Journal Article

RNA interference targeting ANGPTL3 for triglyceride and cholesterol lowering: phase 1 basket trial cohorts

Schwabe, Christian, Baker, John, Given, Bruce, Ballantyne, Christie M., Gladding, Patrick A., Zhou, Rong, Goldberg, Ira J., Clifton, Peter, Sullivan, David, Gaudet, Daniel, Scott, Russell, San Martin, Javier, Chang, Ting, Hamilton, James, Hegele, Robert A., Watts, Gerald F., Melquist, Stacey, Knowles, Joshua W.

2023

Overview

Elevated triglycerides and non-high-density lipoprotein cholesterol (HDL-C) are risk factors for atherosclerotic cardiovascular disease (ASCVD). ARO-ANG3 is an RNA interference therapy that targets angiopoietin-like protein 3 (ANGPTL3), a regulator of lipoprotein metabolism. This first-in-human, phase 1, randomized, placebo-controlled, open-label trial investigated single and repeat ARO-ANG3 doses in four cohorts of fifty-two healthy participants and one cohort of nine participants with hepatic steatosis, part of a basket trial. Safety (primary objective) and pharmacokinetics (in healthy participants) and pharmacodynamics (secondary objectives) of ARO-ANG3 were evaluated. ARO-ANG3 was generally well tolerated, with similar frequencies of treatment-emergent adverse events in active and placebo groups. Systemic absorption of ARO-ANG3 in healthy participants was rapid and sustained, with a mean T max of 6.0–10.5 h and clearance from plasma within 24–48 h after dosing with a mean t ½ of 3.9–6.6 h. In healthy participants, ARO-ANG3 treatment reduced ANGPTL3 (mean −45% to −78%) 85 days after dose. Reductions in triglyceride (median −34% to −54%) and non-HDL-C (mean −18% to −29%) (exploratory endpoints) concentrations occurred with the three highest doses. These early-phase data support ANGPTL3 as a potential therapeutic target for ASCVD treatment. ClinicalTrials.gov identifier: NCT03747224 First-in-human results from five cohorts of healthy volunteers and individuals with hepatic steatosis show that RNA interference treatment targeting ANGPTL3 was well tolerated and led to reduction in triglycerides and non-HDL cholesterol.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/154/152 / 631/61/391/3932 / 692/308/153 / 692/699/75/2099 / Angiopoietin / Arteriosclerosis / Atherosclerosis / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cardiovascular diseases / Cholesterol / Dosage / Fatty liver / High density lipoprotein / Infectious Diseases / Interference / Lipid metabolism / Metabolic Diseases / Molecular Medicine / Neurosciences / Pharmacodynamics / Pharmacokinetics / Placebos / Risk factors / RNA-mediated interference / Steatosis / Therapeutic targets / Triglycerides