RNA Interference Therapy Targeting Apolipoprotein C-III in Hypertriglyceridemia
Abstract
BACKGROUND: Apolipoprotein C-III (APOC3) inhibits triglyceride clearance by reducing lipoprotein lipase–mediated hydrolysis and hepatocyte uptake of triglyceride-rich lipoproteins. ARO-APOC3, a hepatocyte-targeting RNA interference therapeutic, inhibits APOC3 messenger ribonucleic acid expression, lowering triglyceride levels. The objective of this trial was to assess the safety, pharmacodynamic variables, and pharmacokinetic variables of ARO-APOC3 treatment. METHODS: Healthy participants and adults with hypertriglyceridemia were randomly assigned to receive escalating single (day 1) or repeat (days 1 and 29) doses, respectively, of subcutaneous injections of ARO-APOC3 10, 25, 50, or 100 mg or placebo; they were followed up until day 113. Additional cohorts of healthy participants and adults with chylomicronemia received repeat doses of open-label ARO-APOC3. The primary objective was to evaluate the safety and side effect profile of ARO-APOC3. Key secondary and exploratory objectives included pharmacokinetic variables and changes in serum APOC3, triglyceride, and cholesterol levels. RESULTS: Eighty-eight participants received ARO-APOC3 and 24 participants received placebo across double-blind and open-label cohorts. Treatment-emergent adverse events (AEs) of transient, mild to moderate liver transaminase changes occurred in 10 participants: 1 patient receiving ARO-APOC3 25 mg, 5 patients receiving ARO-APOC3 50 mg, and 4 participants receiving ARO-APOC3 100 mg (1 healthy partic…
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The targeted delivery of Olezarsen to hepatocytes reduces hypertriglyceridemia more effectively than current medications.
“The targeted delivery of the olezarsen to the hepatocyte reduces hypertriglyceridemia more effectively than current medications [8,9].”
From Efficacy and safety of Olezarsen in treating hypertriglyceridemia: a systematic review and meta-analysis of randomized controlled trials (2025) · cites this paper as [8]
The favorable safety profile of Olezarsen can be attributed to its ASO-GalNAC3 conjugate design, which ensures targeted delivery to hepatocytes and reduced systemic exposure, resulting in low immunogenicity and reduced hypersensitivity and thrombocytopenia.
“This favorable safety profile can be attributed to ASO-GalNAC3 conjugate design of Olezarsen which ensures targeted delivery of the drug to the hepatocytes and reduced systematic exposure resulting in low immunogenicity and reduced hypersensitivity and thrombocytopenia [8].”
From Efficacy and safety of Olezarsen in treating hypertriglyceridemia: a systematic review and meta-analysis of randomized controlled trials (2025) · cites this paper as [8]
Unlike Plozasiran, which is associated with mild to moderate elevations in liver transaminases, this study found no such liver-related adverse effects with Olezarsen, indicating a superior safety and tolerability profile.
“However, unlike Plozasiran, which is associated with mild to moderate elevations in liver transaminases [8], our study found no such liver-related adverse effects with Olezarsen, indicating a superior safety and tolerability profile.”
From Efficacy and safety of Olezarsen in treating hypertriglyceridemia: a systematic review and meta-analysis of randomized controlled trials (2025) · cites this paper as [8]
Four randomized controlled trials met eligibility criteria and were included in the meta-analysis.
“Ultimately, four RCTs met al.l eligibility criteria and were included in the final analysis [16, 17, 22, 23].”
From The Efficacy and Safety of Plozasiran on Lipid Profile in Dyslipidemic Disorders: A Systematic Review and Meta-Analysis (2026) · cites this paper as [22]
The meta-analysis included 1,514 participants, with 534 assigned to plozasiran and 980 receiving placebo.
“The meta-analysis included data from 4 clinical trials [16, 17, 22, 23], encompassing a total of 1,514 participants—534 assigned to various doses and treatment durations of plozasiran, and 980 receiving placebo.”
From The Efficacy and Safety of Plozasiran on Lipid Profile in Dyslipidemic Disorders: A Systematic Review and Meta-Analysis (2026) · cites this paper as [22]
Trials mitigated the rises in liver transaminases by changing dosing and frequency.
“Moreover, the rises seen in liver transaminases were considered non-serious and associated with higher and more frequent doses of plozasiran, which trials mitigated by changing dosing and frequency [16, 22].”
From The Efficacy and Safety of Plozasiran on Lipid Profile in Dyslipidemic Disorders: A Systematic Review and Meta-Analysis (2026) · cites this paper as [22]
Rises in liver transaminases were considered non-serious.
“Moreover, the rises seen in liver transaminases were considered non-serious and associated with higher and more frequent doses of plozasiran, which trials mitigated by changing dosing and frequency [16, 22].”
From The Efficacy and Safety of Plozasiran on Lipid Profile in Dyslipidemic Disorders: A Systematic Review and Meta-Analysis (2026) · cites this paper as [22]
Changes in ALT and AST levels were dose- and regimen-dependent and associated with higher and more frequent doses of plozasiran.
“Subgroup analyses confirmed that changes in HbA1c, ALT, and AST levels were dose- and regimen-dependent.”
From The Efficacy and Safety of Plozasiran on Lipid Profile in Dyslipidemic Disorders: A Systematic Review and Meta-Analysis (2026) · cites this paper as [22]
Gaudet et al. (2023, 2024) enrolled patients with severe hypertriglyceridemia to evaluate plozasiran's lipid-lowering efficacy.
“Gaudet et al. (2023, 2024) enrolled patients with severe hypertriglyceridemia to evaluate plozasiran’s lipid-lowering efficacy [22, 23].”
From The Efficacy and Safety of Plozasiran on Lipid Profile in Dyslipidemic Disorders: A Systematic Review and Meta-Analysis (2026) · cites this paper as [22]
Olezarsen appears to provide improved safety compared with volanesorsen while maintaining effective triglyceride reduction.
“Olezarsen appears to mitigate these risks while maintaining effective TG reduction [31][32][33]”
From Efficacy of Olezarsen in Severe Hypertriglyceridemia and Acute Pancreatitis Risk: A Systematic Review and Meta-Analysis of Randomized Controlled Trials (2026) · cites this paper as [30]
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- Authors
- Gaudet, D., Clifton, P., Sullivan, D., Baker, J., Schwabe, C., Thackwray, S., Scott, R., Hamilton, J., Given, B., Melquist, S., Zhou, R., Chang, T., San Martin, J., Watts, G. F., Goldberg, I. J., Knowles, J. W., Hegele, R. A., & Ballantyne, C. M.
- Affiliations
- Université de Montréal (CA)
- Royal Adelaide Hospital (AU)
- Royal Prince Alfred Hospital (AU)
- Middlemore Hospital (NZ)
- Auckland Clinical Studies, Auckland, New Zealand
- University of the Sunshine Coast (AU)
- NZ Clinical Research, Christchurch, New Zealand
- Arrowhead Pharmaceuticals (United States) (US)
- Arrowhead Pharmaceuticals, Inc., Pasadena, CA
- The University of Western Australia (AU)
- New York University (US)
- Stanford Medicine (US)
- Western University (CA)
- Baylor College of Medicine (US)
- ORCID
- Venue
- NEJM Evidence
- Publisher
- Massachusetts Medical Society
- Published
- 2023-11-28
- Volume
- 2
- Issue
- 12
- Pages
- EVIDoa2200325-EVIDoa2200325
- ISSN
- 2766-5526 (ISSN-L)
- OpenAlex
- W4388753588
- Cited by
- 71
- References
- 10
- Citations by year
- 2026: 21 · 2025: 23 · 2024: 23 · 2023: 4
- FWCI
- 13.95
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- NEJM Evidence (publishedVersion)
- PubMed (publishedVersion)
- 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
- apolipoprotein C-III, RNA interference therapy, hypertriglyceridemia, chylomicronemia, triglyceride clearance, lipoprotein lipase, pharmacokinetics, pharmacodynamics, liver transaminase elevation, drug safety, dose escalation, triglyceride-rich lipoproteins
- MeSH terms
- Humans, Hypertriglyceridemia, RNA Interference, Apolipoprotein C-III
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