Phase 2 Study of Obeticholic Acid for Lipodystrophy Patients

描述（由申请人提供）：脂肪营养不良是一种罕见的疾病，其特征是脂肪组织的选择性损失。肝脂肪变性是这些患者的常见问题，在某些情况下会发展为肝硬化。尽管对糖尿病和高脂血症进行了积极的管理，但肝脏脂肪变性及其并发症在许多患者中仍是一个治疗挑战。非酒精性脂肪变性尚无既定治疗方法。重组瘦素疗法已被报道可减少全身性脂肪营养不良的低瘦素血症患者的肝脏大小和肝脏脂肪变性，但尚未被批准用于部分脂肪营养不良患者。法尼醇X受体（FXR）在调节肝脏甘油三酯稳态中的作用的新认识 为肝脂肪变性提供了新的治疗选择。初级胆汁酸、胆酸（CA）和鹅去氧胆酸（CDCA）是FXR的内源性天然配体，但与合成配体奥贝胆酸（OCA）相比活性较弱，奥贝胆酸（OCA）的效力是CDCA的100倍。在各种小鼠模型和最近的非酒精性脂肪肝患者中，OCA已被证明可以改善肝脏脂肪变性。此外，在最近的一项2型糖尿病和非酒精性脂肪肝患者研究中，OCA改善了胰岛素敏感性，降低了血清丙氨酸氨基转移酶和γ谷氨酰转移酶水平。因此，我们建议研究奥贝胆酸在减少邓尼根型家族性部分脂肪代谢障碍（FPLD）患者的肝脏脂肪变性方面的疗效和安全性。因此，这项II期、随机、双盲、交叉、安慰剂对照研究旨在研究奥贝胆酸治疗在降低肝脏甘油三酯方面的疗效和安全性。 20例FPLD合并肝脂肪变性患者的脂肪沉积。OCA/安慰剂将以25 mg/天的剂量给药，每次给药4个月。主要终点变量为通过1H磁共振波谱测定的肝脏甘油三酯浓度。我们的研究结果可能会导致开发一种新的治疗干预脂肪代谢障碍患者的肝脂肪变性。

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.