RNA Interference Targeting ANGPTL3 for Triglyceride and Cholesterol Lowering: Phase 1 Basket Trial Cohorts

Authors

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

Language

English

Publication Date

9-1-2023

Journal

Nature Medicine

DOI

10.1038/s41591-023-02494-2

PMID

37626170

PMCID

PMC10504078

PubMedCentral® Posted Date

8-25-2023

PubMedCentral® Full Text Version

Post-print

Abstract

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 Tmax of 6.0–10.5 h and clearance from plasma within 24–48 h after dosing with a mean t½ 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

Keywords

Humans, Triglycerides, Angiopoietin-Like Protein 3, RNA Interference, Cholesterol, Atherosclerosis, Drug development, RNAi therapy, Drug delivery, Dyslipidaemias

Published Open-Access

yes

Recommended Citation

Watts, Gerald F; Schwabe, Christian; Scott, Russell; et al., "RNA Interference Targeting ANGPTL3 for Triglyceride and Cholesterol Lowering: Phase 1 Basket Trial Cohorts" (2023). Faculty, Staff and Students Publications. 6724.
https://digitalcommons.library.tmc.edu/baylor_docs/6724