Otsuka Pharmaceutical Co., Ltd. (OPC) and Otsuka Pharmaceutical Development & Commercialization, Inc. (OPDC) announced results from a phase II clinical trial of OPC-34712, a novel D2 dopamine partial agonist investigational product. In a six-week, double-blind, randomized, placebo-controlled study, OPC-34712 (1.5 ± 0.5 mg), when added to Anti-Depressant Therapy (ADT) in adult patients with Major Depressive Disorder (MDD), who had exhibited an inadequate response to ADT, demonstrated improvement in the Montgomery Åsberg Depression Rating Scale (MADRS) Total Score (p=0.0303), the primary endpoint of the study.

“These data represent proof-of-concept that OPC-34712 may be effective as adjunctive therapy in treating major depressive disorder in patients with an inadequate response to ADT,” said William H Carson, MD, president and CEO, OPDC. “Importantly, these data allow us to advance to phase III development for OPC-34712 with confidence.”

Trial results were presented at the American Psychiatric Association's 2011 annual meeting. “Because many patients who suffer from major depressive disorder do not respond adequately to existing therapies, it's critical that we continue to investigate new compounds as adjunctive therapy,” said Study Investigator Michael E Thase, MD, Professor of Psychiatry, University of Pennsylvania School of Medicine. “The findings from this study advance our knowledge about the utility of adjunctive agents in patients who do not optimally respond to antidepressants alone.”

OPC-34712 is a novel investigational psychotherapeutic compound developed to provide improved efficacy and tolerability (e.g., less akathisia, restlessness and/or insomnia) over established adjunctive treatments for MDD. The compound has broad activity across multiple monoamine systems and exhibits reduced partial agonist activity at D2 dopamine receptors and enhanced affinity for specific serotonin receptors (e.g., 5HT1a, 5HT2a and 5HT7). OPC-34712 is currently poised to enter Phase 3 testing for schizophrenia and adjunctive treatment of MDD and is in phase II testing for adjunctive treatment of adult ADHD.

This phase II multi-centre, double-blind, placebo-controlled study randomized 429 adult MDD patients who exhibited an inadequate response to one to three ADTs in the current episode. The study was designed to assess the efficacy and safety of OPC-34712 as an adjunctive treatment to standard ADT. The ADTs included in the study were desvenlafaxine, escitalopram, fluoxetine, paroxetine, sertraline, and venlafaxine.

The study was comprised of three phases: a screening phase (7–28 days) that identified patients who had not responded to prior ADT within the current depressive episode; a prospective 8-week, single-blind phase to assess response status to ADT; and a randomized phase of 6-week, double-blind assessment of adjunctive OPC-34712 compared to placebo in patients who had an inadequate response to ADT. Inadequate response to prospective ADT was defined as less than 50% decrease in Hamilton Depression Rating Score at the end of the 8-week single-blind phase. Patients were randomized to daily OPC-34712 (0.15 mg, n=62; 0.50 ± 0.25 mg, n=120; or 1.5 ± 0.5 mg, n=121) or placebo (n=126) adjunctive to ADT.

The primary efficacy endpoint was mean change in the MADRS total score from baseline to Week 6 following randomization. Primary analysis objectives were to compare the efficacy of the 0.5 mg/day dose and the 1.5 mg/day dose of OPC-34712 with placebo. Improvements in mean MADRS total score, from baseline to endpoint as compared to placebo, were observed only for subjects receiving adjunctive OPC 34712 at the 1.5 mg/day dose compared with placebo (p=0.0303); improvements in MADRS total score for subjects receiving the 0.5 mg/day dose were not different compared with placebo (p>0.05).

Overall completion rates were 82–87% and similar for all treatment groups. Discontinuations due to adverse events ranged from 0.8% to 3.2% in all treatment groups compared to 0.8% in the placebo study arm. The most common adverse events associated with OPC-34712 (all doses of OPC-34712 cumulatively greater than or equal to 5 percent vs. placebo) were upper respiratory tract infection (6.9% vs. 4.8%), akathisia (6.6% vs. 3.2%), weight gain (6.3% vs. 0.8%), and nasopharyngitis (5.0% vs. 1.6%). Mean changes in body weight from baseline to last visit were: placebo = 0.77 kg, 0.15 mg OPC-34712 = 0.91 kg (p>0.05), 0.5 mg OPC-34712 = 1.33 kg (p<0.05) and 1.5 mg OPC 34712 = 1.66 kg (p<0.05).

Major Depressive Disorder (MDD) is characterized by one or more major depressive episodes, (i.e., at least two weeks of depressed mood or loss of interest accompanied by at least four additional symptoms of depression). MDD affects approximately 14.2 million American adults in a given year, and today it is often treated with antidepressants; however, in many cases patients fail to respond adequately to treatment. Depression is one of the leading causes of disability in the US. In 2000, the total economic burden of treating depression in the US was $83.1 billion, with workplace costs, including missed days and lack of productivity due to illness, accounting for the majority of the total economic burden (62 percent). Other economic burdens in 2000 included $26.1 billion (31 percent) for treatment costs and $5.4 billion (7 percent) for suicide-related costs.