MASH 和纤维化中苏沃杜肽的 2 期随机试验。
A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis.
机构信息
From the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University School of Medicine, Richmond (A.J.S.); Liverpat and University of Paris (P.B.), and Sorbonne Université, Institute for Cardiometabolism and Nutrition, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche Scientifique 1138, Centre de Recherche des Cordeliers (V.R.) - all in Paris; Boehringer Ingelheim, Ingelheim am Rhein (M.F., S.A.H and R.Y.), Saarland University Medical Center, Homburg (J.M.S.), and University of the Saarland, Saarbrücken (J.M.S.) - all in Germany; Covenant Metabolic Specialists, Sarasota, FL (G.W.N.); Houston Methodist Hospital and Houston Research Institute, Houston (M.N.), and the Texas Liver Institute, University of Texas Health San Antonio, San Antonio (E.L. and N.A.) - all in Texas; the University of Turin, Turin, Italy (E.B.); the Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, and Newcastle National Institute for Health and Care Research Biomedical Research Centre, Newcastle upon Tyne Hospitals National Health Service (NHS) Foundation Trust, Newcastle upon Tyne (Q.M.A.), the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Birmingham (P.N.N.), and the Institute of Hepatology, Faculty of Life Sciences and Medicine, King's College London and King's College Hospital, London (P.N.N.) - all in the United Kingdom; Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT (A.H.-T.); and Arizona Liver Health, Chandler (N.A.).
出版信息
N Engl J Med. 2024 Jul 25;391(4):311-319. doi: 10.1056/NEJMoa2401755. Epub 2024 Jun 7.
BACKGROUND
Dual agonism of glucagon receptor and glucagon-like peptide-1 (GLP-1) receptor may be more effective than GLP-1 receptor agonism alone for treating metabolic dysfunction-associated steatohepatitis (MASH). The efficacy and safety of survodutide (a dual agonist of glucagon receptor and GLP-1 receptor) in persons with MASH and liver fibrosis are unclear.
METHODS
In this 48-week, phase 2 trial, we randomly assigned adults with biopsy-confirmed MASH and fibrosis stage F1 through F3 in a 1:1:1:1 ratio to receive once-weekly subcutaneous injections of survodutide at a dose of 2.4, 4.8, or 6.0 mg or placebo. The trial had two phases: a 24-week rapid-dose-escalation phase, followed by a 24-week maintenance phase. The primary end point was histologic improvement (reduction) in MASH with no worsening of fibrosis. Secondary end points included a decrease in liver fat content by at least 30% and biopsy-assessed improvement (reduction) in fibrosis by at least one stage.
RESULTS
A total of 293 randomly assigned participants received at least one dose of survodutide or placebo. Improvement in MASH with no worsening of fibrosis occurred in 47% of the participants in the survodutide 2.4-mg group, 62% of those in the 4.8-mg group, and 43% of those in the 6.0-mg group, as compared with 14% of those in the placebo group (P<0.001 for the quadratic dose-response curve as best-fitting model). A decrease in liver fat content by at least 30% occurred in 63% of the participants in the survodutide 2.4-mg group, 67% of those in the 4.8-mg group, 57% of those in the 6.0-mg group, and 14% of those in the placebo group; improvement in fibrosis by at least one stage occurred in 34%, 36%, 34%, and 22%, respectively. Adverse events that were more frequent with survodutide than with placebo included nausea (66% vs. 23%), diarrhea (49% vs. 23%), and vomiting (41% vs. 4%); serious adverse events occurred in 8% with survodutide and 7% with placebo.
CONCLUSIONS
Survodutide was superior to placebo with respect to improvement in MASH without worsening of fibrosis, warranting further investigation in phase 3 trials. (Funded by Boehringer Ingelheim; 1404-0043 ClinicalTrials.gov number, NCT04771273; EudraCT number, 2020-002723-11.).
背景
胰高血糖素受体和胰高血糖素样肽-1（GLP-1）受体的双重激动可能比单独使用 GLP-1 受体激动剂更能有效治疗代谢功能障碍相关脂肪性肝炎（MASH）。在患有 MASH 和肝纤维化的患者中， survodutide（胰高血糖素受体和 GLP-1 受体的双重激动剂）的疗效和安全性尚不清楚。
方法
在这项为期 48 周的 2 期试验中，我们按照 1:1:1:1 的比例随机分配活检证实患有 MASH 和纤维化阶段 F1 至 F3 的成年人接受每周一次皮下注射 survodutide，剂量为 2.4、4.8 或 6.0mg 或安慰剂。试验分为两个阶段：24 周快速剂量递增阶段，随后是 24 周的维持阶段。主要终点是 MASH 组织学改善（无纤维化恶化）。次要终点包括肝脂肪含量至少减少 30%和通过活检评估的纤维化改善（减少）至少一个阶段。
结果
共有 293 名随机分配的参与者至少接受了一剂 survodutide 或安慰剂。与安慰剂组的 14%相比，2.4mg 组的参与者中有 47%、4.8mg 组的参与者中有 62%和 6.0mg 组的参与者中有 43%的患者 MASH 改善且纤维化无恶化（作为最佳拟合模型的二次剂量反应曲线，差异有统计学意义）。2.4mg 组的参与者中有 63%、4.8mg 组的参与者中有 67%、6.0mg 组的参与者中有 57%和安慰剂组的参与者中有 14%的患者肝脂肪含量至少减少 30%；纤维化改善至少一个阶段的发生率分别为 34%、36%、34%和 22%。与安慰剂相比， survodutide 更常见的不良反应包括恶心（66%比 23%）、腹泻（49%比 23%）和呕吐（41%比 4%）； survodutide 组有 8%的患者发生严重不良事件，安慰剂组有 7%的患者发生严重不良事件。
结论
与安慰剂相比， survodutide 在改善 MASH 方面优于安慰剂且不加重纤维化，值得进一步进行 3 期临床试验。（由勃林格殷格翰公司资助；1404-0043 ClinicalTrials.gov 编号，NCT04771273；EudraCT 编号，2020-002723-11。）
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