Trials

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 randomization 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 antibody that inhibits angiopoietin-like 3 (ANGPTL3). ANGPTL3 is an inhibitor of lipoprotein and endothelial lipase, with resulting increases in levels of triglycerides (TGs) and other lipids.^1-3 Loss-of-function variants in ANGPTL3 have been associated with low levels of both LDL cholesterol and TGs.^4,5 Reference

1. Köster A, Chao YB, Mosior M et al. Transgenic angiopoietin-like (angptl)4 overexpression and targeted disruption of angptl4 and angptl3: regulation of triglyceride metabolism. Endocrinology 2005; 146: 4943-50.
2. Fujimoto K, Koishi R, Shimizugawa T, Ando Y. Angptl3-null mice show low plasma lipid concentrations by enhanced lipoprotein lipase activity. Exp Anim 2006; 55: 27-34.
3. Shimamura M, Matsuda M, Yasumo H et al. Angiopoietin-like protein3 regulates plasma HDL cholesterol through suppression of endothelial lipase. Arterioscler Thromb Vasc Biol 2007; 27: 366-72.
4. 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.
5. Athyros VG, Katsiki N, Dimakopoulou A et al. Drugs that mimic the effect of gene mutations for the prevention or the treatment of atherosclerotic disease: from PCSK9 inhibition to ANGPTL3 inactivation. Curr Pharm Des 2018; 24: 3638-46.

Vupanorsen is a second-generation N-acetyl galactosamine (GalNAc3)-modified antisense oligonucleotide that targets hepatic ANGPTL3 mRNA.¹ ANGPTL3 is an inhibitor of lipoprotein and endothelial lipase, with resulting increases in levels of triglycerides (TGs) and other lipids.^2-4 Loss-of-function variants in ANGPTL3 have been associated with low levels of both LDL cholesterol and TGs.^5,6 Reference

1. 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 Aug 29;ehaa689.  doi: 10.1093/eurheartj/ehaa689. Online ahead of print.
2. Köster A, Chao YB, Mosior M et al. Transgenic angiopoietin-like (angptl)4 overexpression and targeted disruption of angptl4 and angptl3: regulation of triglyceride metabolism. Endocrinology 2005; 146: 4943-50.
3. Fujimoto K, Koishi R, Shimizugawa T, Ando Y. Angptl3-null mice show low plasma lipid concentrations by enhanced lipoprotein lipase activity. Exp Anim 2006; 55: 27-34.
4. Shimamura M, Matsuda M, Yasumo H et al. Angiopoietin-like protein3 regulates plasma HDL cholesterol through suppression of endothelial lipase. Arterioscler Thromb Vasc Biol 2007; 27: 366-72.
5. 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.
6. Athyros VG, Katsiki N, Dimakopoulou A et al. Drugs that mimic the effect of gene mutations for the prevention or the treatment of atherosclerotic disease: from PCSK9 inhibition to ANGPTL3 inactivation. Curr Pharm Des 2018; 24: 3638-46.