Physicians' Academy for Cardiovascular Education
Lower levels of TG and atherogenic lipoproteins with ApoC-III antisense oligonucleotide

Lower levels of TG and atherogenic lipoproteins with ApoC-III antisense oligonucleotide

News - Aug. 29, 2020

Antisense Oligonucleotide Targeting Apolipoprotein C-III (AKCEA-APOCIII-LRx) to Lower Triglycerides and Atherogenic Lipoproteins in Patients with Hypertriglyceridemia and Cardiovascular DIsease Presented at ESC Congress 2020 by Jean-Claude Tardif (Montreal, QC, Canada)

Introduction and methods

Hypertriglyceridemia is associated with increased residual CV risk in patients who receive standard lipid-lowering therapies. Apolipoprotein C-III (apoC-III) is a key regulator of plasma triglyceride (TG) levels and triglyceride-rich lipoprotein (TRL) hepatic uptake through lipoprotein-lipase (LPL) mechanisms. ApoC-III has also LPL-independent mechanisms and may have proatherogenic effects by enhancing vessel wall inflammation. Loss-of-function mutation in apoC-III show reduced levels of TG and TRL, increased HDL-c and approximately 40% reduction of CVD compared to non-carriers. Epidemiologic studies have demonstrated that ApoC-III levels predict CV risk.

This study evaluated AKCEA-APOCIII-LRx, an antisense oligonucleotide targeting hepatic APOC3 mRNA. This compound is a second-generation GalNAc3-conjugated antisense oligonucleotide leading to enhanced intracellular hepatic uptake (compared to first generation antisense oligonucleotides), allowing lower dosing. The study was a multicenter, double-blind, placebo-controlled, dose-ranging, phase 2 study. Eligible patients had either established CVD or were at high risk for CVD with fasting TG levels between ≥200 and ≤500 mg/dL. 114 Patients in 4 parallel cohorts with different dosing strategy were randomized to AKCEA-APOCIII-LRx or placebo (ratio 4:1). Primary endpoint was the mean percentage change in fasting TG levels from baseline to 6 months.

Main results


Treatment with AKCEA-APOCIII-LRx resulted in dose-dependent reductions of ApoC-III and TG levels, as well as reductions in VLDL-c, non-HDL-c and an increase in HDL-c, compared to placebo. The authors suggest that targeting ApoC3 mRNA may reduce the residual CV risk in patients with hypertriglyceridemia.

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

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