This Phase 2 study is a multi-center, dose escalating study in which 80 patients will receive either RG2417 or a placebo for 6 weeks. Patients will be evaluated for the safety and effectiveness of RG2417 on the symptoms of bipolar depression. This study is being conducted under a development agreement with the Stanley Medical Research Institute, under which Repligen will receive approximately $1,000,000 in funding. The Stanley Medical Research Institute is the largest nonprofit provider of funding for research on schizophrenia and bipolar disorder in the United States.
Bipolar disorder, also known as manic depression, is an illness marked by extreme changes in mood, thought, energy and behavior in which a person's mood can alternate between the "poles" of mania (highs) and depression (lows). Bipolar disorder affects more than two million adults in the United States and is usually diagnosed in late adolescence or early adulthood. Bipolar disorder is a chronic illness associated with substantial morbidity and mortality, ranking worldwide behind only unipolar depression and alcohol abuse among psychiatric illnesses for related disabilities and overall economic burden of illness. The lifetime financial burden of bipolar disorder in the United States is about $625,000 per patient, depending on resistance to treatment and persistence of symptoms. Although lithium and anticonvulsants such as valproic acid have substantially improved the prognosis of bipolar disorder, many individuals are unable to tolerate treatment-related side effects, and incomplete clinical response, relapse, and recurrence remain common clinical problems.
"Bipolar depression is a serious chronic illness and treatment is challenging due to the potential for induction of mania, a common side effect of standard treatment with antidepressants," stated Walter C. Herlihy, President and Chief Executive Officer of Repligen. "If this proof of principle study shows evidence that RG2417 improves the symptoms of bipolar depression without inducing mania, it has the potential to be an important new therapy in an area of significant unmet medical need."
Repligen previously completed a 6-week Phase 1 clinical trial of a prodrug of uridine (RG2133) in patients with bipolar disorder or major depression. The results demonstrated that administration of RG2133 in this patient population appeared to be safe, did not induce mania, and provided early evidence of a clinical effect of the drug. The trial evaluated 19 patients and was carried out by investigators at McLean Hospital, the largest psychiatric clinical care, teaching and research affiliate of Harvard Medical School.
Uridine is a biological compound essential for the synthesis of DNA and RNA, the basic hereditary material found in all cells, and numerous other factors essential for cell metabolism. Uridine is synthesized by the power plant of the human cell known as the mitochondria. The rationale for uridine therapy in neuropsychiatric disorders is supported by pre-clinical and clinical research. Researchers at McLean Hospital previously demonstrated that uridine is active in a well-validated animal model of depression. Recent reports indicate that certain genes that encode for mitochondrial proteins are significantly down-regulated in the brains of bipolar patients. This new insight suggests that the symptoms of bipolar disorder may be linked to dysregulation of energy metabolism of the brain.