Effect of Vupanorsen on Non-High-Density Lipoprotein Cholesterol Levels in Statin-Treated Patients With Elevated Cholesterol: TRANSLATE-TIMI 70

Abstract

Background: Genetic loss-of-function variants in ANGPTL3 are associated with lower levels of plasma lipids. Vupanorsen is a hepatically targeted antisense oligonucleotide that inhibits Angiopoietin-like 3 (ANGPTL3) protein synthesis.

Methods: Adults with non-high-density lipoprotein cholesterol (non-HDL-C) ≥100 mg/dL and triglycerides 150 to 500 mg/dL on statin therapy were randomized in a double-blind fashion to placebo or 1 of 7 vupanorsen dose regimens (80, 120, or 160 mg SC every 4 weeks, or 60, 80, 120, or 160 mg SC every 2 weeks). The primary end point was placebo-adjusted percentage change from baseline in non-HDL-C at 24 weeks. Secondary end points included placebo-adjusted percentage changes from baseline in triglycerides, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), and ANGPTL3.

Results: Two hundred eighty-six subjects were randomized: 44 to placebo and 242 to vupanorsen. The median age was 64 (interquartile range, 58-69) years, 44% were female, the median non-HDL-C was 132.4 (interquartile range, 118.0-154.1) mg/dL, and the median triglycerides were 216.2 (interquartile range, 181.4-270.4) mg/dL. 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 (all P<0.001 for all doses). There were dose-dependent reductions in triglycerides that ranged from 41.3% to 56.8% (all P<0.001). 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. ANGPTL3 levels were decreased in a dose-dependent manner by 69.9% to 95.2% (all P<0.001). There were no confirmed instances of significant decline in renal function or platelet count with vupanorsen. Injection site reactions and >3× 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%).

Conclusions: 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.

Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT04516291.

Keywords: Angiopoietin-like proteins; antisense oligonucleotide; lipids; triglycerides.

Figure 1.

Effect of vupanorsen on non–high-density lipoprotein cholesterol at 24 weeks. The effect of vupanorsen on the primary end point of percent change in placebo-adjusted non–high-density lipoprotein cholesterol level at 24 weeks is shown for each dose arm. Data shown are placebo-adjusted least squares mean differences and 95% CIs. Q2W indicates every 2 weeks; and Q4W, every 4 weeks.

Figure 2.

Effect of vupanorsen on additional lipid parameters at 24 weeks. The effects of vupanorsen on the percent change in placebo-adjusted levels of ANGPTL3 (angiopoietin-like protein 3), triglycerides, low-density lipoprotein cholesterol (LDL-C), and ApoB (apolipoprotein B) at 24 weeks are shown for each dose arm. Data shown are placebo-adjusted least squares mean differences. Q2W indicates every 2 weeks; and Q4W, every 4 weeks.

Figure 3.

Effect of vupanorsen on non–HDL-C at 24 weeks in key subgroups. Placebo-adjusted least squares mean difference reductions in non–HDL-C at 24 weeks with vupanorsen (pooled) are shown in key subgroups. MI indicates myocardial infarction; mod, moderate; non-HDL-C, non-high-density lipoprotein cholesterol; and Pint, P value for interaction.