Assessing Therapeutic Options in FCS Management

APOC3 inhibition has emerged as a central therapeutic strategy for familial chylomicronemia syndrome despite the underlying defect in lipoprotein lipase activity. In their discussion, Anthony Giamo, MD, and Nihar R. Desai, MD, outline how olezarsen, an antisense oligonucleotide, and plozasiran, a small interfering RNA, both reduce APOC3 expression, thereby relieving inhibition of lipase pathways. Although FCS patients have severely impaired or absent lipoprotein lipase function, APOC3 inhibition still produces robust triglyceride reductions, likely through enhanced activity of alternative lipases such as hepatic lipase and improved chylomicron clearance.

The faculty review data from pivotal trials—Balance for olezarsen and Palisade for plozasiran—demonstrating dramatic triglyceride lowering in patients with FCS. Giamo notes that, in PALISADE, nearly all plozasiran‑treated patients experienced substantial triglyceride reductions, whereas in BALANCE a large majority, though not all, patients receiving olezarsen responded. These findings support APOC3 inhibition as a foundational pharmacologic approach in FCS, moving beyond purely dietary and symptomatic management toward targeted correction of the chylomicronemia state.

Desai further discusses a Monte Carlo simulation that applied the observed trial‑based triglyceride reductions from olezarsen and plozasiran to simulated FCS populations with varying baseline triglyceride distributions. Across multiple time points and sensitivity analyses, plozasiran‑treated cohorts were more likely to achieve triglyceride levels less than 500 mg/dL—a threshold associated with attenuation of pancreatitis risk—than olezarsen‑treated cohorts. Although the experts acknowledge the absence of head‑to‑head randomized comparisons, they suggest that such simulation data, combined with trial results, can inform therapeutic selection in clinical practice.