ANGPTL3 genetic loss-of-function mutations are related to reduced plasma lipid levels. Vupanorsen is a hepatically targeted antisense oligonucleotide that suppresses the creation of the protein Angiopoietin-like 3 (ANGPTL3). Adults on statin medication with non–high–density lipoprotein cholesterol (non-HDL-C) of 100 mg/dL and triglycerides of 150 to 500 mg/dL were randomized to placebo or one of seven vupanorsen dosage regimens (80, 120, or 160 mg SC every 4 weeks, or 60, 80, 120, or 160 mg SC every 2 weeks). At 24 weeks, the main endpoint was the placebo-adjusted percentage change from baseline in non–HDL-C. Secondary end goals were placebo-adjusted percentage changes from baseline in triglycerides, LDL-C, ApoB, and ANGPTL3.
A total of 286 participants were randomly assigned: 44 to placebo and 242 to vupanorsen. The median non–HDL-C was 132.4 (interquartile range, 118.0–154.1) mg/dL, while the median triglycerides were 216.2 (interquartile range, 181.4–270.4) mg/dL. Vupanorsen caused substantial reductions in non–HDL-C from baseline compared to placebo, ranging from 22.0% in the 60 mg every 2 weeks arm to 27.7% in the 80 mg every 2 weeks arm (all P<0.001 for all dosages). The decreases in triglycerides were dose-dependent and varied from 41.3% to 56.8% (all P<0.001). The effects on LDL-C and ApoB were less dramatic (7.9%–16.0% and 6.0%–15.1%, respectively), and there was no apparent dose-response connection; only the larger decreases were statistically significant. ANGPTL3 levels were reduced from 69.9% to 95.2% in a dose-dependent manner (all P<0.001). There have been no confirmed cases of vupanorsen causing a severe decrease in renal function or platelet count. At higher total monthly dosages (up to 33.3% and 44.4%, respectively), injection site responses and >3 elevations of alanine aminotransferase or aspartate aminotransferase were more prevalent, and there was a dose-dependent increase in hepatic fat fraction (up to 76%).
Vupanorsen at monthly equivalent dosages of 80 to 320 mg lowered non–HDL-C and other lipid markers considerably. At larger dosages, injection site responses and liver enzyme increases were more common, and the hepatic fat percentage increased in a dose-dependent manner.
Reference:www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.122.059266
