RNA Interference Therapy Targeting Apolipoprotein C-III in Hypertriglyceridemia

作者：Daniel Gaudet, Peter Clifton, David Sullivan, John E. Baker, Christian Schwabe, Susan Thackwray, Russell Scott, James Hamilton, Bruce D. Given, Stacey Melquist, Rong Zhou, Ting Chang, Javier San Martín, Gerald F. Watts, Ira J. Goldberg, Joshua W. Knowles, Robert A. Hegele, Christie M. Ballantyne · 发表于：NEJM Evidence · 年份：2023 · DOI：10.1056/evidoa2200325 · 被引用次数：72 · 研究领域：Lipid metabolism and disorders、Lipoproteins and Cardiovascular Health、Cancer, Lipids, and Metabolism

BACKGROUND: Apolipoprotein C-III (APOC3) inhibits triglyceride clearance by reducing lipoprotein lipase–mediated hydrolysis and hepatocyte uptake of triglyceride-rich lipoproteins. ARO-APOC3, a hepatocyte-targeting RNA interference therapeutic, inhibits APOC3 messenger ribonucleic acid expression, lowering triglyceride levels. The objective of this trial was to assess the safety, pharmacodynamic variables, and pharmacokinetic variables of ARO-APOC3 treatment. METHODS: Healthy participants and adults with hypertriglyceridemia were randomly assigned to receive escalating single (day 1) or repeat (days 1 and 29) doses, respectively, of subcutaneous injections of ARO-APOC3 10, 25, 50, or 100 mg or placebo; they were followed up until day 113. Additional cohorts of healthy participants and adults with chylomicronemia received repeat doses of open-label ARO-APOC3. The primary objective was to evaluate the safety and side effect profile of ARO-APOC3. Key secondary and exploratory objectives included pharmacokinetic variables and changes in serum APOC3, triglyceride, and cholesterol levels. RESULTS: Eighty-eight participants received ARO-APOC3 and 24 participants received placebo across double-blind and open-label cohorts. Treatment-emergent adverse events (AEs) of transient, mild to moderate liver transaminase changes occurred in 10 participants: 1 patient receiving ARO-APOC3 25 mg, 5 patients receiving ARO-APOC3 50 mg, and 4 participants receiving ARO-APOC3 100 mg (1 healthy partic...