ANGPTL3 (produced in liver) plays a key role in the regulation of lipid metabolism by inhibiting lipoprotein lipase and endothelial lipase in adipose and muscle tissue. Mendelian randomisation studies have shown that loss-of-function variants in ANGPTL3 were associated with low levels of LDL-C and TG, as well as a reduced risk of coronary artery disease (1,2). The reduction in LDL-C was independent of the LDL receptor. There are currently two therapeutic approaches to targeting ANGPTL3.
Evinacumab is a fully human monoclonal ANGPTL3 antibody. Evinacumab is currently indicated as an adjunct to diet and other LDL-C lowering therapies for the treatment of adult and adolescent patients aged 12 years and older with homozygous familial hypercholesterolaemia (HoFH) (3).
In a pivotal trial, treatment with evinacumab (intravenous 15 mg/kg body weight) halved LDL-C levels (corrected for placebo), regardless of LDL receptor function in patients with HoFH (4). Similar findings were reported in patients with refractory hypercholesterolaemia (5). In patients with severe hypertriglyceridaemia without genetic chylomicronaemia syndrome, treatment with evinacumab led to meaningful reduction in TG (median 68.8%), as well as substantial reductions in non-HDL-C, and apoCIII and B48 (6).
Vupanorsen is a second-generation N-acetyl galactosamine (GalNAc)-modified antisense oligonucleotide that targets hepatic ANGPTL3 mRNA (4). GalNAc is a well-defined liver-targeted moiety which benefits from high affinity with the asialoglycoprotein receptor (ASGPR). This results in enhanced potency compared with the parent modalities without conjugation (7).
In patients with fasting TG > 1.7 mmol/L or > 150 mg/dL, type 2 diabetes, and hepatic steatosis, treatment with vupanorsen 80 mg every 4 weeks reduced TG by ~50%, as well as other atherogenic lipoproteins, including apoCIII by 58% and remnant cholesterol by 38% (8).
View key references >
- Kersten S. New insights into angiopoietin-like proteins in lipid metabolism and cardiovascular disease risk. Curr Opin Lipidol 2019;30:205-11. PUBMED https://pubmed.ncbi.nlm.nih.gov/30893111/
- Dewey FE, Gusarova V, Dunbar RL, et al. Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease. N Engl J Med 2017; 377: 211-21. https://pubmed.ncbi.nlm.nih.gov/28538136/
- EVKEEZA™ (evinacumab). US Prescribing information https://www.regeneron.com/downloads/evkeeza_pi.pdf
- Raal FJ, Rosenson RS, Reeskamp LF, et al. Evinacumab for homozygous familial h hypercholesterolemia. N Engl J Med 2020;383:711-720. PUBMED https://pubmed.ncbi.nlm.nih.gov/32813947/
- Rosenson RS, Burgess LJ, Ebenbichler CF, et al. Evinacumab in patients with refractory hypercholesterolemia. N Engl J Med 2020;383:2307-19. PUBMED https://pubmed.ncbi.nlm.nih.gov/33196153/
- Rosenson RS, Gaudet D, Ballantyne CM, et al. A phase 2 trial of the efficacy and safety of evinacumab in patients with severe hypertriglyceridemia. Presented at ACC.21, Virtual meeting
- Katzmann JL, Packard CJ, Chapman MJ, Katzmann I, Laufs U. Targeting RNA with antisense oligonucleotides and small interfering RNA: JACC State-of-the-Art Review. J Am Coll Cardiol 2020;76:563-79. PUBMED https://pubmed.ncbi.nlm.nih.gov/32731935/
- Gaudet D, Karwatowska-Prokopczuk E, Baum SJ, et al. Vupanorsen, an N-acetyl galactosamine-conjugated antisense drug to ANGPTL3 mRNA, lowers triglycerides and atherogenic lipoproteins in patients with diabetes, hepatic steatosis, and hypertriglyceridaemia. Eur Heart J 2020;41:3936-45. PUBMED https://pubmed.ncbi.nlm.nih.gov/32860031/