Fenofibrate for the treatment of patients with NASH

描述（由申请人提供）： 在美国，非酒精性脂肪性肝炎（NASH）越来越被认为是一种常见的慢性肝病。NASH的特征在于独特的组织学特征，包括脂肪变性、气球样变性、小叶炎症和不同程度的纤维化。它通常与代谢综合征相关，在美国其发病率正在上升。NASH患者有进展为肝硬化并最终发展为肝细胞癌和过早死亡的风险。目前尚无标准的NASH治疗方法。在人类和动物中治疗NAFLD的小型临床试验中评价了几种药物治疗方法，但由于样本量小，缺乏安慰剂，缺乏随访肝活检和/或随访不充分，大多数研究的获益不确定。确定肝损伤发病机制的研究，疾病侵袭性形式的预测因素以及精心设计的研究，这些研究将显示旨在改善脂肪变性和炎症以及减缓疾病进展的医疗干预措施的有效性，这将是对这一日益严重的健康问题的主要贡献。我们提出了一项纤维酸衍生物“非诺贝特”的随机、双盲、安慰剂对照研究，非诺贝特是一种PPARa激动剂，在减少肝脂肪变性和炎症方面具有强效作用，用于治疗组织学证实的NASH患者。我们假设非诺贝特治疗将导致脂肪变性和炎症的显著改善，并改善NASH患者的胰岛素敏感性。我们的具体目标是：（1）评估NASH的组织学改善程度，如通过在经历非诺贝特治疗的患者中使用NASH-CRN评分系统的总体NASH评分降低> 2分所定义的，（2）评估非诺贝特改善NASH患者胰岛素敏感性的作用;（3）探讨非诺贝特对NASH患者肝组织过氧化物酶体增殖物激活受体（PPAR）基因表达及脂肪酸代谢的影响。据我们所知，这是第一个随机，安慰剂对照研究的PPARa激动剂在人类与NASH。NASH患者肝组织中计划的基因表达分析将首次提供这些药物改变人类肝脏基因表达的作用的快照。我们相信，这些研究不仅将对我们理解NASH的发病机制做出重要贡献，而且将为这种非常重要的疾病的治疗选择提供更多的见解

DESCRIPTION (provided by applicant): Non-alcoholic steatohepatitis (NASH) is increasingly recognized as a common form of chronic liver disease in the United States. NASH is characterized by distinct histological features that include steatosis, ballooning degeneration, lobular inflammation and varying degrees of fibrosis. It is commonly associated with the metabolic syndrome, the incidence of which is rising in the U.S. Patients with NASH are at risk of progression to cirrhosis and ultimately to hepatocellular carcinoma and premature death. There is no standard therapy for management of NASH at this point. Several approaches to drug therapy have been evaluated in small clinical trials for the treatment of NAFLD in humans and in animals but most studies have been inconclusive with uncertain benefits because of small sample size, lack of placebo, lack of follow-up liver biopsies and/or inadequate follow-up to evaluate treatment benefit. Studies that identify the pathogenesis of liver injury, predictors of aggressive forms of the disease as well as well designed studies that will show efficacy of medical interventions aimed at improving steatosis and inflammation and slowing down progression of disease will be major contributions for this growing health-problem. We propose a randomized, double-blind, placebo controlled study of a fibric acid derivative 'fenofibrate', a PPARa agonist with potent effects in decreasing hepatic steatosis and inflammation for treatment of patients with histologically proven NASH. We hypothesize that fenofibrate treatment will lead to a significant improvement in steatosis and inflammation and improve insulin sensitivity in patients with NASH. Our specific aims are: (1) To assess the degree of histological improvement of NASH as defined by > 2 point decrease in global NASH score using the NASH-CRN scoring system in patients undergoing treatment with fenofibrate, (2) To assess the effect of fenofibrate in improving insulin sensitivity in patients with NASH and (3) To assess the effect of fenofibrate on PPAR gene expression and fatty acid metabolism in liver tissue of patients with NASH. To our knowledge, this is the first randomized, placebo-controlled study of a PPARa agonist in humans with NASH. The planned gene expression analysis in liver tissue of patients with NASH will provide, for the first time, a snapshot of the action of these drugs to change hepatic gene expression in humans. We believe that the proposed studies will be an important contribution to our understanding not only of the pathogenesis of NASH, but will provide additional insights into treatment options for this very important disease