Despite existing cholesterol-lowering therapies, a significant percentage of patients fail to reach guideline-recommended LDL cholesterol levels. New pharmacological option, such as Olezarsen, offer promising approaches by targeting specific lipid pathways, improving lipid profiles, and reducing cardiovascular risk in different shades of the dyslipidemias. As research advances, these innovations may pave the way for more effective and personalized lipid management strategies.

Background

Cholesterol-lowering drugs have evolved significantly, offering reductions of over 50% in LDL cholesterol with traditional oral statins and up to 70% with injectable biotechnological drugs like PCSK9 inhibitors. Despite these advances, studies such as DA VINCI and SANTORINI reveal that only 20% of patients achieve LDL cholesterol levels recommended by guidelines. To address this gap, several new pharmacological options are being tested and are on the verge of receiving regulatory approval for the treatment of combined dyslipidemia (https://www.ittbiomed.com/zoldasiran-and-plozasiran-a-new-future-for-familial-combined-hyperlipidemia/). Some of these innovations focus on specific lipid targets, such as Apolipoprotein C-III (ApoC-III), highlighting the importance of individualized treatment approaches.

Summary of the Findings

One promising advancement in lipid management is Olezarsen, an antisense oligonucleotide (ASO) designed to lower ApoC-III levels, a key regulator of triglyceride metabolism. Elevated ApoC-III is associated with hypertriglyceridemia and an increased risk of cardiovascular disease. Clinical trials have demonstrated that Olezarsen can significantly reduce triglyceride levels, making it a potential game-changer for patients with dyslipidemia, particularly those with severe hypertriglyceridemia and mixed lipid disorders. This new drug has shown significant lipid-lowering effects in patients with atherosclerosis, including those with genetic hypercholesterolemia. The efficacy and safety of Olezarsen have been evaluated in a randomized, placebo-controlled, double-blind clinical trial (NCT04568434), which led to FDA approval in late 2024 with Priority Review, Fast Track, Breakthrough Therapy, and Orphan Drug designations for this indication. This trial was conducted in 66 adult patients with familial chylomicronemia syndrome (FCS) and fasting triglyceride (TG) levels of at least 880 mg/dL. The primary endpoint of the study was the percent change in fasting TG levels from baseline to month 6 (average of weeks 23, 25, and 27) compared to placebo. Olezarsen resulted in a reduction of more than 40% from baseline, as compared to the control group. The reduction in triglyceride levels was confirmed and remained stable for a total period of 12 months.

Novelty of the Results in the Field

Olezarsen represents a novel approach in lipid management by selectively targeting ApoC-III, a previously underutilized but crucial regulator of triglyceride metabolism. Its efficacy in lowering triglycerides marks a significant step forward in managing hypertriglyceridemia and reducing cardiovascular risk. These new therapies signal a shift toward more targeted, precision-based lipid-lowering strategies, moving beyond broad-spectrum statin use to more individualized approaches. This study further opens the stage for the new anti-ApoC-III therapies currently under evaluation by the FDA.

By Lorenzo Da Dalt, Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, University of Milan.

Link and doi of the publication:

doi:10.1056/NEJMoa2402309