Department of Paediatrics, Amsterdam University Medical Centers, Location University of Amsterdam, The Netherlands (A.W., M.D.R.).
Department of Pediatrics and Adolescent Medicine, Division of Pediatric Pulmonology, Allergology and Endocrinology, Medical University of Vienna, Austria (S.G.-P.).
Circulation. 2024 Jan 30;149(5):343-353. doi: 10.1161/CIRCULATIONAHA.123.065529. Epub 2023 Oct 20.
Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by severely elevated low-density lipoprotein cholesterol (LDL-C) levels due to profoundly defective LDL receptor (LDLR) function. Given that severely elevated LDL-C starts in utero, atherosclerosis often presents during childhood or adolescence, creating a largely unmet need for aggressive LDLR-independent lipid-lowering therapies in young patients with HoFH. Here we present the first evaluation of the efficacy and safety of evinacumab, a novel LDLR-independent lipid-lowering therapy, in pediatric patients with HoFH from parts A and B of a 3-part study.
The phase 3, part B, open-label study treated 14 patients 5 to 11 years of age with genetically proven HoFH (true homozygotes and compound heterozygotes) with LDL-C >130 mg/dL, despite optimized lipid-lowering therapy (including LDLR-independent apheresis and lomitapide), with intravenous evinacumab 15 mg/kg every 4 weeks.
Evinacumab treatment rapidly and durably (through week 24) decreased LDL-C with profound reduction in the first week, with a mean (SE) LDL-C reduction of -48.3% (10.4%) from baseline to week 24. ApoB (mean [SE], -41.3% [9.0%]), non-high-density lipoprotein cholesterol (-48.9% [9.8%]), and total cholesterol (-49.1% [8.1%]) were similarly decreased. Treatment-emergent adverse events were reported in 10 (71.4%) patients; however, only 2 (14.3%) reported events that were considered to be treatment-related (nausea and abdominal pain). One serious treatment-emergent adverse event of tonsillitis occurred (n=1), but this was not considered treatment-related.
Evinacumab constitutes a new treatment for pediatric patients with HoFH and inadequately controlled LDL-C despite optimized lipid-lowering therapy, lowering LDL-C levels by nearly half in these extremely high-risk and difficult-to-treat individuals.
URL: https://www.clinicaltrials.gov; Unique identifier: NCT04233918.
家族性高胆固醇血症（HoFH）是一种罕见的遗传性疾病，其特征是由于 LDL 受体（LDLR）功能严重缺陷，导致低密度脂蛋白胆固醇（LDL-C）水平显著升高。由于严重升高的 LDL-C 始于胎儿期，因此动脉粥样硬化通常在儿童或青少年时期出现，这使得 HoFH 年轻患者对 LDLR 独立的降脂治疗存在极大的未满足需求。在此，我们报告了一种新型 LDLR 独立降脂疗法依维莫司在 HoFH 儿科患者中的疗效和安全性的第 1 部分评估，这是一项 3 部分研究的第 A 部分和第 B 部分。
在这项 3 期第 B 部分、开放性研究中，对 14 名年龄在 5 至 11 岁、经基因证实患有 HoFH（纯合子和复合杂合子）的患者进行了治疗，这些患者的 LDL-C ＞130mg/dL，尽管接受了优化的降脂治疗（包括 LDLR 独立的体外血浆去除和lomitapide），给予每 4 周静脉注射 15mg/kg 的依维莫司。
依维莫司治疗迅速且持久（至第 24 周）降低了 LDL-C，第 1 周降幅明显，与基线相比，第 24 周时 LDL-C 平均（SE）降低了-48.3%（10.4%）。载脂蛋白 B（平均[SE]，-41.3%[9.0%]）、非高密度脂蛋白胆固醇（-48.9%[9.8%]）和总胆固醇（-49.1%[8.1%]）也相应降低。10 名（71.4%）患者报告出现治疗后不良事件；然而，只有 2 名（14.3%）患者报告的事件被认为与治疗相关（恶心和腹痛）。发生 1 例严重的治疗后不良事件（扁桃体炎）（n=1），但该事件不认为与治疗相关。
依维莫司为 LDL-C 控制不佳的 HoFH 儿科患者提供了一种新的治疗选择，这些患者存在极高的风险，治疗难度大，依维莫司将 LDL-C 水平降低了近一半。
