美国西雅图西北肝脏研究所Kris V. Kowdley团队研究了Elafibranor治疗原发性胆汁性胆管炎的疗效和安全性。2023年11月13日出版的《新英格兰医学杂志》发表了这项成果。

原发性胆汁性胆管炎是一种罕见的慢性胆汁淤积性肝病，其特征是叶间胆管破坏，导致胆汁淤积和肝纤维化。Elafibranor是一种口服的过氧化物酶体增殖物激活受体（PPAR）α和δ双重激动剂，其是否有利于治疗原发性胆汁性胆管炎尚不清楚。

在这项跨国、临床3期、双盲、安慰剂对照试验中，研究组将对熊去氧胆酸反应不足或副作用不可接受的原发性胆汁性胆管炎患者（按2:1的比例）随机分配，每天接受一次80 mg剂量的elafibranor或安慰剂。主要终点是第52周的生化缓解（定义为碱性磷酸酶水平<正常范围上限的1.67倍，比基线降低≥15%，总胆红素水平正常）。关键次要终点是第52周碱性磷酸酶水平的正常化，以及从基线到第52周和第24周瘙痒强度的变化，如在最严重瘙痒数值评定量表（WI-NRS；评分范围从0[无瘙痒]到10[可想象的最严重瘙痒]）上所测得的。

共有161名患者接受了随机分组。在51%接受Elafibranor治疗的患者（108例中有55例）和4%接受安慰剂治疗的患者中（53例中有2例）观察到生化缓解（主要终点），差异为47个百分点（95%置信区间[CI]，32-57；P<0.001）。在第52周，Elafibranor组中15%的患者和安慰剂组中0名患者的碱性磷酸酶水平正常化（差异为15个百分点；95%置信区间，6-23；P=0.002）。

在患有中度至重度瘙痒的患者中（Elafibranor组44名患者，安慰剂组22名患者），从基线到第52周，WI-NRS的最小二乘平均变化在两组之间没有显著差异（−1.93对−1.15；差异，−0.78；95%CI，−1.99至0.42；P=0.20）。与安慰剂组相比，Elafibranor组更频繁发生的不良事件包括腹痛、腹泻、恶心和呕吐。

研究结果表明，与安慰剂相比，Elafibranor治疗可显著改善胆汁淤积症的相关生化指标。

附：英文原文

Title: Efficacy and Safety of Elafibranor in Primary Biliary Cholangitis | NEJM

Author: anonymous

Issue&Volume: 2023-11-13

Abstract:

Background

Primary biliary cholangitis is a rare, chronic cholestatic liver disease characterized by the destruction of interlobular bile ducts, leading to cholestasis and liver fibrosis. Whether elafibranor, an oral, dual peroxisome proliferator-activated receptor (PPAR) α and δ agonist, may have benefit as a treatment for primary biliary cholangitis is unknown.

Methods

In this multinational, phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients with primary biliary cholangitis who had had an inadequate response to or unacceptable side effects with ursodeoxycholic acid to receive once-daily elafibranor, at a dose of 80 mg, or placebo. The primary end point was a biochemical response (defined as an alkaline phosphatase level of <1.67 times the upper limit of the normal range, with a reduction of ≥15% from baseline, and normal total bilirubin levels) at week 52. Key secondary end points were normalization of the alkaline phosphatase level at week 52 and a change in pruritus intensity from baseline through week 52 and through week 24, as measured on the Worst Itch Numeric Rating Scale (WI-NRS; scores range from 0 [no itch] to 10 [worst itch imaginable]).

Results

A total of 161 patients underwent randomization. A biochemical response (the primary end point) was observed in 51% of the patients (55 of 108) who received elafibranor and in 4% (2 of 53) who received placebo, for a difference of 47 percentage points (95% confidence interval [CI], 32 to 57; P<0.001). The alkaline phosphatase level normalized in 15% of the patients in the elafibranor group and in none of the patients in the placebo group at week 52 (difference, 15 percentage points; 95% CI, 6 to 23; P=0.002). Among patients who had moderate-to-severe pruritus (44 patients in the elafibranor group and 22 in the placebo group), the least-squares mean change from baseline through week 52 on the WI-NRS did not differ significantly between the groups (1.93 vs. 1.15; difference, 0.78; 95% CI, 1.99 to 0.42; P=0.20). Adverse events that occurred more frequently with elafibranor than with placebo included abdominal pain, diarrhea, nausea, and vomiting.

Conclusions

Treatment with elafibranor resulted in significantly greater improvements in relevant biochemical indicators of cholestasis than placebo.

DOI: 10.1056/NEJMoa2306185

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2306185