加拿大多伦多总医院Gideon M. Hirschfield团队研究了Seladelpar治疗原发性胆汁性胆管炎的疗效与安全性。相关论文于2024年2月21日发表在《新英格兰医学杂志》上。

原发性胆汁性胆管炎患者的有效治疗方法很有限。Seladelpar是一种过氧化物酶体增殖物激活受体δ激动剂，具有潜在的益处。

在这项为期12个月的3期临床双盲安慰剂对照试验中，研究组随机分配（以2:1的比例）对熊去氧胆酸反应不足或有不可接受副作用史的患者接受口服seladelpar，剂量为每日10 mg或安慰剂。主要终点是生化反应，其定义为12个月时碱性磷酸酶水平低于正常范围上限的1.67倍，比基线下降15%或更多，总胆红素水平正常。关键次要终点是12个月时碱性磷酸酶水平的正常化，以及基线评分至少为4（表示中度至重度瘙痒）的患者从基线到6个月瘙痒数值评定量表评分的变化（范围为0[无瘙痒]到10[可想象的最严重瘙痒]）。

在193名接受随机分组和治疗的患者中，93.8%的患者接受了熊去氧胆酸作为标准护理背景治疗。Seladelpar组有生化反应的患者比例高于安慰剂组（61.7%对20.0%；差异为41.7个百分点；95%置信区间[CI]为27.7至53.4，P<0.001）。接受seladelpar治疗的患者碱性磷酸酶水平正常化的比例也高于接受安慰剂治疗的患者（25.0%对0%；差异为25.0个百分点；95%可信区间，18.3至33.2，P<0.001）。

与安慰剂组相比，Seladelpar组在瘙痒数值评定量表上的得分下降幅度更大（与基线相比，最小二乘平均变化为−3.2与−1.7；最小二乘平均差异为−1.5；95%置信区间为−2.5至−0.5，P=0.005）。Seladelpar组86.7%的患者和安慰剂组84.6%的患者报告了不良事件，严重不良事件分别为7.0%和6.2%。

研究结果表明，在这项涉及原发性胆汁性胆管炎患者的试验中，seladelpar的生化反应和碱性磷酸酶正常化患者的百分比明显高于安慰剂。Seladelpar还显著减少了基线时有中度至重度瘙痒患者的瘙痒。两组不良事件的发生率和严重程度相似。

附：英文原文

Title: A Phase 3 Trial of Seladelpar in Primary Biliary Cholangitis

Author: Gideon M. Hirschfield, Christopher L. Bowlus, Marlyn J. Mayo, Andreas E. Kremer, John M. Vierling, Kris V. Kowdley, Cynthia Levy, Alejandra Villamil, Alma L. Ladrón de Guevara Cetina, Ewa Janczewska, Ehud Zigmond, Sook-Hyang Jeong, Yusuf Yilmaz, Yiannis Kallis, Christophe Corpechot, Peter Buggisch, Pietro Invernizzi, Maria Carlota Londoo Hurtado, Sandrin Bergheanu, Ke Yang, Yun-Jung Choi, Daria B. Crittenden, Charles A. McWherter

Issue&Volume: 2024-02-21

Abstract:

Background

Effective treatments for patients with primary biliary cholangitis are limited. Seladelpar, a peroxisome proliferator–activated receptor delta agonist, has potential benefits.

Methods

In this phase 3, 12-month, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients who had had an inadequate response to or who had a history of unacceptable side effects with ursodeoxycholic acid to receive oral seladelpar at a dose of 10 mg daily or placebo. The primary end point was a biochemical response, which was defined as an alkaline phosphatase level less than 1.67 times the upper limit of the normal range, with a decrease of 15% or more from baseline, and a normal total bilirubin level at month 12. Key secondary end points were normalization of the alkaline phosphatase level at month 12 and a change in the score on the pruritus numerical rating scale (range, 0 [no itch] to 10 [worst itch imaginable]) from baseline to month 6 among patients with a baseline score of at least 4 (indicating moderate-to-severe pruritus).

Results

Of the 193 patients who underwent randomization and treatment, 93.8% received ursodeoxycholic acid as standard-of-care background therapy. A greater percentage of the patients in the seladelpar group than in the placebo group had a biochemical response (61.7% vs. 20.0%; difference, 41.7 percentage points; 95% confidence interval [CI], 27.7 to 53.4, P<0.001). Normalization of the alkaline phosphatase level also occurred in a greater percentage of patients who received seladelpar than of those who received placebo (25.0% vs. 0%; difference, 25.0 percentage points; 95% CI, 18.3 to 33.2, P<0.001). Seladelpar resulted in a greater reduction in the score on the pruritus numerical rating scale than placebo (least-squares mean change from baseline, 3.2 vs. 1.7; least-squares mean difference, 1.5; 95% CI, 2.5 to 0.5, P=0.005). Adverse events were reported in 86.7% of the patients in the seladelpar group and in 84.6% in the placebo group, and serious adverse events in 7.0% and 6.2%, respectively.

Conclusions

In this trial involving patients with primary biliary cholangitis, the percentage of patients who had a biochemical response and alkaline phosphatase normalization was significantly greater with seladelpar than with placebo. Seladelpar also significantly reduced pruritus among patients who had moderate-to-severe pruritus at baseline. The incidence and severity of adverse events were similar in the two groups.

DOI: 10.1056/NEJMoa2312100

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2312100