Elafibranor 治疗原发性胆汁性胆管炎的疗效和安全性。
Efficacy and Safety of Elafibranor in Primary Biliary Cholangitis.
机构信息
From Liver Institute Northwest, Seattle (K.V.K.); the Division of Gastroenterology and Hepatology, UC Davis School of Medicine, Sacramento (C.L.B.); Schiff Center for Liver Diseases, University of Miami, Miami (C.L.); the Department of Gastroenterology, Ege University Faculty of Medicine, İzmir, Turkey (U.S.A.); Gastroenterology and Hepatology Division, Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil (M.R.A.-S.); Medicina Interna Metabolica, Baggiovara Hospital, Azienda Ospedaliero-Universitaria di Modena and Università di Modena e Reggio Emilia, Modena (P.A.), and the Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, and the European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Fondazione IRCCS San Gerardo dei Tintori, Monza (P.I.) - all in Italy; Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago (M.A.), and Sección de Gastroenterología, Hospital San Juan de la Serena, Coquimbo (J.M. Valera) - both in Chile; the Reference Center for Inflammatory Biliary Disease and Autoimmune Hepatitis, European Reference Network RARE-LIVER, Saint-Antoine Hospital and Research Center, AP-HP, Sorbonne University, Paris (C.C.), GENFIT, Loos (J.-M.G., D.R., B.T.), and Ipsen, Boulogne-Billancourt (S.M.) - all in France; the Department of Gastroenterology and Hepatology, Antwerp University Hospital, and InflaMed Center of Excellence, Laboratory of Experimental Medicine and Paediatrics, Faculty of Medicine and Health Sciences, Antwerp University - both in Antwerp, Belgium (S.M.F.); the Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London (M.A.H.), the Institute of Cellular Medicine and NIHR Newcastle Biomedical Research Center, Newcastle University, Newcastle Upon Tyne (D.J.) - all in the United Kingdom; the Department of Gastroenterology and Hepatology, Mediclinic Durbanville, and Tiervlei Trial Centre - both in Cape Town, South Africa (F.C.K.); the Texas Liver Institute, University of Texas Health, San Antonio (E.L.), the Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas (M.J.M.), and the Departments of Medicine and Surgery, Baylor College of Medicine, Houston (J.M. Vierling) - all in Texas; the Liver Institute of Virginia, Bon Secours Mercy Health, Richmond (M.L.S.); the Liver Unit, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada (M.G.S.); Liver Unit, European Reference Network RARE-LIVER, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, CiberEhd, Barcelona (V.V.); Hepatic Autoimmunity Unit, Hospital Italiano de Buenos Aires, Buenos Aires (A.V.); GENFIT (C.A., J.D.) and Ipsen (B.M., J.S., C.O.Z.) - both in Cambridge, MA; and the Metabolic Liver Research Program, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, and the Department of Medicine II, Saarland University and Saarland University Medical Center, Homburg - both in Germany (J.M.S.).
出版信息
N Engl J Med. 2024 Feb 29;390(9):795-805. doi: 10.1056/NEJMoa2306185. Epub 2023 Nov 13.
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. (Funded by GENFIT and Ipsen; ELATIVE ClinicalTrials.gov number, NCT04526665.).
背景
原发性胆汁性胆管炎是一种罕见的慢性胆汁淤积性肝病，其特征为肝内小胆管破坏，导致胆汁淤积和肝纤维化。是否口服双重过氧化物酶体增殖物激活受体（PPAR）α和δ激动剂 Elafibranor 可作为原发性胆汁性胆管炎的治疗药物尚不清楚。
方法
在这项多中心、3 期、双盲、安慰剂对照试验中，我们将对熊去氧胆酸治疗应答不足或不良反应不能耐受的原发性胆汁性胆管炎患者，按 2:1 的比例随机分配，接受每日 1 次 Elafibranor（剂量为 80mg）或安慰剂治疗。主要终点是在第 52 周时生化应答（定义为碱性磷酸酶水平低于正常值上限的 1.67 倍，较基线下降≥15%，总胆红素水平正常）。主要次要终点是第 52 周时碱性磷酸酶水平正常，第 52 周及第 24 周时瘙痒严重程度的变化，通过最差瘙痒数字评分量表（WI-NRS；评分范围 0[无瘙痒]至 10[最严重瘙痒]）进行评估。
结果
共有 161 名患者接受了随机分组。Elafibranor 组 51%（55/108 例）患者出现生化应答（主要终点），而安慰剂组为 4%（2/53 例），差异为 47 个百分点（95%置信区间[CI]，32 至 57；P<0.001）。第 52 周时，Elafibranor 组 15%（15/108 例）患者碱性磷酸酶水平正常，安慰剂组无患者正常（差异为 15 个百分点；95%CI，6 至 23；P=0.002）。在中重度瘙痒（Elafibranor 组 44 例，安慰剂组 22 例）的患者中，通过 WI-NRS 从基线到第 52 周的最小二乘均值变化在两组间无显著差异（-1.93 与-1.15；差异，-0.78；95%CI，-1.99 至 0.42；P=0.20）。Elafibranor 组较安慰剂组更常发生的不良事件包括腹痛、腹泻、恶心和呕吐。
结论
与安慰剂相比，Elafibranor 治疗可显著改善胆汁淤积的相关生化指标。（由 GENFIT 和 Ipsen 资助；ELATIVE ClinicalTrials.gov 编号，NCT04526665。）
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