Novel Cholesterol Drug Vupanorsen Shows Promising Effect But With Notable Safety Concerns
Genetic loss-of-function variants in Angiopoietin-like 3 (ANGPTL3) are associated with lower levels of plasma lipids. A recent study suggests that high dose ANGPTL3 inhibitors reduce non-high-density lipoprotein cholesterol (non-HDL-C) and triglycerides however accompanied by few safety concerns. The study findings were published in the journal Circulation on April 03, 2022.
Vupanorsen is an N-acetyl galactosamine–conjugated antisense oligonucleotide targeting ANGPTL3 mRNA in the liver. A phase 2a trial of vupanorsen in patients with hypertriglyceridemia, hepatic steatosis, and type 2 diabetes showed significant reductions in triglycerides at all doses studied, as well as reductions in non–high-density lipoprotein cholesterol (non-HDL-C) at the highest doses. Therefore Dr Brian A. Bergmark and hi steam conducted a phase 2b dose-escalation TRANSLATE (Targeting ANGPTL3 with an Antisense Oligonucleotide in Adults with Dyslipidemia)–TIMI (Thrombolysis in Myocardial Infarction) 70 trial.
In TRANSLATE-TIMI 70 trial the researchers assessed the effect of escalating doses of vupanorsen on non–HDL-C levels in statin-treated adults with hyperlipidemia. They included 286 patients with non-high-density lipoprotein cholesterol (non-HDL-C) ≥100 mg/dL and triglycerides 150 to 500 mg/dL on statin therapy. The researchers further randomized them to placebo (n=44) or 1 of 7 vupanorsen dose regimens (n=242) (80, 120, or 160 mg SC every 4 weeks, or 60, 80, 120, or 160 mg SC every 2 weeks). The major outcome assessed was placebo-adjusted percentage change from baseline in non-HDL-C at 24 weeks. The researchers also assessed the placebo-adjusted percentage changes from baseline in triglycerides, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB) and ANGPTL3.
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