Daniels Stephen, Caprio Sonia, Chaudhari Umesh, Manvelian Garen, Baccara-Dinet Marie T, Brunet Aurelie, Scemama Michel, Loizeau Virginie, Bruckert Eric
University of Colorado School of Medicine, Aurora, CO, USA.
Yale Pediatric Endocrinology, New Haven, CT, USA.
J Clin Lipidol. 2020 May-Jun;14(3):322-330.e5. doi: 10.1016/j.jacl.2020.03.001. Epub 2020 Mar 28.
Heterozygous familial hypercholesterolemia (HeFH) is a genetic disorder characterized by elevated levels of low-density lipoprotein cholesterol (LDL-C).
This phase 2 dose-finding study (NCT02890992) evaluated the efficacy, safety, and dose selection of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab in pediatric HeFH patients.
HeFH patients (n = 42) who were aged 8-17 years, had body weight (BW) ≥25 kg, and had LDL-C ≥130 mg/dL despite optimal statin/other lipid-modifying therapies were enrolled in 4 cohorts according to BW: cohort #1: 30 mg (<50 kg) or 50 mg (≥50 kg) every 2 weeks (Q2W), #2: 40 mg (<50 kg) or 75 mg (≥50 kg) Q2W, #3: 75 mg (<50 kg) or 150 mg (≥50 kg) every 4 weeks (Q4W), #4: 150 mg (<50 kg) or 300 mg (≥50 kg) Q4W. Primary endpoint was LDL-C % change from baseline to week 8.
Mean age was 12.4 years and 95% of patients were on a statin. Baseline LDL-C levels were 160.0-188.9 mg/dL and free PCSK9 was 186.4-201.7 ng/mL across the cohorts. At week 8, the higher dose cohorts (2 and 4) demonstrated the greatest reductions in LDL-C (-46% and -45%, respectively). Free PCSK9 levels were lowest at week 8 in cohorts 2 and 4 (42.2 ng/mL and 8.6 ng/mL, respectively). Adverse events were reported in 50-90% of patients across the cohorts, and 2 patients discontinued due to adverse events.
In pediatric HeFH patients, LDL-C reductions were greatest in the higher dose cohorts. Alirocumab was generally well tolerated at all doses.
杂合子家族性高胆固醇血症（HeFH）是一种遗传性疾病，其特征是低密度脂蛋白胆固醇（LDL-C）水平升高。
这项2期剂量探索研究（NCT02890992）评估了前蛋白转化酶枯草溶菌素/kexin 9型（PCSK9）抑制剂阿利西尤单抗在儿童HeFH患者中的疗效、安全性和剂量选择。
年龄在8至17岁、体重（BW）≥25 kg且尽管接受了最佳他汀类药物/其他调脂治疗但LDL-C≥130 mg/dL的HeFH患者，根据体重被纳入4个队列：队列1：每2周（Q2W）30 mg（<50 kg）或50 mg（≥50 kg）；队列2：Q2W 40 mg（<50 kg）或75 mg（≥50 kg）；队列3：每4周（Q4W）75 mg（<50 kg）或150 mg（≥50 kg）；队列4：Q4W 150 mg（<50 kg）或300 mg（≥50 kg）。主要终点是从基线到第8周LDL-C的百分比变化。
平均年龄为12.4岁，95%的患者正在服用他汀类药物。各队列的基线LDL-C水平为160.0 - 188.9 mg/dL，游离PCSK9为186.4 - 201.7 ng/mL。在第8周时，较高剂量队列（队列2和队列4）的LDL-C降低幅度最大（分别为-46%和-45%）。队列2和队列4在第8周时游离PCSK9水平最低（分别为42.2 ng/mL和8.6 ng/mL）。各队列中有50% - 90%的患者报告了不良事件，2例患者因不良事件停药。
在儿童HeFH患者中，较高剂量队列的LDL-C降低幅度最大。阿利西尤单抗在所有剂量下总体耐受性良好。
