Olezarsen for Managing Severe Hypertriglyceridemia and Pancreatitis Risk.

Area of Science:

• Cardiovascular Medicine
• Pharmacology
• Genetics

Background:

• Severe hypertriglyceridemia poses a significant risk for acute pancreatitis.
• The therapeutic potential of olezarsen, an antisense oligonucleotide targeting apolipoprotein C-III mRNA, remains under investigation for this patient group.

Purpose of the Study:

• To evaluate the efficacy and safety of olezarsen in patients with severe hypertriglyceridemia.
• To assess olezarsen's impact on triglyceride levels, lipid profiles, and acute pancreatitis incidence.

Main Methods:

• Two double-blind, randomized, placebo-controlled trials (CORE-TIMI 72a and CORE2-TIMI 72b) were conducted.
• 1061 patients received monthly olezarsen (50 mg or 80 mg) or placebo for 12 months.
• Primary outcome: percent change in triglyceride level at 6 months; secondary outcomes: lipid changes and pancreatitis events.

Main Results:

• Olezarsen demonstrated significant placebo-adjusted reductions in triglyceride levels at 6 months (up to -72.2%) and 12 months.
• Decreases were observed in apolipoprotein C-III, remnant cholesterol, and non-HDL cholesterol levels with olezarsen.
• The incidence of acute pancreatitis was significantly lower with olezarsen (rate ratio 0.15; P<0.001).

Conclusions:

• Olezarsen treatment resulted in significant triglyceride reduction and decreased acute pancreatitis incidence in severe hypertriglyceridemia patients.
• While generally well-tolerated, the 80 mg dose showed increased liver enzyme elevations and thrombocytopenia.
• A dose-dependent increase in hepatic fat fraction was noted with olezarsen.