比利时安特卫普大学医学院Sven M. Francque团队研究了泛PPAR激动剂lanifibranor治疗NASH的随机对照试验。2021年10月20日出版的《新英格兰医学杂志》发表了这项成果。

非酒精性脂肪性肝炎（NASH）的临床治疗颇为棘手。Lanifibranor是一种泛PPAR（过氧化物酶体增殖物激活受体）激动剂，在NASH发病机制中调节关键的代谢、炎症和纤维化途径。

在这项临床2b期、双盲、随机、安慰剂对照试验中，研究组招募非肝硬化、高活性NASH患者，将其按1:1:1的比例随机分配，分别接受1200 mg或800 mg lanifibranor或安慰剂治疗，每日1次，持续24周。

主要终点是SAF-A评分（脂肪变性、活动度、纤维化[SAF]评分系统，包括球囊和炎症评分）至少降低2分，且纤维化没有恶化；SAF-A得分范围从0到4，得分越高表明疾病活动越严重。次要终点包括NASH缓解和纤维化消退。

共有247名患者接受了随机分组，其中103名（42%）患有2型糖尿病，188名（76%）患有严重（中度）或晚期纤维化。Lanifibranor 1200 mg剂量组中SAF-A评分至少降低2分且纤维化没有恶化的患者占55%，显著高于安慰剂组的33%；800 mg剂量组为48%，与安慰剂组无显著差异。

Lanifibranor 1200 mg剂量组和800 mg剂量组中分别有49%和39%的患者NASH有所缓解，且纤维化没有恶化，安慰剂组为22%；分别有48%和34%的患者至少改善1个纤维化分期，且NASH未恶化，安慰剂组为29%；分别35%和25%的患者NASH缓解且至少改善1个纤维化分期，安慰剂组为9%。

Lanifibranor组患者的肝酶水平降低，大多数脂质、炎症和纤维化生物标志物水平提高。因不良事件的退组率不到5%，且各试验组之间情况相似。与安慰剂组相比，Lanifibranor组腹泻、恶心、外周水肿、贫血和体重增加的发生率更高。

研究结果表明，在这项涉及活动性NASH患者的2b期试验中，服用1200 mg剂量的lanifibranor后，SAF-A评分至少降低2分且纤维化没有恶化的患者百分比显著高于安慰剂。该发现支持在3期试验中进一步评估lanifibranor。

附：英文原文

Title: A Randomized, Controlled Trial of the Pan-PPAR Agonist Lanifibranor in NASH

Author: Sven M. Francque, M.D., Ph.D.,, Pierre Bedossa, M.D., Ph.D.,, Vlad Ratziu, M.D., Ph.D.,, Quentin M. Anstee, M.D., Ph.D.,, Elisabetta Bugianesi, M.D., Ph.D.,, Arun J. Sanyal, M.D.,, Rohit Loomba, M.D., M.H.Sc.,, Stephen A. Harrison, M.D.,, Rozalina Balabanska, M.D.,, Lyudmila Mateva, M.D., Ph.D.,, Nicolas Lanthier, M.D., Ph.D.,, Naim Alkhouri, M.D.,, Christophe Moreno, M.D., Ph.D.,, Jrn M. Schattenberg, M.D.,, Diana Stefanova-Petrova, M.D.,, Luisa Vonghia, M.D., Ph.D.,, Régine Rouzier, M.D.,, Maeva Guillaume, M.D., Ph.D.,, Alexander Hodge, M.B., B.S., Ph.D.,, Manuel Romero-Gómez, M.D., Ph.D.,, Philippe Huot-Marchand, M.Sc.,, Martine Baudin, M.D.,, Marie-Paule Richard, M.D.,, Jean-Louis Abitbol, M.D.,, Pierre Broqua, Ph.D.,, Jean-Louis Junien, Ph.D.,, and Manal F. Abdelmalek, M.D., M.P.H.

Issue&Volume: 2021-10-20

Abstract:

Background

Management of nonalcoholic steatohepatitis (NASH) is an unmet clinical need. Lanifibranor is a pan-PPAR (peroxisome proliferator–activated receptor) agonist that modulates key metabolic, inflammatory, and fibrogenic pathways in the pathogenesis of NASH.

Methods

In this phase 2b, double-blind, randomized, placebo-controlled trial, patients with noncirrhotic, highly active NASH were randomly assigned in a 1:1:1 ratio to receive 1200 mg or 800 mg of lanifibranor or placebo once daily for 24 weeks. The primary end point was a decrease of at least 2 points in the SAF-A score (the activity part of the Steatosis, Activity, Fibrosis [SAF] scoring system that incorporates scores for ballooning and inflammation) without worsening of fibrosis; SAF-A scores range from 0 to 4, with higher scores indicating more-severe disease activity. Secondary end points included resolution of NASH and regression of fibrosis.

Results

A total of 247 patients underwent randomization, of whom 103 (42%) had type 2 diabetes mellitus and 188 (76%) had significant (moderate) or advanced fibrosis. The percentage of patients who had a decrease of at least 2 points in the SAF-A score without worsening of fibrosis was significantly higher among those who received the 1200-mg dose, but not among those who received the 800-mg dose, of lanifibranor than among those who received placebo (1200-mg dose vs. placebo, 55% vs. 33%, P=0.007; 800-mg dose vs. placebo, 48% vs. 33%, P=0.07). The results favored both the 1200-mg and 800-mg doses of lanifibranor over placebo for resolution of NASH without worsening of fibrosis (49% and 39%, respectively, vs. 22%), improvement in fibrosis stage of at least 1 without worsening of NASH (48% and 34%, respectively, vs. 29%), and resolution of NASH plus improvement in fibrosis stage of at least 1 (35% and 25%, respectively, vs. 9%). Liver enzyme levels decreased and the levels of the majority of lipid, inflammatory, and fibrosis biomarkers improved in the lanifibranor groups. The dropout rate for adverse events was less than 5% and was similar across the trial groups. Diarrhea, nausea, peripheral edema, anemia, and weight gain occurred more frequently with lanifibranor than with placebo.

Conclusions

In this phase 2b trial involving patients with active NASH, the percentage of patients who had a decrease of at least 2 points in the SAF-A score without worsening of fibrosis was significantly higher with the 1200-mg dose of lanifibranor than with placebo. These findings support further assessment of lanifibranor in phase 3 trials.

DOI: 10.1056/NEJMoa2036205

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2036205