For patients with severe hypertriglyceridemia, monthly treatment with olezarsen significantly reduced triglyceride levels and the incidence of acute pancreatitis compared with placebo, according to findings from two pivotal trials, CORE-TIMI 72a and CORE2-TIMI 72b.¹
Olezarsen is an antisense oligonucleotide designed to inhibit the production of apolipoprotein C-III (ApoC-III), a key protein in the regulation of triglyceride metabolism. By targeting ApoC-III messenger RNA, the therapy aims to lower triglyceride levels and associated clinical risks.
The analysis combined data from two double-blind, randomised, placebo-controlled trials involving 1,061 patients with severe hypertriglyceridemia. Participants were assigned in a 1:1:1 ratio to receive monthly subcutaneous injections of olezarsen 50 mg, olezarsen 80 mg, or a matching placebo for 12 months.
The primary outcome was the placebo-adjusted percent change from baseline in triglyceride levels at six months. Secondary outcomes included the change in triglycerides at 12 months, as well as changes in levels of ApoC-III, remnant cholesterol, and non-high-density lipoprotein (non-HDL) cholesterol at six and 12 months. The incidence of acute pancreatitis was a key clinical outcome assessed across both trials.
At six months, olezarsen demonstrated a significant reduction in triglyceride levels. In the CORE-TIMI 72a trial, the placebo-adjusted least-squares mean change from baseline was -62.9 percentage points for the 50 mg group and -72.2 percentage points for the 80 mg group. In the CORE2-TIMI 72b trial, the reductions were -49.2 and -54.5 percentage points for the 50 mg and 80 mg groups, respectively (p<0.001 for all comparisons).¹
These reductions were sustained at 12 months, with olezarsen also showing greater decreases in ApoC-III, remnant cholesterol, and non-HDL cholesterol compared to placebo (p<0.001 for all). Clinically, the incidence of acute pancreatitis was substantially lower in the combined olezarsen groups than in the placebo group (mean rate ratio, 0.15; 95% CI, 0.05 to 0.40; p<0.001).
The overall incidence of adverse events was similar across all groups. However, elevations in liver enzymes and thrombocytopenia were more common with the 80 mg dose of olezarsen, and a dose-dependent increase in hepatic fat fraction was noted.
The findings from these trials suggest that targeting ApoC-III with olezarsen is an effective strategy for managing severe hypertriglyceridemia. The investigators concluded that:
> Among patients with severe hypertriglyceridemia, treatment with olezarsen led to a significantly greater reduction in the triglyceride level at 6 months and in the incidence of acute pancreatitis than placebo.¹
This study was funded by Ionis Pharmaceuticals.
References
1. Marston NA, Bergmark BA, Alexander VJ, et al. Olezarsen for Managing Severe Hypertriglyceridemia and Pancreatitis Risk. N Engl J Med 2025. https://doi.org/10.1056/NEJMoa2512761.
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