• Robert S Rosenson, Daniel Gaudet, Robert A Hegele, Christie M Ballantyne, Stephen J Nicholls, Kathryn J Lucas, Javier San Martin, Rong Zhou, Ma'an Muhsin, Ting Chang, Jennifer Hellawell, Gerald F Watts, and ARCHES-2 Trial Team.
• From the Metabolism and Lipids Program, Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York (R.S.R.); Université de Montréal, Montreal (D.G.), and Robarts Research Institute, London, ON (R.A.H.) - both in Canada; Baylor College of Medicine and the Texas Heart Institute - both in Houston (C.M.B.); Monash Victorian Heart Institute, Monash University, Melbourne, VIC (S.J.N.), and the School of Medicine, University of Western Australia, and the Department of Cardiology, Royal Perth Hospital, Perth (G.F.W.) - all in Australia; Lucas Research, Morehead City, NC (K.J.L.); and Arrowhead Pharmaceuticals, Pasadena, CA (J.S.M., R.Z., M.M., T.C., J.H.).
• N. Engl. J. Med. 2024 Sep 12; 391 (10): 913925913-925.

BackgroundAngiopoietin-like 3 (ANGPTL3) inhibits lipoprotein and endothelial lipases and hepatic uptake of triglyceride-rich lipoprotein remnants. ANGPTL3 loss-of-function carriers have lower levels of triglycerides, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and non-HDL cholesterol and a lower risk of atherosclerotic cardiovascular disease than noncarriers. Zodasiran is an RNA interference (RNAi) therapy targeting expression of ANGPTL3 in the liver.MethodsWe conducted a double-blind, placebo-controlled, dose-ranging phase 2b trial to evaluate the safety and efficacy of zodasiran in adults with mixed hyperlipidemia (fasting triglyceride level of 150 to 499 mg per deciliter and either an LDL cholesterol level of ≥70 mg per deciliter or a non-HDL cholesterol level of ≥100 mg per deciliter). Eligible patients were randomly assigned in a 3:1 ratio to receive subcutaneous injections of zodasiran (50, 100, or 200 mg) or placebo on day 1 and week 12 and were followed through week 36. The primary end point was the percent change in the triglyceride level from baseline to week 24.ResultsA total of 204 patients underwent randomization. At week 24, substantial mean dose-dependent decreases from baseline in ANGPTL3 levels were observed with zodasiran (difference in change vs. placebo, -54 percentage points with 50 mg, -70 percentage points with 100 mg, and -74 percentage points with 200 mg), and significant dose-dependent decreases in triglyceride levels were observed (difference in change vs. placebo, -51 percentage points, -57 percentage points, and -63 percentage points, respectively) (P<0.001 for all comparisons). Other differences in change from baseline as compared with placebo included the following: for non-HDL cholesterol level, -29 percentage points with 50 mg, -29 percentage points with 100 mg, and -36 percentage points with 200 mg; for apolipoprotein B level, -19 percentage points, -15 percentage points, and -22 percentage points, respectively; and for LDL cholesterol level, -16 percentage points, -14 percentage points, and -20 percentage points, respectively. We observed a transient elevation in glycated hemoglobin levels in patients with preexisting diabetes who received the highest dose of zodasiran.ConclusionsIn patients with mixed hyperlipidemia, zodasiran was associated with significant decreases in triglyceride levels at 24 weeks. (Funded by Arrowhead Pharmaceuticals; ARCHES-2 ClinicalTrials.gov number, NCT04832971.).Copyright © 2024 Massachusetts Medical Society.

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