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Fazirsiran治疗α1抗胰蛋白酶缺乏相关肝病安全有效
作者:小柯机器人 发布时间:2022/6/30 19:29:07

德国亚琛工业大学医院Pavel Strnad团队研究了Fazirsiran治疗α1抗胰蛋白酶缺乏相关肝病的疗效。2022年6月25日出版的《新英格兰医学杂志》发表了这项成果。

α1抗胰蛋白酶(AAT)缺乏症是由于携带纯合SERPINA1“Z”突变(蛋白酶抑制剂[PI]ZZ)所致。Z等位基因产生一种称为Z-AAT的突变AAT蛋白,该蛋白在肝细胞中积聚,可导致进行性肝病和纤维化。这项开放标签的临床2期试验研究了fazirsiran(一种RNA干扰疗法)治疗AAT缺乏相关肝病的安全性和有效性。

研究组将具有PI-ZZ基因型和肝纤维化的成年人随机分配,分别在第1天和第4周皮下注射200毫克(队列1中4名患者和队列2中8名患者】)或100毫克(队列1b中4名患者)的fazirsiran,然后每12周注射一次。主要结局是通过液相色谱-质谱法测量的肝脏Z-AAT水平从基线检查到第24周(队列1和1b)或第48周(队列2)的变化。

所有患者Z-AAT在肝脏中的累积量均减少(第24周或48周时中位减少83%)。血清中的最低点约减少了90%,治疗也与组织学球负荷的降低有关(从基线检查时的平均得分7.4[0~9分,得分越高表明球负荷越大]降低至第24或48周时的平均得分2.3)。所有队列的肝酶浓度均降低。24或48周后,15名患者中有7名出现纤维化消退,2名患者出现纤维化进展。未出现导致试验中止或停药的不良事件。四个严重不良事件(病毒性心肌炎、憩室炎、呼吸困难和前庭神经炎)均得到缓解。

研究结果表明,在这项小型试验中,fazirsiran与血清和肝脏中Z-AAT水平的显著降低以及肝酶浓度的同时改善有关。

附:英文原文

Title: Fazirsiran for Liver Disease Associated with Alpha1-Antitrypsin Deficiency | NEJM

Author: Pavel Strnad, M.D.,, Mattias Mandorfer, M.D., Ph.D.,, Gourab Choudhury, M.D.,, William Griffiths, M.D.,, Christian Trautwein, M.D.,, Rohit Loomba, M.D.,, Thomas Schluep, Sc.D.,, Ting Chang, Ph.D.,, Min Yi, Ph.D.,, Bruce D. Given, M.D.,, James C. Hamilton, M.D.,, Javier San Martin, M.D.,, and Jeffery H. Teckman, M.D.

Issue&Volume: 2022-06-25

Abstract:

Background

Alpha1-antitrypsin (AAT) deficiency results from carriage of a homozygous SERPINA1 “Z” mutation (proteinase inhibitor [PI] ZZ). The Z allele produces a mutant AAT protein called Z-AAT, which accumulates in hepatocytes and can lead to progressive liver disease and fibrosis. This open-label, phase 2 trial investigated the safety and efficacy of fazirsiran, an RNA interference therapeutic, in patients with liver disease associated with AAT deficiency.

Methods

We assigned adults with the PI ZZ genotype and liver fibrosis to receive fazirsiran at a dose of 200 mg (cohorts 1 [4 patients] and 2 [8 patients]) or 100 mg (cohort 1b [4 patients]) subcutaneously on day 1 and week 4 and then every 12 weeks. The primary end point was the change from baseline to week 24 (cohorts 1 and 1b) or week 48 (cohort 2) in liver Z-AAT concentrations, which were measured by means of liquid chromatography–mass spectrometry.

Results

All the patients had reduced accumulation of Z-AAT in the liver (median reduction, 83% at week 24 or 48). The nadir in serum was a reduction of approximately 90%, and treatment was also associated with a reduction in histologic globule burden (from a mean score of 7.4 [scores range from 0 to 9, with higher scores indicating a greater globule burden] at baseline to 2.3 at week 24 or 48). All cohorts had reductions in liver enzyme concentrations. Fibrosis regression was observed in 7 of 15 patients and fibrosis progression in 2 of 15 patients after 24 or 48 weeks. There were no adverse events leading to trial or drug discontinuation. Four serious adverse events (viral myocarditis, diverticulitis, dyspnea, and vestibular neuronitis) resolved.

Conclusions

In this small trial, fazirsiran was associated with a strong reduction of Z-AAT concentrations in the serum and liver and concurrent improvements in liver enzyme concentrations.

DOI: 10.1056/NEJMoa2205416

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2205416

 

期刊信息

The New England Journal of Medicine:《新英格兰医学杂志》,创刊于1812年。隶属于美国麻省医学协会,最新IF:70.67
官方网址:http://www.nejm.org/
投稿链接:http://www.nejm.org/page/author-center/home