Reductions in remnant cholesterol and VLDL cholesterol through inhibition of ANGPTL3 protein synthesis: an analysis from the TRANSLATE-TIMI 70 trial.

Aims: Remnant cholesterol and very low-density lipoprotein cholesterol (VLDL-C) are increasingly recognized risk factors for atherosclerotic disease with few therapeutic options. Angiopoietin-like 3 (ANGPTL3), a key protein in the metabolism of triglyceride-rich lipoproteins, is a promising target.

Methods And Results: TRANSLATE-TIMI 70 was a double-blind, placebo-controlled randomized trial testing seven dose regimens of vupanorsen, an antisense oligonucleotide against ANGPTL3, in adults with non-HDL-C ≥ 100 mg/dL and triglycerides 150-500 mg/dL.

Hepatic fat changes with antisense oligonucleotide therapy targeting ANGPTL3.

Background: Angiopoietin-like protein 3 (ANGPTL3) is a novel therapeutic target for hyperlipidemia. Vupanorsen, an antisense oligonucleotide targeting ANGPTL3, reduced triglycerides up to 57% in a phase 2b trial, but caused dose-dependent increases in hepatic fat fraction (HFF).

Objective: To determine the degree of HFF progression with escalating doses of vupanorsen, differential HFF increases in key patient subgroups, and the correlation between changes in HFF and liver enzymes.

Effect of Vupanorsen on Non-High-Density Lipoprotein Cholesterol Levels in Statin-Treated Patients With Elevated Cholesterol: TRANSLATE-TIMI 70.

Background: Genetic loss-of-function variants in are associated with lower levels of plasma lipids. Vupanorsen is a hepatically targeted antisense oligonucleotide that inhibits Angiopoietin-like 3 (ANGPTL3) protein synthesis.

Methods: Adults with non-high-density lipoprotein cholesterol (non-HDL-C) ≥100 mg/dL and triglycerides 150 to 500 mg/dL on statin therapy were randomized in a double-blind fashion to placebo or 1 of 7 vupanorsen dose regimens (80, 120, or 160 mg SC every 4 weeks, or 60, 80, 120, or 160 mg SC every 2 weeks).