Physicians' Academy for Cardiovascular Education
Antisense to ANGPLT3 reduces TG and atherogenic lipoproteins

Antisense to ANGPLT3 reduces TG and atherogenic lipoproteins

News - Aug. 29, 2020

Vupanorsen, an N-acetyl Galactosamide-conjugated Antisense drug to ANGPTL3 mRNA, lowers triglycerides and atherogenic lipoproteins in patients with diabetes, hepatic steatosis and hypertriglyceridemia.

Presented at ESC Congress 2020 by Daniel Gaudet (Montreal, QC, Canada)

Introduction and methods

ANGPTL3 is an inhibitor of lipoprotein lipase (LPL) and endothelial lipase (EL) and secreted by the liver. Loss-of-function mutations in ANGPTL3 are associated with a phenotype called familial combined hypolipidemia and affected individuals have reduced triglyceride (TG) and triglyceride-rich lipoproteins (TRL) levels, decreased plasma LDL particles clearance, and increased insulin sensitivity and approximately 40% lower risk of CAD compared to non-carriers. Preclinical studies have shown that lowering of ANGPLT3 results in decreased extent of atherosclerosis.

Vupanorsen (AKCEA-ANGPTL3-LRx) is an antisense oligonucleotide targeting hepatic ANGPLT3 mRNA and a second generation GalNAc3-conjugated antisense oligonucleotide with enhanced intracellular uptake in hepatocytes, allowing lower dosing (compared to first generation compounds).

This was a multicenter, double-blind, placebo-controlled, dose-ranging phase 2 study. It enrolled T2DM patients with hepatic steatosis, and fasting TG levels >150 mg/dL. 105 Patients were included in 3 cohorts with different dosing strategy and within cohort they were randomized to vupanorsen or placebo (ratio 3:1) for a treatment period of 6 months. Primary endpoint was mean percentage change in fasting TG from baseline to 6 months in each cohort.

Main results


Reducing ANGPTL3 levels with vupanorsen in T2DM patients with hepatic steatosis and mild hypertriglyceridemia resulted in reduction of plasma TG levels, as well as significant reduction in other apoB-containing atherogenic lipoproteins. Vupanorsen had a favorable safety and tolerability profile. The authors suggest that vuparnosen may provide a new strategy for reduction of residual CV risk.

- Our reporting is based on the information provided at the ESC congress 2020 -

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