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FDA Agrees to Review Brexpiprazole for Treatment of Schizophrenia and Major Depression

Approval decision set for July 2015

The FDA has determined that the new drug application (NDA) for brexpiprazole (Otsuka Pharmaceutical Co., Ltd./H. Lundbeck A/S) as monotherapy in adult patients with schizophrenia and as adjunctive treatment of major depressive disorder (MDD) in adult patients is sufficiently complete to allow a substantive review, and the NDA was considered filed as of September 9, 2014. The Prescription Drug User Fee Act (PDUFA) date for completion of the review is July 11, 2015.

The NDA was supported by seven completed placebo-controlled phase II or III studies in the proposed indications — three studies in schizophrenia and four studies with brexpiprazole as adjunctive therapy in MDD. The dossier included data from more than 6,000 participants of whom more than 5,000 received brexpiprazole.

One phase II and two phase III placebo-controlled studies have been completed using brexpiprazole in adults with schizophrenia. More than 1,700 patients were enrolled in these trials.

In the first pivotal phase III study (N = 625), brexpiprazole 2 mg/day and 4 mg/day both demonstrated significantly greater improvement of symptoms compared with placebo, as measured by the change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score at week 6 (P < 0.05).

In the second pivotal phase III study (N = 650), brexpiprazole 4 mg/day again demonstrated significantly greater improvement of symptoms compared with placebo (P < 0.05) in the change from baseline in the PANSS total score at week 6. Brexpiprazole 2 mg/day showed numerical, non-significant improvement compared with placebo at week 6.

Results from the phase II study were presented at the 24th Annual U.S. Psychiatric and Mental Health Congress in November 2011. The study showed a clinically meaningful improvement from baseline, as measured by the PANSS total score, at week 6, although it did not achieve statistical separation from placebo.

Four additional studies evaluated brexpiprazole as adjunctive therapy for adult patients with MDD who had demonstrated a consistent, inadequate response to at least two regimens of prior antidepressant treatment. The patients received antidepressants for 8 weeks, single-blinded, in the two phase III studies. Those with an inadequate response during this prospective phase were provided antidepressant therapy and were randomly assigned to adjunctive treatment with either brexpiprazole or placebo for 6 weeks. The primary efficacy endpoint was the change in the Montgomery–Åsberg Depression Rating Scale (MADRS) total score from baseline at week 6. More than 3,900 patients entered the prospective phase and more than 1,800 patients were included in the randomized phase of the four studies.

The first pivotal phase III results were presented at the 22nd European Psychiatry Association Congress (EPA) in March 2014. This two-arm enrolled approximately 380 patients and demonstrated an improvement of symptoms with an antidepressant plus brexpiprazole 2 mg that was significantly greater than that achieved with an antidepressant plus placebo (P <: 0.001).

The second pivotal phase III study was a three-arm trial in which approximately 675 patients were randomly assigned to treatment with an antidepressant plus placebo, brexpiprazole 1 mg, or brexpiprazole 3 mg. Patients in both brexpiprazole groups showed greater improvement in symptoms, as measured by the MADRS, compared with placebo (1 mg: P > 0.05; 3 mg: P < 0.05). Results from the second pivotal phase III study in MDD have not been published.

The first clinical phase II study enrolled 425 patients in four arms and was presented at the 164th Annual Meeting of the American Psychiatric Association in May 2011. The patients exhibited greater improvements than that achieved with adjunctive placebo in the MADRS total score with brexpiprazole 1.5 mg/day after 6 weeks of treatment (P < 0.05). The second phase II study in MDD enrolled 372 patients and has not been published.

Data from the phase III program for brexpiprazole in the treatment of schizophrenia and as adjunctive therapy of MDD have been submitted to the 53rd Congress of the American College of Neuropsychopharmacology (ACNP), to be held December 7–11, 2014 in Phoenix, Arizona.

Brexpiprazole is an investigational psychotropic compound. It is a serotonin–dopamine activity modulator (SDAM) that acts as a partial agonist at 5-HT1A and dopamine D2 receptors at similar potency. It is also an antagonist at 5-HT2A and noradrenaline alpha1B/2C receptors.

Source: Otsuka Pharmaceutical Co.; September 24, 2014.

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