Raal Frederick J, Hegele Robert A, Ruzza Andrea, López J Antonio G, Bhatia Ajay K, Wu Johnny, Wang Huei, Gaudet Daniel, Wiegman Albert, Wang Jian, Santos Raul D
Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa (F.J.R.).
Department of Medicine and Biochemistry, Robarts Research Institute, University of Western Ontario, London, Canada (R.A.H., J.W.).
Arterioscler Thromb Vasc Biol. 2024 May;44(5):1156-1164. doi: 10.1161/ATVBAHA.123.320268. Epub 2024 Mar 28.
Pediatric patients with homozygous familial hypercholesterolemia (HoFH) have an increased risk of atherosclerotic cardiovascular disease and difficulty meeting low-density lipoprotein cholesterol (LDL-C) goals. In this post hoc analysis, we evaluated pooled safety and efficacy data from 3 studies in pediatric patients with HoFH treated with the PCSK9 (proprotein convertase subtilisin/kexin type 9) monoclonal antibody inhibitor evolocumab.
Patients with HoFH aged 10 to 17 years received treatment with open-label evolocumab 420 mg subcutaneously monthly or biweekly in the TAUSSIG, RAMAN, or HAUSER-OLE clinical studies. All patients received background statins with or without ezetimibe. Study duration ranged from 12 to 260 weeks. The primary end point was treatment-emergent adverse events per 100 patient-years. Efficacy end points were changes from baseline to week 12 in lipids and PCSK9.
Of the 39 patients in the pooled analysis, 69.2% were males, median age was 13.0 years, and 79.5% (31/39) had genotyped HoFH with pathogenic variants. Overall, median exposure to evolocumab was 18.2 (Q1, Q3: 3.0, 18.5) months. Treatment-emergent adverse events with an exposure-adjusted patient incidence rate of ≥5% were upper respiratory tract infection (6.6%), influenza (5.2%), and acne (5.0%) per 100 patient-years. Exposure-adjusted patient incidence of serious treatment-emergent adverse events was 13.3% per 100 patient-years. Excluding 4 patients receiving lipoprotein apheresis, week 12 median percentage change from baseline in LDL-C was -2.9% (Q1, Q3: -21.7, 1.5); however, 42.9% (15/35) of patients achieved ≥15% reduction in LDL-C from baseline. Residual LDLR (LDL receptor) activity was not associated with a reduction in LDL-C.
In this pooled data analysis from 3 studies in pediatric patients with HoFH, evolocumab was well tolerated, with no new safety signals reported. These safety findings are consistent with findings from previous studies of evolocumab. Patients showed marked variability in LDL-C reduction. Results from this pooled analysis support guidelines suggesting a trial of PCSK9 inhibitor therapy regardless of estimated residual LDLR function.
URL: https://www.clinicaltrials.gov; Unique identifier: NCT01624142, NCT03403374, and NCT02624869.
纯合子家族性高胆固醇血症（HoFH）患儿发生动脉粥样硬化性心血管疾病的风险增加，且难以达到低密度脂蛋白胆固醇（LDL-C）目标。在这项事后分析中，我们评估了3项关于用前蛋白转化酶枯草溶菌素/kexin 9型（PCSK9）单克隆抗体抑制剂依洛尤单抗治疗HoFH患儿的研究的汇总安全性和有效性数据。
年龄在10至17岁的HoFH患者在TAUSSIG、RAMAN或HAUSER-OLE临床研究中接受开放标签的依洛尤单抗治疗，每月或每两周皮下注射420mg。所有患者均接受了基础他汀类药物治疗，部分患者联合或不联合依折麦布。研究持续时间为12至260周。主要终点是每100患者年出现的治疗中出现的不良事件。有效性终点是从基线到第12周血脂和PCSK9的变化。
在汇总分析的39例患者中，69.2%为男性，中位年龄为13.0岁，79.5%（31/39）的患者对HoFH进行了基因分型且存在致病变异。总体而言，依洛尤单抗的中位暴露时间为18.2（第一四分位数，第三四分位数：3.0，18.5）个月。暴露调整后的患者发病率≥5%的治疗中出现的不良事件为每100患者年上呼吸道感染（6.6%）、流感（5.2%）和痤疮（5.0%）。暴露调整后的严重治疗中出现的不良事件患者发病率为每100患者年13.3%。排除4例接受脂蛋白分离置换法的患者后，LDL-C从基线到第12周的中位百分比变化为-2.9%（第一四分位数，第三四分位数：-21.7，1.5）；然而，42.9%（15/35）的患者LDL-C较基线降低了≥15%。残余LDLR（LDL受体）活性与LDL-C降低无关。
在这项对3项HoFH患儿研究的汇总数据分析中，依洛尤单抗耐受性良好，未报告新的安全信号。这些安全性发现与先前依洛尤单抗研究的结果一致。患者的LDL-C降低情况存在显著差异。这项汇总分析的结果支持了相关指南，即无论估计的残余LDLR功能如何，均建议试用PCSK9抑制剂治疗。
网址：https://www.clinicaltrials.gov；唯一标识符：NCT01624142、NCT03403374和NCT02624869。
