Novel Cholesterol Drug Vupanorsen Shows Promising Effect But With Notable Safety Concerns

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.

Key findings of the study:

• Upon analysis, the researchers found that vupanorsen resulted in significant decreases from baseline over placebo in non-HDL-C ranging from 22.0% in the 60 mg every 2 weeks arm to 27.7% in the 80 mg every 2 weeks arm.
• They noted dose-dependent reductions in triglycerides that ranged from 41.3% to 56.8%.
• They observed that the effects on LDL-C and ApoB were more modest (7.9%-16.0% and 6.0%-15.1%, respectively) and without a clear dose-response relationship, ‚ and only the higher reductions achieved statistical significance.
• They found that the ANGPTL3 levels were decreased in a dose-dependent manner by 69.9% to 95.2%.
• They noted no confirmed instances of a significant decline in renal function or platelet count with vupanorsen.
• However, they reported that injection site reactions and >3x elevations of alanine aminotransferase or aspartate aminotransferase were more common at higher total monthly doses (up to 33.3% and 44.4%, respectively), and there was a dose-dependent increase in hepatic fat fraction (up to 76%).

The authors concluded, "Vupanorsen administered at monthly equivalent doses from 80 to 320 mg significantly reduced non-HDL-C and additional lipid parameters. Injection site reactions and liver enzyme elevations were more frequent at higher doses, and there was a dose-dependent increase in hepatic fat fraction."

For further information:

DOI: https://doi.org/10.1161/CIRCULATIONAHA.122.059266

Keywords:

Hepatic function, ANGPTL3 inhibitors, non-HDL Cholesterol, TRANSLATE-TIMI 70 trial, Dyslipidemia, hyperlipidemia, vupanorsen, dose escalation study, injection site reactions, alanine aminotransferase, aspartate aminotransferase, Journal Circulation.