Vupanorsen, an antisense oligonucleotide targeting angiopoietin-like 3 (ANGPTL3), reduced non-high-density lipoprotein (non-HDL) cholesterol by up to 28% in patients who were already taking statins, according to findings from the TRANSLATE-TIMI 70 trial presented April 3 at ACC.22 and simultaneously published in Circulation. Researchers also noted significant reductions in other lipid parameters including triglyceride levels, low-density lipoprotein (LDL) cholesterol and apolipoprotein B (ApoB) levels.

Researchers enrolled 286 patients at 55 medical centers in the U.S., Canada and Poland with non-HDL cholesterol of 100 mg/dL or higher, triglycerides of 150-500 mg/dL and who were already taking a statin. The median patient age was 64 years and 44% were female. Participants were randomly assigned to receive either a placebo (n= 44) or one of seven vupanorsen doses ranging from 80 milligrams once per month to 160 milligrams every two weeks via subcutaneous injection (n=242).

The study met its primary endpoint, with those assigned to the vupanorsen groups achieving, on average, significant reductions at 24 weeks in non-HDL cholesterol. Additionally, those patients taking vupanorsen had a 41.3%-56.8% reduction in triglycerides, and modest reductions in LDL cholesterol of up to 16.2% and ApoB levels of up to 15.1%. ANGPTL3 levels were reduced by 69.9%-95.2% in those taking vupanorsen.

"Vupanorsen reduced non-HDL cholesterol at all doses studied in a statistically significant way and cut triglyceride levels in half. Whether these reductions would be sufficient to translate into a clinically meaningful cardiovascular risk reduction remains unclear," said Brian Bergmark, MD, FACC, investigator for the TIMI Study Group and the study's lead author.

According to Bergmark, there were no confirmed instances of significant decline in renal function or platelet count with vupanorsen. However, participants taking vupanorsen at higher doses saw an increased rate of injection site reactions and elevations in liver enzymes. In addition, the researchers also observed a dose-dependent increase in hepatic fat fraction of up to 76%.

"Regardless of the future of this compound, we did find out some information that may be quite relevant for future studies," Bergmark said. "There are numerous other compounds targeting this pathway or adjacent metabolic pathways through similar mechanisms, and it will be interesting to see how this plays out for other agents."

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: ACC Annual Scientific Session, ACC22, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypercholesterolemia, Cholesterol, LDL, Cholesterol, HDL

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