Emricasan对改善肝硬化患者肝功能的作用

StephenW

SUMMARY AND COMMENT | GASTROENTEROLOGY

June 27, 2018

Emricasan for Improving Liver Function in Patients with Cirrhosis

Atif Zaman, MD, MPH reviewing Frenette CT et al. Clin Gastroenterol Hepatol 2018 Jun 15

This promising pan-caspase inhibitor appeared to improve biomarkers and liver function in some patients with cirrhosis.

Caspases, a family of cysteine proteases, mediate apoptosis and inflammation, which are associated with many chronic liver diseases that lead to hepatic fibrosis. Emricasan, a pan-caspase inhibitor, has been shown to reduce serum markers for apoptosis and inflammation in chronic liver disease.

In this manufacturer–sponsored and designed, multicenter, double-blind, randomized, placebo-controlled study in patients with Child-Pugh A or B cirrhosis, patients randomly received emricasan 25 mg or placebo twice daily for 3 months. Thereafter, all patients received open-label emricasan for an additional 3 months. The primary endpoint was a change from baseline in levels of serum keratin 18 (CK-18) at 3 months. Secondary endpoints included model for end-stage liver disease (MELD) and Child-Pugh score changes from baseline.

Serum levels of full-length CK-18, but not cleaved CK-18, decreased significantly in the emricasan but not in the placebo group. Although MELD and Child-Pugh score changes were similar in both groups, emricasan group patients with baseline MELD ≥15 had significant decreases in both MELD and Child-Pugh scores. These improvements endured or increased during the open-label phase. Adverse events were similar between the two groups.
Comment

In this small study, emricasan appeared to improve caspase-related biomarkers, such as CK-18. More importantly, it improved liver function in patients with cirrhosis and MELD >15. Liver function improvement could possibly occur in lower-MELD-score patients, but the small sample size likely obscured the treatment effect. Further studies with larger sample sizes, powered to have MELD as the primary outcome, and including a diverse cirrhosis population, are needed to determine its value in clinical practice.

Editor Disclosures at Time of Publication

Disclosures for Atif Zaman, MD, MPH at time of publication

Grant/Research support:
       

Merck

Citation(s):

Frenette CT et al. Emricasan improves liver function in patients with cirrhosis and high model for end-stage liver disease scores compared with placebo. Clin Gastroenterol Hepatol 2018 Jun 15; [e-pub]. (https://doi.org/10.1016/j.cgh.2018.06.012)

StephenW

总结和评论|胃肠病

2018年6月27日

Emricasan对改善肝硬化患者肝功能的作用

Atif Zaman，医学博士，MPH回顾了Frenette CT等人。 Clin Gastroenterol Hepatol 2018年6月15日

这种有前景的泛半胱天冬酶抑制剂似乎可以改善一些肝硬化患者的生物标志物和肝功能。

半胱氨酸蛋白酶家族半胱氨酸蛋白酶介导细胞凋亡和炎症，这与许多导致肝纤维化的慢性肝病有关。 Emricasan是一种泛半胱天冬酶抑制剂，已被证明可降低慢性肝病患者血清凋亡和炎症标志物的浓度。

在由制造商赞助和设计的多中心，双盲，随机，安慰剂对照研究中，患儿接受Child-Pugh A或B肝硬化患者，随机接受emricasan 25 mg或安慰剂，每日两次，共3个月。此后，所有患者接受开放标签的Emricasan再服用3个月。主要终点是血清角蛋白18（CK-18）水平在3个月时从基线的变化。次要终点包括终末期肝病模型（MELD）和Child-Pugh评分从基线变化。

全长CK-18，但未切割的CK-18的血清水平在Emricasan中显着降低，但在安慰剂组中不显着。尽管两组MELD和Child-Pugh评分变化相似，但基线MELD≥15的Emricasan组患者的MELD和Child-Pugh评分均显着下降。这些改进在开放标签阶段期间持续或增加。两组之间的不良事件相似。
评论

在这项小型研究中，emricasan似乎改善了caspase相关的生物标志物，如CK-18。更重要的是，它改善了肝硬化患者的肝功能，MELD> 15。肝功能改善可能发生在MELD评分较低的患者中，但小样本量可能会影响治疗效果。需要更大样本量的研究，以MELD为主要结局，并包括多种肝硬化人群，以确定其在临床实践中的价值。

出版时的编辑披露

Atif Zaman，MD，MPH在出版时披露

拨款/研究支持：


默克

引用（S）：

Frenette CT等人Emricasan改善肝硬化患者的肝功能，与安慰剂组相比，终末期肝病分数高。 Clin Gastroenterol Hepatol 2018年6月15日; [E-PUB]。 （https://doi.org/10.1016/j.cgh.2018.06.012）