What is the recommended use of Olezarsen (investigational drug) for treatment?

Olezarsen for Treatment of Hypertriglyceridemia

Olezarsen is recommended for patients with moderate to severe hypertriglyceridemia (triglyceride levels ≥200 mg/dL) who are at high cardiovascular risk, with dosing of 50-80 mg subcutaneously every 4 weeks. 1

Mechanism of Action and Efficacy

• Olezarsen is an antisense oligonucleotide (ASO) that targets messenger RNA for apolipoprotein C-III (apoC-III), which is an inhibitor of triglyceride clearance 2
• In clinical trials, olezarsen demonstrated significant triglyceride reduction of 49-60% compared to placebo in patients with moderate hypertriglyceridemia 1, 3
• The medication shows dose-dependent effects, with 50 mg and 80 mg monthly doses providing similar efficacy in reducing triglyceride levels 1

Patient Selection Criteria

• Primary candidates are patients with moderate hypertriglyceridemia (triglyceride levels 200-499 mg/dL) plus increased cardiovascular risk 2, 1
• Also appropriate for patients with severe hypertriglyceridemia (triglyceride levels ≥500 mg/dL) 2, 1
• Most beneficial for patients already on standard lipid-lowering therapies (such as statins) who have not achieved adequate triglyceride control 2

Dosing Recommendations

• The recommended dosage is either 50 mg or 80 mg administered subcutaneously every 4 weeks 1
• Both doses show similar efficacy, with the 50 mg dose reducing triglycerides by 49.3 percentage points and the 80 mg dose by 53.1 percentage points compared to placebo 1
• Administration is via subcutaneous injection 1, 3

Clinical Benefits Beyond Triglyceride Lowering

• Significantly reduces levels of apoC-III, apolipoprotein B, and non-HDL cholesterol 1
• Improves overall atherogenic risk profile by reducing triglyceride-rich lipoprotein particles (TRL-P) by 51% 4
• Remodels lipoprotein particle distribution, increasing large LDL particles by 186% and decreasing small LDL particles by 39% 4
• Increases total HDL particle concentration by 15%, primarily through increases in small HDL subspecies 4

Safety Profile

• Clinical trials showed similar rates of adverse events and serious adverse events between olezarsen and placebo groups 1
• Most common adverse event is mild erythema at the injection site 3
• No significant concerns regarding hepatic, renal, or platelet abnormalities were identified in clinical trials 1, 3
• Well-tolerated in ethnically diverse populations, including Japanese Americans 5

Monitoring Recommendations

• Baseline and follow-up lipid profile including triglycerides, apoB, and non-HDL cholesterol 1
• Monitor for injection site reactions 3
• No specific additional monitoring requirements have been identified based on current evidence 1

Potential Advantages Over Other Triglyceride-Lowering Therapies

• Provides more substantial triglyceride reduction (49-60%) than currently available therapies 1, 3
• Monthly dosing schedule may improve adherence compared to daily oral medications 1
• Targets a genetically validated pathway for triglyceride reduction 1
• Does not affect LDL cholesterol levels, making it complementary to statin therapy 1

Clinical Trial Evidence

• The Bridge-TIMI 73a trial demonstrated significant triglyceride reduction in patients with predominantly moderate hypertriglyceridemia at elevated cardiovascular risk 1
• The Essence-TIMI 73b trial is ongoing and has enrolled nearly 1,500 patients to further evaluate efficacy and safety 2
• This trial includes a coronary computed tomography angiography substudy that will examine changes in noncalcified plaque volume, potentially providing insights into effects on atherosclerosis 2

Olezarsen represents a promising new approach for patients with hypertriglyceridemia who remain at elevated cardiovascular risk despite conventional therapies, with robust triglyceride-lowering efficacy and a favorable safety profile based on current evidence.