NGM282 Improves Liver Fibrosis and Histology in 12 Weeks in Patients With Nonalcoholic Steatohepatitis
NGM282 Improves Liver Fibrosis and Histology in 12 Weeks in Patients With Nonalcoholic Steatohepatitis
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DOI：
10.1002/hep.30590
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发表时间：
2020-04-01
期刊：
影响因子：
13.5
通讯作者：
DePaoli, Alex M.
中科院分区：
文献类型：
--
作者：
Harrison, Stephen A.;Rossi, Stephen J.;DePaoli, Alex M.
NGM282是一种工程化的成纤维细胞生长因子19类似物，在一项针对经活检确诊为非酒精性脂肪性肝炎（NASH）患者的多中心、随机、双盲、安慰剂对照研究中，能快速且显著降低肝脏脂肪含量。然而，尚不清楚这些变化是否会伴有组织学改善。在这项开放标签研究中，我们评估了NGM282在经活检确诊为非酒精性脂肪性肝炎患者中的组织学疗效。对43例患者的配对肝脏活检样本进行了评估，这些患者每日皮下注射一次NGM282（1毫克，n = 24；3毫克，n = 19），持续12周，评估时对时间点、受试者和临床信息设盲。在第12周时，NGM282显著降低了非酒精性脂肪性肝病活动评分（NAS；-1.9；95%置信区间，-2.6至-1.2；1毫克组P < 0.001；-2.2，-3.1至-1.3；3毫克组P < 0.001）和纤维化评分（-0.5；-0.9至0；3毫克组P = 0.035）。总体而言，分别接受1毫克或3毫克NGM282治疗的患者中，有50%和63%的患者NAS改善了2分或更多且纤维化无恶化。在接受1毫克或3毫克NGM282治疗的患者中，分别有25%和42%的患者肝纤维化改善了一个阶段或更多且脂肪性肝炎无恶化。使用NGM282治疗导致肝脏脂肪含量相对降低（1毫克组和3毫克组分别为-58%和-67%），校正T1（cT1；-8%和-9%）、丙氨酸氨基转移酶（ALT；-67%和-60%）、天冬氨酸氨基转移酶（-57%和-52%）以及纤维生成生物标志物Ⅲ型胶原新表位特异性N末端前肽（Pro - C3；-22%和-33%）和增强肝纤维化评分（ELF；-3%和-6%）在第12周时出现相应变化。在组织学有反应者中观察到Pro - C3、ELF和cT1的降低幅度大于无反应者，但肝脏脂肪含量、7α - 羟基 - 4 - 胆甾烯 - 3 - 酮或ALT并非如此。结论：在这项开放标签研究中，NGM282在12周内改善了NASH的组织学特征，NAS和纤维化评分显著降低，同时无创成像和血清标志物也有所改善。
NGM282, an engineered fibroblast growth factor 19 analogue, rapidly and significantly reduced liver fat content in a multicenter, randomized, double-blind, placebo-controlled study in patients with biopsy-confirmed nonalcoholic steatohepatitis (NASH). However, it is unclear whether these changes would be accompanied by histological improvement. In this open-label study, we assessed the histological efficacy of NGM282 in patients with biopsy-confirmed nonalcoholic steatohepatitis. Paired liver biopsies from 43 patients who received subcutaneous NGM282 (1 mg, n = 24; 3 mg, n = 19) once daily for 12 weeks were evaluated blinded to time point, subject, and clinical information. At week 12, NGM282 significantly reduced nonalcoholic fatty liver disease activity score (NAS; -1.9; 95% confidence interval, -2.6 to -1.2; P < 0.001 in the 1 mg group; -2.2, -3.1 to -1.3; P < 0.001 in the 3 mg group) and fibrosis (-0.5; -0.9 to 0; P = 0.035 in the 3 mg group) scores. Overall, 50% and 63% of the patients receiving NGM282 1 mg or 3 mg, respectively, improved NAS by 2 or more points without fibrosis worsening. Of the patients receiving NGM282 1 mg or 3 mg, 25% and 42%, respectively, improved liver fibrosis by one stage or more without worsening of steatohepatitis. Treatment with NGM282 led to relative reductions in liver fat content (-58% and -67% in the 1 mg and 3 mg groups, respectively), corrected T1 (cT1; -8% and -9%), alanine aminotransferase (ALT) (-67% and -60%), aspartate aminotransferase (-57% and -52%), and fibrogenesis biomarkers neoepitope-specific N-terminal propeptide of type III collagen (Pro-C3; -22% and -33%) and enhanced liver fibrosis score (ELF; -3% and -6%) at week 12. Greater reductions in Pro-C3, ELF, and cT1, but not in liver fat content, 7alpha-hydroxy-4-cholesten-3-one, or ALT, were observed in histological responders than in nonresponders. Conclusion: In this open-label study, NGM282 improved the histological features of NASH in 12 weeks with significant reductions in NAS and fibrosis scores, accompanied by improvements in noninvasive imaging and serum markers.