ESPEYB21 12. Type 2 Diabetes, Metabolic Syndrome and Lipids Lipid Metabolism (5 abstracts)
12.16. Evinacumab for pediatric patients with homozygous familial hypercholesterolemia
Wiegman A , Greber-Platzer S , Ali S , Reijman MD , Brinton EA , Charng MJ , Srinivasan S , Baker-Smith C , Baum S , Brothers JA , Hartz J , Moriarty PM , Mendell J , Bihorel S , Banerjee P , George RT , Hirshberg B & Pordy R
Circulation. 2024 Jan 30;149(5):343-353. doi:10.1161/CIRCULATIONAHA.123.065529.
Homozygous familial hypercholesterolemia (HoFH) is a severe disorder caused by genetic mutations in LDLR (encoding the LDL receptor), APOB or PCSK9. LDL-C levels in HoFH are extremely elevated)>400 mg/dL(even in utero, leading to cardiovascular events, and disability or death during childhood and adolescence. Conventional medications have minimal efficacy, since LDL-C levels cannot be reduced through upregulation of hepatic LDL receptors.
Angiopoietin-like 3 (ANGPTL3) is a hepatically secreted protein that acts as a potent inhibitor of lipoprotein lipase, the primary enzyme responsible for clearing triglyceride-rich lipoproteins from the circulation. Additionally, ANGPTL3 inhibits endothelial lipase, which aids the clearance of HDL from the bloodstream. Humans with loss-of-function variants in one copy of ANGPTL3 have reduced serum LDL levels. Individuals with complete ANGPTL3 deficiency due to biallelic inactivating mutations have very low plasma lipid concentrations and tend to have less coronary atherosclerosis than those without ANGPTL3 deficiency
Evinacumab is a fully human monoclonal antibody that selectively binds to and inhibits ANGPTL3. When used alongside other lipid-lowering treatments, it reduced LDL-C by ~50% in adults and adolescents aged 12+ years HoFH and was generally well-tolerated. Furthermore, reductions in plaque volumes were observed among adolescents after 6 months of evinacumab.
This is the first study to evaluate the efficacy and safety of evinacumab in children aged 5-11 years with HoFH. This 3-part, open-label study began with a 16-week phase assessing the safety, pharmacokinetics, and pharmacodynamics of a single intravenous dose of evinacumab (15 mg/kg) in 6 patients. It found comparable pharmacokinetics in children and adults. The second part was a 24-week, phase 3 study evaluating the efficacy, safety, and pharmacokinetics of evinacumab in 14 patients. The mean % change in LDL-C from baseline to week 24 was 48%. The third part is an ongoing 48-week, phase 3 extension, to evaluate long-term safety and efficacy.
The U.S. Food and Drug Administration (FDA) extended their approval of Evkeeza® (evinacumab-dgnb) as an adjunct to other lipid-lowering therapies to treat children aged 5-11 with HoFH.
References: 1. Dingman R, Bihorel S, Gusarova V, Mendell J, Pordy R. Evinacumab: Mechanism of action, clinical, and translational science. Clin Transl Sci. 2024 Jun;17(6):e13836. doi:10.1111/cts.13836.
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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