Zodasiran, an RNAi Therapeutic Targeting ANGPTL3, for Mixed Hyperlipidemia
Abstract
Background Angiopoietin-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. 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. Research Summary Zodasiran for Mixed Hyperlipidemia 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 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 .)
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- Authors
- Rosenson, R. S., Gaudet, D., Hegele, R. A., Ballantyne, C. M., Nicholls, S. J., Lucas, K. J., San Martin, J., Zhou, R., Muhsin, M., Chang, T., Hellawell, J., & Watts, G. F.
- Affiliations
- The University of Western Australia (AU)
- 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.).
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2024-09-12
- Volume
- 391
- Issue
- 10
- Pages
- 913-925
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W4399140511
- Semantic Scholar
- ef34f731fcb2432ffbceefafa0d53fc7e4f68cde
- Cited by
- 213
- References
- 31
- Citations by year
- 2026: 75 · 2025: 105 · 2024: 32
- FWCI
- 56.55
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- Funders
- Arrowhead Pharmaceuticals
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- ANGPTL3, RNA interference, mixed dyslipidemia, triglyceride lowering, non-HDL cholesterol, apolipoprotein B, atherosclerotic cardiovascular disease risk, dose-response relationship, safety and tolerability, hypertriglyceridemia, dyslipidemia
- MeSH terms
- RNAi Therapeutics, Angiopoietin-Like Protein 3, Aged, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Hyperlipidemias, Injections, Subcutaneous, Cholesterol, LDL, Liver, Male, Middle Aged, Triglycerides, Treatment Outcome, RNA, Small Interfering
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