaluating the efficacy, safety and tolerability of brexpiprazole in the treatment of agitation in patients with dementia of the Alzheimer’s type.

The primary endpoint of both trials was change from baseline in the Cohen-Mansfield Agitation Inventory (CMAI) total score, a 29-item scale to systematically assess the symptoms of agitation.1 The key secondary endpoint was the change from baseline in the Clinical Global Impression-Severity of Illness (CGI-S) score, a 7-point scale assessing overall severity of the patient’s agitation.1 These studies were conducted in multiple countries in North America and Europe, and in the Russian Federation.

In both studies, patients treated with brexpiprazole showed improvements in symptoms of agitation relative to placebo. In the first study, the improvement in the primary endpoint of CMAI for 2 mg brexpiprazole was statistically better than placebo (p<0.05) and appeared more robust than the improvements on the key secondary endpoint of CGI-S (p>0.05). In the second study, the improvements in the primary endpoint of CMAI (p>0.05) appeared less robust than improvements observed on the key secondary endpoint of CGI-S (p<0.05). In both studies, there was variability in the data from different countries, perhaps associated with differing standards of care; the data from Russian sites showed especially poor separation between placebo and drug.

Regarding safety and tolerability, both studies confirmed the profile of brexpiprazole as observed in the clinical trials for schizophrenia and for adjunctive treatment of major depressive disorder (MDD). The most common adverse events in patients receiving brexpiprazole versus placebo (incidence >3% and greater than placebo) were insomnia (4.7% vs. 3.3%), agitation (3.5% vs. 2.9%), and somnolence (3.3% vs. 2.2%). Overall mortality during the studies was 0.86% and none of the deaths were considered to be related to treatment.

Both trials were randomized, double-blind, placebo-controlled phase III studies that enrolled a combined total of approximately 700 participants. Trial participants were between 51 and 90 years of age with a diagnosis of probable Alzheimer’s disease and symptoms of agitation. Both outpatients and patients living in institutional care settings were included in the trials. One of the trials studied fixed doses of either 1 or 2 mg per day of brexpiprazole or placebo, while the other trial studied a flexible-dose range of 0.5 mg, 1 mg or 2 mg per day of brexpiprazole, or placebo. Both trials were 12 weeks in duration.

The companies plan to meet with the FDA to discuss the results of the studies. The results will be presented in scientific congresses over the next year.

Brexpiprazole was approved by the U.S. Food and Drug Administration in July 2015 to treat patients with schizophrenia and as an adjunctive treatment for patients with MDD. Brexpiprazole was also approved in February 2017 by Health Canada for the treatment of schizophrenia. In both countries brexpiprazole is distributed and marketed under the brand name Rexulti.

Brexpiprazole was discovered by Otsuka and is being co-developed by Otsuka and Lundbeck. The mechanism of action for brexpiprazole in the adjunctive treatment of major depressive disorder or schizophrenia is unknown. However, the efficacy of brexpiprazole 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. Brexpiprazole exhibits high affinity (sub-nanomolar) for these receptors as well as for noradrenaline alpha1B/2C receptors.