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Olezarsen for Hypertriglyceridemia in Patients at High Cardiovascular Risk
Brian A Bergmark1, Nicholas A Marston1, Thomas A Prohaska1
1From the TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston (B.A.B., N.A.M., A.Z., F.A.M., S.A.M., E.L.G., S.Z., R.P.G., M.S.S.); Ionis Pharmaceuticals, Carlsbad (T.A.P., V.J.A., E.K.-P., S.T.), and the Division of Cardiovascular Medicine, Department of Medicine, University of California, San Diego, La Jolla (S.T.) - both in California; and the Department of Medicine, Université de Montréal and Ecogene-21 Clinical Research Centre, Quebec, QC, Canada (D.G.).
Background:
Reducing the levels of triglycerides and triglyceride-rich lipoproteins remains an unmet clinical need. Olezarsen is an antisense oligonucleotide targeting messenger RNA for apolipoprotein C-III (APOC3), a genetically validated target for triglyceride lowering.
Methods:
In this phase 2b, randomized, controlled trial, we assigned adults either with moderate hypertriglyceridemia (triglyceride level, 150 to 499 mg per deciliter) and elevated cardiovascular risk or with severe hypertriglyceridemia (triglyceride level, ≥500 mg per deciliter) in a 1:1 ratio to either a 50-mg or 80-mg cohort. Patients were then assigned in a 3:1 ratio to receive monthly subcutaneous olezarsen or matching placebo within each cohort. The primary outcome was the percent change in the triglyceride level from baseline to 6 months, reported as the difference between each olezarsen group and placebo. Key secondary outcomes were changes in levels of APOC3, apolipoprotein B, non-high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol.
Results:
A total of 154 patients underwent randomization at 24 sites in North America. The median age of the patients was 62 years, and the median triglyceride level was 241.5 mg per deciliter. The 50-mg and 80-mg doses of olezarsen reduced triglyceride levels by 49.3 percentage points and 53.1 percentage points, respectively, as compared with placebo (P<0.001 for both comparisons). As compared with placebo, each dose of olezarsen also significantly reduced the levels of APOC3, apolipoprotein B, and non-HDL cholesterol, with no significant change in the LDL cholesterol level. The risks of adverse events and serious adverse events were similar in the three groups. Clinically meaningful hepatic, renal, or platelet abnormalities were uncommon, with similar risks in the three groups.
Conclusions:
In patients with predominantly moderate hypertriglyceridemia at elevated cardiovascular risk, olezarsen significantly reduced levels of triglycerides, apolipoprotein B, and non-HDL cholesterol, with no major safety concerns identified. (Funded by Ionis Pharmaceuticals; Bridge-TIMI 73a ClinicalTrials.gov number, NCT05355402.).
Insights
Olezarsen effectively lowers triglyceride and apolipoprotein C-III levels in patients with hypertriglyceridemia. This study demonstrated significant triglyceride reduction with no major safety concerns, addressing an unmet clinical need.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
- Genetics
Background:
- Elevated triglycerides and triglyceride-rich lipoproteins represent a significant unmet clinical need.
- Apolipoprotein C-III (APOC3) is a validated genetic target for lowering triglycerides.
- Olezarsen is an antisense oligonucleotide designed to reduce APOC3 mRNA levels.
Purpose of the Study:
- To evaluate the efficacy and safety of olezarsen in adults with moderate or severe hypertriglyceridemia.
- To assess the impact of olezarsen on triglyceride levels and other lipid parameters.
Main Methods:
- A phase 2b, randomized, controlled trial involving 154 adults with hypertriglyceridemia.
- Participants were assigned to monthly subcutaneous olezarsen (50 mg or 80 mg) or placebo.
- Primary outcome: percent change in triglyceride level from baseline to 6 months.
Main Results:
- Olezarsen (50 mg and 80 mg) significantly reduced triglyceride levels by 49.3% and 53.1%, respectively, compared to placebo (P<0.001).
- Both doses significantly decreased APOC3, apolipoprotein B, and non-HDL cholesterol levels.
- Adverse events and serious adverse events were similar across groups; no major safety concerns were identified.
Conclusions:
- Olezarsen demonstrated significant efficacy in reducing triglycerides, apolipoprotein B, and non-HDL cholesterol in patients with hypertriglyceridemia.
- The treatment was well-tolerated with no major safety concerns identified.
- Olezarsen represents a promising therapeutic option for managing hypertriglyceridemia.
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