Zodasiran, an RNAi Therapeutic Targeting ANGPTL3, for Mixed Hyperlipidemia.

Journal

The New England journal of medicine
ISSN: 1533-4406
Titre abrégé: N Engl J Med
Pays: United States
ID NLM: 0255562

Informations de publication

Date de publication:
29 May 2024
Historique:
medline: 29 5 2024
pubmed: 29 5 2024
entrez: 29 5 2024
Statut: aheadofprint

Résumé

Angiopoietin-like 3 (ANGPTL3) inhibits lipoprotein and endothelial lipases and hepatic uptake of triglyceride-rich lipoprotein remnants. We 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. A 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. In 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.).

Sections du résumé

BACKGROUND BACKGROUND
Angiopoietin-like 3 (ANGPTL3) inhibits lipoprotein and endothelial lipases and hepatic uptake of triglyceride-rich lipoprotein remnants.
METHODS METHODS
We 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.
RESULTS RESULTS
A 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.
CONCLUSIONS CONCLUSIONS
In 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.).

Identifiants

DOI: 10.1056/NEJMoa2404147 PMID: 38809174
pubmed: 38809174
doi: 10.1056/NEJMoa2404147
doi:

Banques de données

ClinicalTrials.gov
['NCT04832971']

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2024 Massachusetts Medical Society.

Auteurs

Robert S Rosenson (RS)

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.).

Daniel Gaudet (D)

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.).

Robert A Hegele (RA)

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.).

Christie M Ballantyne (CM)

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.).

Stephen J Nicholls (SJ)

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.).

Kathryn J Lucas (KJ)

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.).

Javier San Martin (J)

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.).

Rong Zhou (R)

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.).

Ma'an Muhsin (M)

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.).

Ting Chang (T)

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.).

Jennifer Hellawell (J)

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.).

Gerald F Watts (GF)

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.).

Classifications MeSH