Efficacy and Safety of Aldafermin, an Engineered FGF19 Analog, in a Randomized, Double-Blind, Placebo-Controlled Trial of Patients With Nonalcoholic Steatohepatitis
Efficacy and Safety of Aldafermin, an Engineered FGF19 Analog, in a Randomized, Double-Blind, Placebo-Controlled Trial of Patients With Nonalcoholic Steatohepatitis
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DOI：
10.1053/j.gastro.2020.08.004
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发表时间：
2021-01-01
期刊：
影响因子：
29.4
通讯作者：
Lieu, Hsiao D.
中科院分区：
文献类型：
--
作者：
Harrison, Stephen A.;Neff, Guy;Lieu, Hsiao D.
背景与目的：Aldafermin是成纤维细胞生长因子19的工程类似物，抑制胆汁酸合成并调节代谢稳态。我们报告了一项为期24周的2期研究的结果，该研究对非酒精性脂肪性肝炎（NASH）患者进行了连续的肝活检。方法：我们对美国9个中心的78例NASH患者进行了双盲研究。关键的入选标准是活检证实的NASH，非酒精性脂肪肝活动评分≥ 4，NASH临床研究网络分类的2期或3期纤维化，以及通过磁共振成像-质子密度脂肪分数测量的绝对肝脏脂肪含量≥ 8%。患者随机（1：2）分配至安慰剂组（n = 25）或aldafermin 1 mg组（n = 53），每日皮下注射，持续24周。主要结局是第24周时肝脏脂肪绝对含量相对于基线的变化。次要结局包括纤维化改善和NASH消退的血清标志物和组织学指标。研究结果：第24周时，与安慰剂组相比，aldafermin组的绝对肝脏脂肪含量显著降低（降低7.7%）（降低2.7%;差异，降低5.0%; 95%置信区间，降低8.0%-1.9%; P = 0.002）。与安慰剂相比，Aldafermin使7 α-羟基-4-异戊烯-3-酮、胆汁酸、丙氨酸和天冬氨酸转氨酶以及III型胶原蛋白（Pro-C3）的新表位特异性N-末端前肽水平显著降低。38%接受aldafermin的患者与18%接受安慰剂的患者实现了纤维化改善（>= 1期），NASH未恶化（P = 0.10）。在24%的aldafermin组患者和9%的安慰剂组患者中观察到NASH消退，无纤维化恶化（P = 0.20）。阿达菲明组没有患者因不良事件停药，安慰剂组有4%的患者因不良事件停药。结论：在NASH患者的II期试验中，aldafermin减少了肝脏脂肪，并产生了改善纤维化的趋势。
BACKGROUND & AIMS: Aldafermin, an engineered analog of fibroblast growth factor 19, inhibits bile acid synthesis and regulates metabolic homeostasis. We report results from a 24-week, phase 2 study, with serial liver biopsies, of patients with nonalcoholic steatohepatitis (NASH). METHODS: We performed a double-blind study of 78 patients with NASH at 9 centers in the United States. Key inclusion criteria were biopsy-proven NASH with Nonalcoholic Fatty Liver Disease Activity Score >= 4, stage 2 or 3 fibrosis by NASH Clinical Research Network classification, and absolute liver fat content >= 8%, measured by magnetic resonance imaging-proton density fat fraction. Patients were randomly assigned (1:2) to groups given subcutaneous placebo (n = 25) or aldafermin 1 mg (n = 53) daily for 24 weeks. The primary outcome was change in absolute liver fat content from baseline at week 24. Secondary outcomes included serum markers and histologic measures of fibrosis improvement and NASH resolution. RESULTS: At week 24, the aldafermin group had a significant reduction in absolute liver fat content (reduction of 7.7%) compared with placebo (reduction of 2.7%; difference, reduction of 5.0%; 95% confidence interval, reduction of 8.0%-1.9%; P = .002). Aldafermin produced significantly greater decreases in levels of 7 alpha-hydroxy-4-cholesten-3-one, bile acids, alanine and aspartate aminotransferases, and neoepitope-specific N-terminal propeptide of type III collagen (Pro-C3) than placebo. Fibrosis improvement (>= 1 stage) with no worsening of NASH was achieved in 38% of patients receiving aldafermin vs 18% of patients receiving placebo (P = .10). NASH resolution with no worsening of fibrosis was observed in 24% of patients given aldafermin vs 9% of patients given placebo (P = .20). Discontinuations due to adverse events occurred in no patients in the aldafermin group and 4% of patients in the placebo group. CONCLUSIONS: In a phase 2 trial of patients with NASH, aldafermin reduced liver fat and produced a trend toward fibrosis improvement.