Effect of Vupanorsen on Non–High-Density Lipoprotein Cholesterol Levels in Statin-Treated Patients With Elevated Cholesterol: TRANSLATE-TIMI 70
Authors: Brian A. Bergmark, Nicholas A. Marston, Candace R. Bramson, Madelyn Curto, Vesper Ramos, Alexandra Jevne, Julia F. Kuder, Jeong-Gun Park, Sabina A. Murphy, Subodh Verma, Wojtek Wojakowski, Steven G. Terra, Marc S. Sabatine, Stephen D. Wiviott, Diane Carbonneau, Raphael Poulin-Robitaille, Jeffrey Wayne, Keung Lee, Samuel Mujica Trenche, Petros Dzongowski, Daniel Gaudet, Joanna Van, Dilawar Ajani, Harold Bays, John O’Mahony, Adam Janas, John Scott, Moustafa Ashraf Moustafa, Thomas Ransom, Sabrina Benjamin, Naresh Aggarwal, Pawel Bogdanski, Douglas Friars, Robert Schlosser, Boguslaw Okopien, Madhusudan Budhraja, Lawrence Feld, Leslie Klaff, Guy Tellier, Giuseppe Mazza, Iwona Wierzbicka, Ewa Jazwinska-Tarnawska, Fernando Boccalandro, Julio Rosenstock, Elizabeth Marquez, Kim Barbel-Johnson, Katarzyna Madziarska, Kenneth Heaton, Jean-Claude Tardif, John Rubino, Miguel Trevino, Katie Moriarty, Anil Gupta, Wojciech Wojakowski, James Fidelholtz, Dinesh Gupta, Hani Alasaad, Shane Christensen, Parag Shah, Stephanie Li, Mark Sherman, Andre Frechette, Cecilia Arango, Alan Egan, Sunny Srivastava, Archna Bajaj, Carlos Ince Jr, Aleksander Zurakowski
Journal: Circulation (2022)

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.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 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%).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.