2016年EASL：Emricasan可改善肝硬化人民炎症和肝功能

StephenW

EASL 2016: Emricasan May Improve Inflammation and Liver Function in People with Cirrhosis

   
Details
    Category: Other Liver Disease   
    Published on Friday, 22 April 2016 00:00
    Written by Liz Highleyman


The novel caspase inhibitor emricasan (IDN-6556) led to improvements in various biomarkers and decreases in MELD scores in patients with liver cirrhosis due to hepatitis C, heavy alcohol use, or other causes, which significant declines among those who started with worse liver dysfunction, according to a late-breaking presentation at the European Association for the Study of the Liver's International Liver Congress (EASL 2016) last week in Barcelona.

Caspases are protease enzymes that play a role in apoptosis (programmed cell death) and inflammation, contributing to progression of chronic liver disease. Emricasan is a first-in-class pan-caspase inhibitor that has been shown to decrease biomarkers of apoptosis and inflammation in people with liver disease.

Catherine Frenette from the Scripps Clinic in San Diego and colleagues evaluated the effects of emricasan in people with cirrhosis who had MELD scores between 11 and 18. The MELD score is an indicator of liver disease severity calculated using bilirubin and creatinine levels and blood clotting capacity (INR), used to predict how urgently a patient needs a liver transplant. Scores of 10-19 predicted 3-month mortality of 6%, rising to more than 70% with a score above 40.

This multicenter Phase 2 study enrolled 86 participants with liver cirrhosis. Nearly two-thirds were men, most were white, and the mean age was 58 years. The main causes of liver disease were heavy alcohol use (38%), hepatitis C (29%), and non-alcoholic steatohepatitis (23%).

The mean MELD score at study entry was 12.8, though 22% had MELD >15. The mean Child- Pugh score was 6.9, with 56% being Child-Pugh class B, indicating significant functional impairment but not yet decompensation. Mean alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were 30.9 and 52.2 U/L, respectively.

Hepatitis C patients receiving or planning antiviral treatment, hepatitis B patients on therapy for less than 3 months, and HIV-positive people were excluded, as were those with very advanced liver disease (e.g., recent bleeding varices, uncontrolled ascites, serious encephalopathy, or Child-Pugh class C.)

Participants were randomly assigned to receive 25 mg oral emricasan or placebo twice-daily for 3 months, followed by a second 3-month open-label phase in which everyone received emricasan.

Results

    74 participants completed the 3-month randomized treatment phase, while 12 discontinued early (4 on emricasan, 8 on placebo).
    After 3 months of therapy, emricasan was associated with significant decreases in the serum apoptosis and inflammation markers caspase 3/7 and cCK18, with the former change being significant overall and the latter for people with high baseline MELD scores.
    MELD scores decreased overall in the emricasan group while rising slightly in the placebo group (-0.1 vs +0.1), but the difference did not reach statistical significance (p=0.50).
    Child-Pugh scores also fell overall in the emricasan group and rose in the placebo group (-0.2 vs +0.1), but again this was not significant (p=0.1).
    However, in a pre-specified analysis looking at patients with more advanced disease who had baseline MELD scores of 15 or higher, those who received emricasan did show significant improvement compared to placebo recipients in MELD scores, Child-Pugh scores, bilirubin levels, and blood clotting capacity.
    A similar proportion of patients experienced clinical worsening events in the emricasan and placebo groups (both 14%), including development or worsening of ascites or encephalopathy.
    Treatment was generally safe and well-tolerated, with similar adverse events, serious events, laboratory abnormalities, vital signs, and incidence of cancer and infections in the emricasan and placebo groups.
    The most common adverse events in the emricasan group were headache, 16%), nausea 14%), and fatigue 9%).

These findings confirmed the mechanism of action and showed that emricasan "improved measures of liver function in patients with baseline MELD >15" and had a "reassuring safety profile," the researchers concluded. "These results support further study of emricasan in patients with cirrhosis and liver impairment."

Asked about evidence from other diseases suggesting that caspase inhibitors are associated with increased risk for infections, Frenette noted that emricasan is a liver-specific drug and in this study infections did not occur more often in the emricasan compared to the placebo group.

4/22/16

Reference

C Frenette, G Morelli, M Shiffman, et al. Emricasan(IDN-6556) orally for three months in patients with cirrhosis and MELD scores 11-18 improves clinical parameters of cirrhosis in patients with baseline MELD score >15. EASL International Liver Congress 2016. Barcelona, April 13-17, 2016. Abstract LB05.

StephenW

2016年EASL：Emricasan可改善肝硬化人民炎症和肝功能

   
详细信息
    分类：其它肝病
    发布时间上周五，2016年4月22日00:00
    撰写由Liz Highleyman


新颖的蛋白酶抑制剂emricasan（IDN-6556）导致了不同的生物标志物的改进和肝硬化患者由于丙型肝炎，酗酒，或其他原因，在MELD评分下降而那些谁与糟糕的肝功能不全开始之间显著下跌，根据在欧洲协会了最新演示肝脏的国际肝病大会（EASL 2016）上周在巴塞罗那的研究。

胱天蛋白酶是蛋白酶发挥细胞凋亡（程序性细胞死亡）和炎症中起作用的酶，促进慢性肝脏疾病的进展。 Emricasan是已经被证明能减少细胞凋亡和炎症的生物标志物在人与肝病的第一的一流的泛半胱天冬酶抑制剂。

来自斯克里普斯诊所在圣地亚哥和他的同事凯瑟琳Frenette评估emricasan的影响与肝硬化的人谁11和18之间有MELD评分MELD评分是利用胆红素和肌酐水平和血液凝固能力计算肝脏疾病严重程度的指标（ INR），用于预测患者如何迫切需要肝脏移植。 10-19比分预测的6％，3个月的死亡率，上升到超过70％以上40分。

这项多中心2期研究纳入86人参加的肝硬化。近三分之二为男性，多数是白人，平均年龄为58​​岁。肝脏疾病的主要原因是酗酒（38％），丙型肝炎（29％）和非酒精性脂肪性肝炎（23％）。

平均MELD评分在研究开始时为12.8，虽然22％的MELD> 15。平均儿童期Pugh评分为6.9，56％为Child-Pugh分级B级，表示显著的功能障碍，但尚未代偿。平均谷丙转氨酶（ALT）和天冬氨酸氨基转移酶（AST）水平分别为30.9和52.2 U / L，分别。

接受或计划进行抗病毒治疗，乙肝患者在治疗不到3个月，和HIV阳性的人丙型肝炎患者被排除在外，因为是那些具有非常先进的肝脏疾病（例如，最近出血静脉曲张，不受控制腹水，严重的脑病，或Child-Pugh分级C类）

参与者被随机分配到每天两次收到25毫克口服emricasan或安慰剂治疗3个月，之后，大家都收到emricasan第二个3个月的开放标签的阶段。

结果

    74参加者完成3个月的随机治疗阶段，而早期的12停产（4 emricasan，8安慰剂）。
    治疗3个月后，emricasan与在血清细胞凋亡和caspase 3/7和cCK18显著减少炎症标志有关，前者变化是显著全面，后者为高的人基线MELD评分。
    MELD评分的emricasan组中整体下降，而安慰剂组（-0.1 +0.1 VS）的小幅上涨，但差异无统计学意义（P = 0.50）。
    Child-Pugh分级分数也在emricasan集团整体下跌和上涨，安慰剂组（-0.2 +0.1 VS）的，但同样这不是显著（P = 0.1）。
    然而，在预先指定的分析寻找更晚期疾病谁具有15或更高的基线MELD分数​​，那些谁收到emricasan没有显示显著改善相比MELD分数​​，Child-Pugh分级分数，胆红素水平安慰剂接受者，并血液凝固的能力。
    患者类似的比例在经历了emricasan组和安慰剂组临床恶化事件（均为14％），包括开发或腹水或脑病恶化。
    治疗是通常安全和良好耐受的，具有相似的不良事件，严重不良事件，实验室异常，生命体征和癌症发病率和感染在emricasan组和安慰剂组。
    该emricasan组中最常见的副作用是头痛，16％），恶心14％），和疲劳9％）。

这些发现证实了其作用机制，并表明emricasan“患者的基线MELD> 15肝功能改进措施”，有一个“令人放心的安全性，”研究人员得出结论。 “这些结果支持emricasan进一步研究肝硬化和肝损害。”

询问有关从其他疾病表明蛋白酶抑制剂与用于感染的风险增加相关的证据，Frenette指出emricasan是肝特异性药物，并在本次研究的感染没有更经常在emricasan相比安慰剂组发生。

16年4月22日

参考

ÇFrenette，G莫雷利，女Shiffman等。 Emricasan（IDN-6556）口服的患者三个月肝硬化MELD评分11-18改善患者的基线MELD评分> 15的肝硬化临床参数。 EASL国际肝病会议2016年巴塞罗那，4月13日至17日，2016年摘要LB05。

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