The DOI matches its Crossref record; 50 of the 51 references it cites were found in a registry or an index.
Antisense Inhibition of Apolipoprotein C-III in Patients with Hypertriglyceridemia
Open accessAbstract
BACKGROUND: Apolipoprotein C-III (APOC3) is a key regulator of plasma triglyceride levels. Elevated triglyceride levels are associated with a risk of adverse cardiovascular events and pancreatitis. ISIS 304801 is a second-generation antisense inhibitor of APOC3 synthesis. METHODS: We conducted a randomized, double-blind, placebo-controlled, dose-ranging, phase 2 study to evaluate ISIS 304801 in untreated patients with fasting triglyceride levels between 350 mg per deciliter (4.0 mmol per liter) and 2000 mg per deciliter (22.6 mmol per liter) (ISIS 304801 monotherapy cohort), as well as in patients receiving stable fibrate therapy who had fasting triglyceride levels between 225 mg per deciliter (2.5 mmol per liter) and 2000 mg per deciliter (ISIS 304801-fibrate cohort). Eligible patients were randomly assigned to receive either ISIS 304801, at doses ranging from 100 to 300 mg, or placebo, once weekly for 13 weeks. The primary outcome was the percentage change in APOC3 level from baseline. RESULTS: A total of 57 patients were treated in the ISIS 304801 monotherapy cohort (41 received active agent, and 16 received placebo), and 28 patients were treated in the ISIS 304801-fibrate cohort (20 received active agent, and 8 received placebo). The mean (±SD) baseline triglyceride levels in the two cohorts were 581±291 mg per deciliter (6.6±3.3 mmol per liter) and 376±188 mg per deciliter (4.2±2.1 mmol per liter), respectively. Treatment with ISIS 304801 resulted in dose-dependent and prolonged decreases in plasma APOC3 levels when the drug was administered as a single agent (decreases of 40.0±32.0% in the 100-mg group, 63.8±22.3% in the 200-mg group, and 79.6±9.3% in the 300-mg group, vs. an increase of 4.2±41.7% in the placebo group) and when it was administered as an add-on to fibrates (decreases of 60.2±12.5% in the 200-mg group and 70.9±13.0% in the 300-mg group, vs. a decrease of 2.2±25.2% in the placebo group). Concordant reductions of 31.3 to 70.9% were observed in triglyceride levels. No safety concerns were identified in this short-term study. CONCLUSIONS: We found that treatment with ISIS 304801 was associated with significant lowering of triglyceride levels, among patients with a broad range of baseline levels, through selective antisense inhibition of APOC3 synthesis. (Funded by Isis Pharmaceuticals; ClinicalTrials.gov number, NCT01529424.).
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“In a randomized, placebo-controlled, double-blind phase 2 trial of 57 patients with elevated triglycerides, volanesorsen reduced ApoC-III by up to − 80% and triglycerides by − 71% [175].”
From Established and Emerging Lipid-Lowering Drugs for Primary and Secondary Cardiovascular Prevention (2023) · cites this paper as [175]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Volanesorsen is an antisense oligonucleotide that targets APOC3 messenger RNA (mRNA) and reduces plasma apolipoprotein C-III levels, as well as the degree of chylomicronemia and plasma triglyceride levels.”
From Olezarsen, Acute Pancreatitis, and Familial Chylomicronemia Syndrome (2024) · cites this paper as [24]
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“Volanesorsen (previously known as ISIS-APOC-III RX ) is a second-generation ASO developed to inhibit apoCIII”
From The Forgotten Lipids: Triglycerides, Remnant Cholesterol, and Atherosclerotic Cardiovascular Disease Risk (2019) · cites this paper as [170]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Volanesorsen, a second-generation antisense oligonucleotide (ASO) targeting hepatic APOC3 mRNA, has shown the capacity to lower TG by up to 77% in patients with Familial chylomicronemia syndrome (FCS) [114]”
From Targeting triglycerides for cardiovascular risk reduction (2026) · cites this paper as [114]
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In the citing paper
“Several miRNAs and antisense oligonucleotides (ASOs) are currently under investigation in clinical trials for various diseases (Kanasty et al., 2013;van Rooij and Kauppinen, 2014;Gaudet et al., 2015).”
From microRNA-33 Regulates ApoE Lipidation and Amyloid-β Metabolism in the Brain (2015) · cites this paper as Gaudet et al., 2015
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“Several novel therapies that potently reduce triglyceride levels are currently in development.[6][7][8]”
From Association of Triglyceride-Lowering LPL Variants and LDL-C–Lowering LDLR Variants With Risk of Coronary Heart Disease (2019) · cites this paper as [8]
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In the citing paper
“The agent has been approved in the European Union and the United Kingdom for the treatment of familial chylomicronemia syndrome and in Brazil for the treatment of familial chylomicronemia syndrome and familial partial lipodystrophy. 23-25”
From Olezarsen, Acute Pancreatitis, and Familial Chylomicronemia Syndrome (2024) · cites this paper as [24]
Experimental — accuracy not yet measuredIn the citing paper
“In a Phase 2 trial of volanesorsen, 300 mg given weekly to HTG patients (NCT01529424), TG levels were reduced by 80%.68”
From Clinical review on triglycerides (2020) · cites this paper as [68]
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Cites
Grundy, S. M., Bilheimer, D. W., Chait, A., Clark, L. T., Denke, M. A., Havel, R. J., Hazzard, W. R., Hulley, S. B., Hunninghake, D. B., Kreisberg, R. A., et al. (1993) · JAMA · doi:10.1001/jama.269.23.3015 · Cited by 27,944
Detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III)
Grundy, S. M., Becker, D. M., Clark, L. T., Cooper, R., Denke, M. A., Howard, J. L., Hunninghake, D. B., Illingworth, D. R., Luepker, R. V., McBride, P. E., et al. (2002) · Civil War Book Review · Cited by 12,198
Triglycerides and Cardiovascular Disease: A Scientific Statement From the American Heart Association
Miller, M., Stone, N. J., Ballantyne, C., Bittner, V., Criqui, M. H., Ginsberg, H. N., Goldberg, A. C., Howard, W. J., Jacobson, M. S., Kris-Etherton, P. M., et al. (2011) · Circulation · doi:10.1161/cir.0b013e3182160726 · Cited by 1,871
Mechanism of Action of Fibrates on Lipid and Lipoprotein Metabolism
Staels, B., Dallongeville, J., Auwerx, J., Schoonjans, K., Leitersdorf, E., & Fruchart, J.-C. (1998) · Circulation · doi:10.1161/01.cir.98.19.2088 · Cited by 1,786
Triglycerides and cardiovascular disease
Nordestgaard, B. G., & Varbo, A. (2014) · The Lancet · doi:10.1016/s0140-6736(14)61177-6 · Cited by 1,419
Sarwar, N., Danesh, J., Eiriksdottir, G., Sigurdsson, G., Wareham, N., Bingham, S., Boekholdt, S. M., Khaw, K.-T., & Gudnason, V. (2007) · Circulation · doi:10.1161/circulationaha.106.637793 · Cited by 1,408
Chapman, M. J., Ginsberg, H. N., Amarenco, P., Andreotti, F., Borén, J., Catapano, A. L., Descamps, O. S., Fisher, E., Kovanen, P. T., Kuivenhoven, J. A., et al. (2011) · European Heart Journal · doi:10.1093/eurheartj/ehr112 · Cited by 1,227
Remnant Cholesterol as a Causal Risk Factor for Ischemic Heart Disease
Varbo, A., Benn, M., Tybjærg-Hansen, A., Jørgensen, A. B., Frikke-Schmidt, R., & Nordestgaard, B. G. (2013) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2012.08.1026 · Cited by 1,115
Loss-of-Function Mutations in APOC3, Triglycerides, and Coronary Disease
The TG and HDL Working Group of the Exome Sequencing Project, N. H. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1307095 · Cited by 1,071
Research works printed but not linked: 1
- Brunzell JD, 1973, Trans Assoc Am Physicians, 86, 245
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Borén, J., Chapman, M. J., Krauss, R. M., Packard, C. J., Bentzon, J. F., Binder, C. J., Daemen, M. J., Demer, L. L., Hegele, R. A., Nicholls, S. J., et al. (2020) · European Heart Journal · doi:10.1093/eurheartj/ehz962 · Cited by 1,601
Ginsberg, H. N., Packard, C. J., Chapman, M. J., Borén, J., Aguilar-Salinas, C. A., Averna, M., Ference, B. A., Gaudet, D., Hegele, R. A., Kersten, S., et al. (2021) · European Heart Journal · doi:10.1093/eurheartj/ehab551 · Cited by 979
Self-citationCrooke, S. T., Witztum, J. L., Bennett, C. F., & Baker, B. F. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.03.004 · Cited by 841
Self-citationFerence, B. A., Kastelein, J. J. P., Ray, K. K., Ginsberg, H. N., Chapman, M. J., Packard, C. J., Laufs, U., Oliver-Williams, C., Wood, A. M., Butterworth, A. S., et al. (2019) · JAMA · doi:10.1001/jama.2018.20045 · Cited by 703
Self-citationVolanesorsen and Triglyceride Levels in Familial Chylomicronemia Syndrome
Witztum, J. L., Gaudet, D., Freedman, S. D., Alexander, V. J., Digenio, A., Williams, K. R., Yang, Q., Hughes, S. G., Geary, R. S., Arca, M., et al. (2019) · New England Journal of Medicine · doi:10.1056/nejmoa1715944 · Cited by 669
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Metadata
- Authors
- Gaudet, D., Alexander, V. J., Baker, B. F., Brisson, D., Tremblay, K., Singleton, W., Geary, R. S., Hughes, S. G., Viney, N. J., Graham, M. J., Crooke, R. M., Witztum, J. L., Brunzell, J. D., & Kastelein, J. J. P.
- Affiliations
- University of Washington (US)
- Ionis Pharmaceuticals (United States) (US)
- Université de Montréal (CA)
- University of California San Diego (US)
- Amsterdam UMC Location University of Amsterdam (NL)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2015-07-30
- Volume
- 373
- Issue
- 5
- Pages
- 438-447
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2315899065
- Semantic Scholar
- b8b4f0ae969760d3373ca1d9082abfee85fe16d9
- Cited by
- 528
- References
- 51
- Citations by year
- 2026: 23 · 2025: 28 · 2024: 27 · 2023: 32 · 2022: 51 · 2021: 46 · 2020: 63 · 2019: 61 · 2018: 68 · 2017: 58 · 2016: 58 · 2015: 13
- FWCI
- 47.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (acceptedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- apolipoprotein C-III, antisense oligonucleotides, hypertriglyceridemia, triglyceride lowering, fibrate therapy, dose-ranging, cardiovascular risk, pancreatitis risk, triglyceride metabolism, monotherapy
- MeSH terms
- Adult, Aged, Aged, 80 and over, Dose-Response Relationship, Drug, Double-Blind Method, Drug Therapy, Combination, Female, Humans, Cholesterol, HDL, Male, Middle Aged, Oligonucleotides, Triglycerides, Hypertriglyceridemia, Apolipoprotein C-III, Fibric Acids
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