Olezarsen for hypertriglyceridemia and familial chylomicronemia syndrome: A Next-generation APOC3-targeted RNA therapy

Abstract:

Olezarsen is a next-generation N acetylgalactosamine-conjugated antisense oligonucleotide (ASO) designed to selectively suppress the synthesis of apolipoprotein C-III (ApoC-III), hence reducing triglyceride (TG)-rich lipoproteins and reducing the metabolic burden of familial chylomicronemia syndrome (FCS) and severe hypertriglyceridemia (HTG). Olezarsen achieves highly efficient ApoC-III inhibition and substantial, sustained TG lowering, simultaneously minimizing systemic exposure and related adverse eventsas observed with earlier ASO therapies. Evidence accumulated from Phase 2 and pivotal Phase 3 clinical trials, namely ESSENCE–TIMI 73b, CORE–TIMI 72a/72b, and BALANCE which established consistent ~ 50%–70% reductions in plasma TGs and 60%–80% decline in ApoC-III levels among patients with severe HTG. These lipid level improvements extend to remnant cholesterol and nonhigh-density lipoprotein cholesterol, and importantly, resulted in meaningful reductions in acute pancreatitis risk in population groups who are predisposed to recurrent episodes. Compared with conventional therapy, Olezarsen exhibits enhanced hepatoselectivity and a distinctly favorable platelet safety profile, allowing its suitability for long-term management. The once-monthly subcutaneous dosing regimen further enhances adherence potential and real-world feasibility experience. With the United States Food and Drug Administration approval granted in 2024 for the treatment of FCS, Olezarsen stands as a major evolution in precision lipid therapeutics. Regulatory review is ongoing globally for broader HTG indications. Although cardiovascular outcome data and extended postmarketing surveillance results are still awaited, present clinical evidence establishes Olezarsen as a transformative therapy for patients with FCS, severe HTG, and treatment-refractory TG elevation, efficiently addressing an unmet clinical need in reducing both metabolic risk and pancreatitis-related morbidity.