Journal article
RNA Interference Therapy Targeting Apolipoprotein C-III in Hypertriglyceridemia
NEJM Evidence, Vol.2(12), pp.1-15
2023
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 participant and 3 patients with hypertriglyceridemia). These events were asymptomatic, and transaminase levels returned to near baseline by the end of the trial. No AEs related to thrombocytopenia or platelet declines were reported. In the hypertriglyceridemia cohorts, the day 113 mean changes from baseline in APOC3 at the 10-, 25-, 50-, and 100-mg doses were −62.0%, −81.7%, −90.1%, and −94.4%, respectively, compared with −1.6% with placebo. This corresponded to median changes in triglyceride levels of −65.6%, −69.9%, −81.2%, and −81.0% compared with −2.8% with placebo.
CONCLUSIONS:
In this small trial of short duration, ARO-APOC3 was associated with few AEs and reduced serum levels of APOC3 and triglycerides in healthy participants and patients with hypertriglyceridemia.
Details
- Title
- RNA Interference Therapy Targeting Apolipoprotein C-III in Hypertriglyceridemia
- Authors
- Davide Gaudet (Corresponding Author) - Université de MontréalPeter M Clifton (Author) - Royal Adelaide HospitalDavid Sullivan (Author) - Royal Prince Alfred HospitalJohn Baker (Author) - Middlemore HospitalChristian Schwabe (Author) - New Zealand Clinical ResearchSusan Thackwray (Author) - University of the Sunshine Coast, Queensland, School of Health and Sport Sciences - LegacyRussell Scott (Author) - New Zealand Clinical ResearchJames Hamilton (Author) - Arrowhead PharmaceuticalsBruce Given (Author) - Arrowhead PharmaceuticalsStacey Melquist (Author) - Arrowhead PharmaceuticalsRong Zhou (Author) - Arrowhead PharmaceuticalsTing Chang (Author) - Arrowhead PharmaceuticalsJavier San Martin (Author) - Arrowhead PharmaceuticalsGerald F Watts (Author) - University of Western AustraliaIra J Goldberg (Author) - New York UniversityJoshua W Knowles (Author) - Stanford MedicineRobert A Hegele (Author) - Western UniversityChristie M Ballantyne (Author) - Baylor College of Medicine
- Publication details
- NEJM Evidence, Vol.2(12), pp.1-15
- Publisher
- Massachusetts Medical Society
- DOI
- 10.1056/EVIDoa2200325
- ISSN
- 2766-5526
- Data Availability
- A data sharing statement provided by the authors is available with the full text of this article.
- Grant note
- Funded by Arrowhead Pharmaceuticals, Inc.; ClinicalTrials.gov number, NCT03783377
- Organisation Unit
- School of Health and Sport Sciences - Legacy
- Language
- English
- Record Identifier
- 99982896602621
- Output Type
- Journal article
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