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

• Published in: Circulation (New York, N.Y.) Vol. 145; no. 18; pp. 1377 - 1386
• Main Authors: Bergmark, Brian A., Marston, Nicholas A., Bramson, Candace R., Curto, Madelyn, Ramos, Vesper, Jevne, Alexandra, Kuder, Julia F., Park, Jeong-Gun, Murphy, Sabina A., Verma, Subodh, Wojakowski, Wojtek, Terra, Steven G., Sabatine, Marc S., Wiviott, Stephen D.
• Format: Journal Article
• Language: English
• Published: United States Lippincott Williams & Wilkins 03.05.2022
• Subjects: Adult; Angiopoietin-Like Protein 3; Angiopoietin-like Proteins - genetics; Apolipoproteins B; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Double-Blind Method; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - adverse effects; Hypercholesterolemia; Injection Site Reaction; Lipoproteins; Male; Middle Aged; Original s; Triglycerides; Angiopoietin-like proteins; lipids; triglycerides; antisense oligonucleotide
• DOI: 10.1161/CIRCULATIONAHA.122.059266
• ISSN: 0009-7322; 1524-4539

Genetic loss-of-function variants in are associated with lower levels of plasma lipids. Vupanorsen is a hepatically targeted antisense oligonucleotide that inhibits Angiopoietin-like 3 (ANGPTL3) protein synthesis. 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. 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 <0.001 for all doses). There were dose-dependent reductions in triglycerides that ranged from 41.3% to 56.8% (all <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 <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%). 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. URL: https://clinicaltrials.gov; Unique identifier: NCT04516291.