Effect of Vupanorsen on Non–High-Density Lipoprotein Cholesterol Levels in Statin-Treated Patients With Elevated Cholesterol: TRANSLATE-TIMI 70
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. , Carbonneau Diane , Poulin-Robitaille Raphael , Wayne Jeffrey , Lee Keung , Mujica Trenche Samuel , Dzongowski Petros , Gaudet Daniel , Van Joanna , Ajani Dilawar , Bays Harold , O’Mahony John , Janas Adam , Scott John , Moustafa Moustafa Ashraf , Ransom Thomas , Benjamin Sabrina , Aggarwal Naresh , Bogdanski Pawel , Friars Douglas , Schlosser Robert , Okopien Boguslaw , Budhraja Madhusudan , Feld Lawrence , Klaff Leslie , Tellier Guy , Mazza Giuseppe , Wierzbicka Iwona , Jazwinska-Tarnawska Ewa , Boccalandro Fernando , Rosenstock Julio , Marquez Elizabeth , Barbel-Johnson Kim , Madziarska Katarzyna , Heaton Kenneth , Tardif Jean-Claude , Rubino John , Trevino Miguel , Moriarty Katie , Gupta Anil , Wojakowski Wojciech , Fidelholtz James , Gupta Dinesh , Alasaad Hani , Christensen Shane , Shah Parag , Li Stephanie , Sherman Mark , Frechette Andre , Arango Cecilia , Egan Alan , Srivastava Sunny , Bajaj Archna , Ince Jr Carlos , Zurakowski Aleksander 
Published: April 2022

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.