Phase 2 Study of Obeticholic Acid for Lipodystrophy Patients

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DESCRIPTION (provided by applicant): Lipodystrophies are rare disorders characterized by selective loss of adipose tissue. Hepatic steatosis is a common problem in these patients and in some it progresses to cirrhosis. Despite aggressive management of diabetes and hyperlipidemia, hepatic steatosis and its complications present a therapeutic challenge in many patients. There is no established therapy for nonalcoholic steatosis. Recombinant leptin therapy has been reported to reduce liver size and hepatic steatosis in hypoleptinemic patients with generalized lipodystrophies but has not been approved for partial lipodystrophy patients. Recent insight into the role of farnesoid X receptor (FXR), in regulating hepatic triglyceride homeostasis offers new treatment options for hepatic steatosis. Primary bile acids, cholic acid (CA) and chenodeoxycholic acid (CDCA) are endogenous natural ligands for FXR but have weak activity compared to the synthetic ligand, obeticholic acid (OCA), which is 100 times more potent than CDCA. In various mouse models and recently in patients with nonalcoholic fatty liver disease, OCA has been shown to improve hepatic steatosis. Furthermore, OCA improved insulin sensitivity and lowered serum alanine aminotransferase and gamma glutamyl transferase levels in a recent study of patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease. Therefore, we propose to investigate the efficacy and safety of obeticholic acid in reducing hepatic steatosis in patients with familial partial lipodystrophy of the Dunnigan variety (FPLD). Thus, this Phase II, randomized, double- blind, cross-over, placebo-controlled study is designed to investigate the efficacy and safety of obeticholic acid therapy in reducing hepatic triglyceride deposition in 20 FPLD patients with hepatic steatosis. OCA/placebo will be administered in a dose of 25 mg/day for four months each. The primary end point variable will be hepatic triglyceride concentration as determined by 1H magnetic resonance spectroscopy. Our results may lead to development of a novel therapeutic intervention for hepatic steatosis in patients with lipodystrophies.