ESPE Yearbook of Paediatric Endocrinology

Eur Heart J. 2024 Jul 12;45(27):2422-2434. doi: 10.1093/eurheartj/ehae325

Brief Summary: In this long-term, open-label Phase 3 trial of 116 individuals with homozygous familial hypercholesterolemia (HoFH), evinacumab administered every 4-weeks reduced low-density lipoprotein cholesterol (LDL-C) levelsby 43.6% overall, with greater reductions in adolescents (55.4%) than adults (41.7%).

Comment: Homozygous familial hypercholesterolemia (HoFH)is characterized by extremely elevated plasma LDL-C and accelerated atherosclerosis. Its estimated prevalence is ~1:350,000 to 1:400,000. The most common genetic cause is a variant in the LDL-receptor (LDLR) gene (85%to 90%). ¹ Less frequently, variants occur in the apolipoprotein B (APOB) gene (5% to 10%), the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene (1% to 3%) or the rare autosomal recessive form caused by biallelic variant of the LDLR adaptor protein 1 (LDLRAP1). If left untreated, HoFH results in fatal and nonfatal myocardial infarctions as early as the first two decades of life. Current treatments, including diet, statins, ezetimibe, and PCSK9 inhibitors, often fail to achieve sufficient LDL-C reduction in most subjects affected by HoFH.

Angiopoietin-like protein 3 (ANGPTL3) is a hepatokine that inhibits lipoprotein lipase (LPL), an enzyme responsible for breaking down triglycerides from chylomicrons and very low-density lipoproteins (VLDL), as well as endothelial lipase (EL), which hydrolyzes HDL phospholipids and lowers HDL-C levels. Genetic deficiency in ANGPTL3 is associated with a lower risk of ASCVD and reduced plasma concentrations of LDL-cholesterol, triglyceride-rich lipoproteins (TRLs), and HDL-cholesterol. Inhibition of ANGPTL3 enhances the activity of both LPL and EL, thereby increasing lipolysis and remodeling of VLDL particles. This promotes the conversion of VLDL to intermediate-density lipoproteins (IDL), facilitates hepatic clearance of VLDL remnants and IDL particles, and ultimately reduces the production of LDL particles.

Evinacumab is a fully human monoclonal antibody that specifically binds to and inhibits ANGPTL3. It was approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in 2021 as an adjunct to other lipid-lowering therapies for the treatment of HoFH in adult and adolescent patients aged ≥12 years, and in 2023 for children aged 5–11 years. The current study evaluated the long-term safety and efficacy of evinacumab over a median duration of 104 weeks (range: 28–196) in adults and adolescents with HoFH.

Evinacumab treatment for up to 4 years effectively reduced LDL-C levelsand other lipids and lipoproteins in patients with HoFH, with a safety profile that was consistent with previous studies.

An editorial accompanying the article highlighted several limitations and unresolved gaps.² These include the absence of a control group, follow-up data available for less than 50% of the cohort beyond two years, the small number of adolescent patients over 12 years of age, and the lack of data on children. Additionally, 80% of participants were white adults, limiting generalizability. Current guidelines recommend initiating treatment for HoFH at diagnosis, ideally by age 2; however, this study only included individuals aged 12+ years. The editorial also emphasized the need to simplify treatment by transitioning from intravenous to subcutaneous administration of evinacumab.

References: 1. van den Bosch SE, Corpeleijn WE, Hutten BA, Wiegman A. How Genetic Variants in Children with Familial Hypercholesterolemia Not Only Guide Detection, but Also Treatment. Genes (Basel). 2023 Mar 7;14(3):669. doi: 10.3390/genes14030669. PMID: 36980941; PMCID: PMC10048736.2. Watts GF, Tamehri Zadeh SS, Chan DC. ANGPTL3 as a therapeutic target for treating homozygous familial hypercholesterolaemia: a shot in the arm for evinacumab. European Heart Journal. 2024 Jul 14;45(27):2435-8.