Vupanorsen, an N-acetyl galactosamine-conjugated antisense drug to ANGPTL3 mRNA, lowers triglycerides and atherogenic lipoproteins in patients with diabetes, hepatic steatosis, and hypertriglyceridaemia
Open accessAbstract
Aims: Loss-of-function mutations in ANGPTL3 are associated with beneficial effects on lipid and glucose metabolism and reduced risk of coronary artery disease. Vupanorsen (AKCEA-ANGPTL3-L Rx ) is an N-acetyl galactosamine-conjugated antisense oligonucleotide targeted to the liver that selectively inhibits angiopoietin-like 3 (ANGPTL3) protein synthesis. Methods and results: This was a double-blind, placebo-controlled, dose-ranging, Phase 2 study. Patients (N =105) with fasting triglycerides >150 mg/dL (>1.7 mmol/L), type 2 diabetes, and hepatic steatosis were treated for 6 months with 40 or 80 mg every 4 weeks (Q4W), or 20 mg every week (QW) of vupanorsen, or placebo given subcutaneously. The primary efficacy endpoint was per cent change in fasting triglycerides from baseline at 6 months. Median baseline triglycerides were 2.84 mmol/L (252 mg/dL). Significant reductions in triglycerides of 36%, 53%, 47%, and in ANGPTL3 of 41%, 59%, 56%, were observed in the 40 mg Q4W, 80 mg Q4W, and 20 mg QW groups, respectively, compared with 16% reduction in triglycerides and 8% increase in ANGPTL3 in placebo. Compared with placebo, vupanorsen 80 mg Q4W reduced apolipoprotein C-III (58%), remnant cholesterol (38%), total cholesterol (19%), non-high-density lipoprotein cholesterol (HDL-C; 18%), HDL-C (24%), and apolipoprotein B (9%). There was no improvement in glycaemic parameters, or hepatic fat fraction. Treatment with vupanorsen was not associated with clinically significant changes in platelet counts, and the most common adverse events were those at the injection site, which were generally mild. Conclusion: Vupanorsen results in a favourable lipid/lipoprotein profile and provides a potential strategy for residual cardiovascular risk reduction.
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In a phase 2a trial in adults with diabetes, hypertriglyceridemia, and hepatic steatosis, total monthly doses of 40 or 80 mg of vupanorsen reduced non-HDL-C by up to 19%.
“In a phase 2a trial in adults with diabetes, hypertriglyceridemia, and hepatic steatosis, reductions in triglycerides up to 53% and in non-HDL-C up to 19% were seen with total monthly doses of 40 or 80 mg. 10”
From Effect of Vupanorsen on Non–High-Density Lipoprotein Cholesterol Levels in Statin-Treated Patients With Elevated Cholesterol: TRANSLATE-TIMI 70 (2022) · cites this paper as [10]
In a phase 2a trial in adults with diabetes, hypertriglyceridemia, and hepatic steatosis, total monthly doses of 40 or 80 mg of vupanorsen reduced triglycerides by up to 53%.
“In a phase 2a trial in adults with diabetes, hypertriglyceridemia, and hepatic steatosis, reductions in triglycerides up to 53% and in non-HDL-C up to 19% were seen with total monthly doses of 40 or 80 mg. 10”
From Effect of Vupanorsen on Non–High-Density Lipoprotein Cholesterol Levels in Statin-Treated Patients With Elevated Cholesterol: TRANSLATE-TIMI 70 (2022) · cites this paper as [10]
A significant increase in hepatic fat fraction was also seen in the 80 mg every 4 weeks dose arm in the phase 2a study of vupanorsen.
“although a significant increase in hepatic fat fraction was also seen in the 80 mg every 4 weeks dose arm in the phase 2a study of vupanorsen.10”
From Effect of Vupanorsen on Non–High-Density Lipoprotein Cholesterol Levels in Statin-Treated Patients With Elevated Cholesterol: TRANSLATE-TIMI 70 (2022) · cites this paper as [10]
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- Authors
- Gaudet, D., Karwatowska-Prokopczuk, E., Baum, S. J., Hurh, E., Kingsbury, J., Bartlett, V. J., Figueroa, A. L., Piscitelli, P., Singleton, W., Witztum, J. L., Geary, R. S., Tsimikas, S., O'Dea, L. S. L., & the Vupanorsen Study Investigators
- Affiliations
- Université de Montréal (CA)
- Akcea Therapeutics, Inc , Boston, MA, USA
- Excel Medical Clinical Trials, LLC , Boca Raton, FL, USA
- Ionis Pharmaceuticals (United States) (US)
- University of California San Diego (US)
- Corresponding author
- Gaudet, Daniel
- ORCID
- Venue
- European Heart Journal
- Publisher
- Oxford University Press (OUP)
- Published
- 2020-08-29
- Volume
- 41
- Issue
- 40
- Pages
- 3936-3945
- ISSN
- 0195-668X (ISSN-L)
- 1522-9645
- PMC
- PMC7750927
- OpenAlex
- W3082366829
- Cited by
- 279
- References
- 18
- Citations by year
- 2026: 30 · 2025: 35 · 2024: 40 · 2023: 49 · 2022: 51 · 2021: 66 · 2020: 8
- FWCI
- 26.90
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- European Heart Journal (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc)
- Funders
- Ionis Pharmaceuticals, Inc
- Akcea Therapeutics, Inc.
- 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, antisense oligonucleotides, hypertriglyceridemia, type 2 diabetes, hepatic steatosis, triglyceride lowering, atherogenic lipoproteins, apolipoprotein C-III, remnant cholesterol, apolipoprotein B, non-HDL cholesterol, HDL cholesterol, cardiovascular risk reduction, loss-of-function mutations
- MeSH terms
- Angiopoietin-like Proteins, Angiopoietin-Like Protein 3, Diabetes Mellitus, Type 2, Double-Blind Method, Pharmaceutical Preparations, Galactosamine, Humans, Lipoproteins, RNA, Messenger, Triglycerides, Hypertriglyceridemia
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