National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Birmingham, United Kingdom; University Hospitals Birmingham, Birmingham, United Kingdom; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom; Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Canada.
Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, Hepatology and Gastroenterology Department, Saint-Antoine University Hospital, Assistance Publique-Hopitaux de Paris, and INSERM UMR S938, Sorbonne University, Paris, France.
J Hepatol. 2019 Mar;70(3):483-493. doi: 10.1016/j.jhep.2018.10.035. Epub 2018 Nov 9.
BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is an inflammatory, cholestatic and progressively fibrotic liver disease devoid of effective medical intervention. NGM282, an engineered, non-tumorigenic FGF19 analogue, potently regulates CYP7A1-mediated bile acid homeostasis. We assessed the activity and safety of NGM282 in patients with PSC.
In this double-blind, placebo-controlled phase II trial, 62 patients who had PSC confirmed by cholangiography or biopsy and an elevated alkaline phosphatase (ALP) >1.5 × the upper limit of normal were randomly assigned 1:1:1 to receive NGM282 1 mg, 3 mg or placebo once daily for 12 weeks. The primary outcome was the change in ALP from baseline to week 12. Secondary and exploratory outcomes included changes in serum biomarkers of bile acid metabolism and fibrosis. Efficacy analysis was by intention-to-treat.
At 12 weeks, there were no significant differences in the mean change from baseline in ALP between the NGM282 and placebo groups, and therefore, the primary endpoint was not met. However, NGM282 significantly reduced levels of 7alpha-hydroxy-4-cholesten-3-one (a marker of hepatic CYP7A1 activity, LS mean differences -6.2 ng/ml (95% CI -10.7 to -1.7; p = 0.008) and -9.4 ng/ml (-14.0 to -4.9; p <0.001) in the NGM282 1 mg and 3 mg groups, respectively, compared with placebo) and bile acids. Importantly, fibrosis biomarkers that predict transplant-free survival, including Enhanced Liver Fibrosis score and Pro-C3, were significantly improved following NGM282 treatment. Most adverse events were mild to moderate in severity, with gastrointestinal symptoms more frequent in the NGM282 treatment groups.
In patients with PSC, NGM282 potently inhibited bile acid synthesis and decreased fibrosis markers, without significantly affecting ALP levels.
We present for the first time, the clinical and laboratory effects of a first-in-class, engineered analogue of the endocrine hormone FGF19 in patients with primary sclerosing cholangitis (PSC). By incorporating non-invasive markers of fibrosis, beyond standard liver injury markers, we show that NGM282 impacted on fibrosis turnover and hepatic inflammation without changing alkaline phosphatase. Our findings demonstrate the complexities of using highly potent rational agents in PSC, and furthermore challenge the dogma about what the appropriate endpoints should be for trials in PSC.
原发性硬化性胆管炎（PSC）是一种炎症性、胆汁淤积性和进行性纤维化的肝脏疾病，目前尚无有效的医学干预措施。NGM282 是一种经过工程改造的非致瘤性 FGF19 类似物，能够有效调节 CYP7A1 介导的胆汁酸稳态。我们评估了 NGM282 治疗 PSC 患者的疗效和安全性。
这是一项双盲、安慰剂对照的 II 期临床试验，62 例经胆管造影或活检证实的 PSC 患者和碱性磷酸酶（ALP）升高（>1.5×正常值上限）被随机分配至 NGM282 1mg、3mg 或安慰剂组，每天一次，治疗 12 周。主要终点是从基线到第 12 周时 ALP 的变化。次要终点和探索性终点包括血清胆汁酸代谢和纤维化生物标志物的变化。疗效分析采用意向治疗。
12 周时，NGM282 组和安慰剂组之间的 ALP 自基线的平均变化无显著差异，因此主要终点未达到。然而，NGM282 显著降低了 7α-羟基-4-胆甾烯-3-酮（一种肝 CYP7A1 活性的标志物，LS 均值差值分别为-6.2ng/ml（95%CI -10.7 至-1.7；p=0.008）和-9.4ng/ml（-14.0 至-4.9；p<0.001），而安慰剂组）和胆汁酸的水平。重要的是，预测无移植生存的纤维化生物标志物，包括增强肝脏纤维化评分和 Pro-C3，在 NGM282 治疗后均显著改善。大多数不良事件的严重程度为轻度至中度，NGM282 治疗组更常见胃肠道症状。
在 PSC 患者中，NGM282 可强力抑制胆汁酸合成并降低纤维化标志物，而 ALP 水平无显著变化。
我们首次报道了一种内源性激素 FGF19 的工程化类似物在原发性硬化性胆管炎（PSC）患者中的临床和实验室疗效。通过纳入除标准肝损伤标志物之外的纤维化非侵入性标志物，我们表明 NGM282 可影响纤维化转化和肝炎症，而不改变碱性磷酸酶。我们的发现表明，在 PSC 中使用高活性的合理药物具有复杂性，并且进一步挑战了关于 PSC 试验适当终点的观念。
