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Abstract：
Lomitapide is a microsomal triglyceride transfer protein inhibitor for patients with homozygous familial hypercholesterolaemia. Due to its mechanism of action, potential hepatic effects of lomitapide are of clinical interest. This study aimed to determine the long-term hepatic safety of lomitapide.
Data were aggregated from the pivotal phase 3 and extension phase clinical trial with lomitapide (median 5.1 years; serum total bilirubin, transaminases, cytokeratin-18 [CK-18] and enhanced liver fibrosis [ELF] score, fat-soluble vitamins and essential fatty acids), 8-year data from the Lomitapide Observational Worldwide Evaluation Registry (LOWER) and real-world evidence from a cohort of patients treated with lomitapide in Italy (hepatic elastography, and FIB-4 score for hepatic fibrosis).
In the phase 3 trial and the LOWER registry, any asymptomatic excursions in liver transaminase levels were not associated with elevations in bilirubin, and no Hy\'s law cases were detected in up to 8 years follow-up. There were no clinically relevant increases among hepatic biomarkers CK-18, CK-18 fragments or ELF score and fat-soluble vitamins and essential fatty acids remained above normal levels. In 34 patients treated in Italy with lomita pide for more than 9 years, elevations in hepatic fat were mild-to-moderate; hepatic stiffness remained normal, and the mean FIB-4 score remained below the fibrosis threshold value of 2.67.
These data indicate that the hepatic safety of lomitapide remains favourable with no clinically significant elevations in hepatic biomarkers and hepatic stiffness remained normal for more than 9 years follow-up. PHASE 3 TRIAL: NCT00730236; extension phase: NCT00943306; LOWER: NCT02135705.
Data were aggregated from the pivotal phase 3 and extension phase clinical trial with lomitapide (median 5.1 years; serum total bilirubin, transaminases, cytokeratin-18 [CK-18] and enhanced liver fibrosis [ELF] score, fat-soluble vitamins and essential fatty acids), 8-year data from the Lomitapide Observational Worldwide Evaluation Registry (LOWER) and real-world evidence from a cohort of patients treated with lomitapide in Italy (hepatic elastography, and FIB-4 score for hepatic fibrosis).
In the phase 3 trial and the LOWER registry, any asymptomatic excursions in liver transaminase levels were not associated with elevations in bilirubin, and no Hy\'s law cases were detected in up to 8 years follow-up. There were no clinically relevant increases among hepatic biomarkers CK-18, CK-18 fragments or ELF score and fat-soluble vitamins and essential fatty acids remained above normal levels. In 34 patients treated in Italy with lomita pide for more than 9 years, elevations in hepatic fat were mild-to-moderate; hepatic stiffness remained normal, and the mean FIB-4 score remained below the fibrosis threshold value of 2.67.
These data indicate that the hepatic safety of lomitapide remains favourable with no clinically significant elevations in hepatic biomarkers and hepatic stiffness remained normal for more than 9 years follow-up. PHASE 3 TRIAL: NCT00730236; extension phase: NCT00943306; LOWER: NCT02135705.
摘要：
背景：Lomitapide是一种用于纯合型家族性高胆固醇血症患者的微粒体甘油三酯转运蛋白抑制剂。由于其作用机制,lomitapide潜在的肝脏效应具有临床意义。本研究旨在确定lomitapide的长期肝脏安全性。
方法：数据来自洛米他的关键3期和延长期临床试验（中位数5.1年；血清总胆红素，转氨酶，细胞角蛋白-18[CK-18]和增强肝纤维化[ELF]评分，脂溶性维生素和必需脂肪酸），来自Lomitapide观察性全球评估注册（LOWER）的8年数据以及来自意大利接受lomitapide治疗的患者队列的真实证据（肝弹性成像，和肝纤维化的FIB-4评分）。
结果：在3期试验和LOWER注册中，肝转氨酶水平的任何无症状偏移与胆红素升高无关。在长达8年的随访中，没有发现Hy的法律案件。在肝生物标志物CK-18，CK-18片段中没有临床相关的增加，或ELF评分和脂溶性维生素和必需脂肪酸保持高于正常水平。在意大利接受lomitapide治疗长达9.0年的34例患者中，肝脏脂肪升高轻度至中度；肝脏僵硬度保持正常，平均FIB-4评分仍低于纤维化阈值2.67。
结论：这些数据表明，lomitapide的肝安全性仍然良好，肝生物标志物没有临床显着升高，肝硬度在长达9.0年的随访中保持正常。
方法：数据来自洛米他的关键3期和延长期临床试验（中位数5.1年；血清总胆红素，转氨酶，细胞角蛋白-18[CK-18]和增强肝纤维化[ELF]评分，脂溶性维生素和必需脂肪酸），来自Lomitapide观察性全球评估注册（LOWER）的8年数据以及来自意大利接受lomitapide治疗的患者队列的真实证据（肝弹性成像，和肝纤维化的FIB-4评分）。
结果：在3期试验和LOWER注册中，肝转氨酶水平的任何无症状偏移与胆红素升高无关。在长达8年的随访中，没有发现Hy的法律案件。在肝生物标志物CK-18，CK-18片段中没有临床相关的增加，或ELF评分和脂溶性维生素和必需脂肪酸保持高于正常水平。在意大利接受lomitapide治疗长达9.0年的34例患者中，肝脏脂肪升高轻度至中度；肝脏僵硬度保持正常，平均FIB-4评分仍低于纤维化阈值2.67。
结论：这些数据表明，lomitapide的肝安全性仍然良好，肝生物标志物没有临床显着升高，肝硬度在长达9.0年的随访中保持正常。
