Vupanorsen lowers lipids in statin-treated individuals with high cholesterol levels

In the management of statin-treated patients with elevated cholesterol levels, the antisense oligonucleotide targeting angiopoietin-like protein 3 (ANGPTL3) vupanorsen reduces levels of nonhigh-density lipoprotein cholesterol (non-HDL-C) and other lipid parameters, according to the results of TRANSLATE-TIMI 70.

However, this benefit comes with liver enzyme elevations at higher doses and a dose-dependent increase in hepatic fat fraction.

A total of 286 adults with non-HDL-C ≥100 mg/dL and triglycerides 150–500 mg/dL on statin therapy were randomized to receive placebo (n=44) or one of the following subcutaneous vupanorsen (n=242) dose regimens: 80, 120, or 160 mg every 4 weeks, or 60, 80, 120, or 160 mg every 2 weeks.

The median age of the population was 64 years, and 44 percent were women. The median baseline non-HDL-C was 132.4 mg/dL, while the median baseline triglycerides were 216.2 mg/dL. At 24 weeks, the primary endpoint of placebo-adjusted percentage change from baseline in non-HDL-C with vupanorsen was significant, ranging from 22.0 percent in the 60-mg-every-2-weeks arm to 27.7 percent in the 80-mg-every-2-weeks arm (p<0.001 for all doses).

Vupanorsen also yielded dose-dependent reductions in triglycerides that ranged from 41.3 percent to 56.8 percent (all P<0.001). Meanwhile, the drug had modest effects on low-density lipoprotein cholesterol (LDL-C; 7.9–16.0 percent) and apolipoprotein B (ApoB; 6.0–15.1 percent) and without a clear dose-response relationship. ANGPTL3 levels, on the other hand, markedly decreased in a dose-dependent manner by 69.9 percent to 95.2 percent (p<0.001).

In terms of safety, vupanorsen-treated patients developed injection site reactions and more than threefold elevations in alanine aminotransferase or aspartate aminotransferase, which were more common at higher total monthly doses (up to 33.3 percent and 44.4 percent, respectively). Furthermore, there was a dose-dependent increase in hepatic fat fraction (up to 76 percent).