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

Author:

Bergmark Brian A.1ORCID,Marston Nicholas A.1ORCID,Bramson Candace R.2,Curto Madelyn2,Ramos Vesper2,Jevne Alexandra1,Kuder Julia F.1,Park Jeong-Gun1,Murphy Sabina A.1,Verma Subodh3ORCID,Wojakowski Wojtek4ORCID,Terra Steven G.2,Sabatine Marc S.1ORCID,Wiviott Stephen D.1ORCID,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

Affiliation:

1. TIMI Study Group, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (B.A.B., N.A.M., A.J., J.F.K., J.-G.P., S.A.M., M.S.S., S.D.W.).

2. Pfizer, Inc, New York, NY (C.R.B., M.C., V.R., S.G.T.).

3. Department of Surgery, University of Toronto, Canada (S.V.).

4. Medical University of Silesia, Katowice, Poland (W.W.).

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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine

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