Clinical considerations for the treatment of patients with familial chylomicronemia syndrome using a hepatic-targeted APOC3 antisense oligonucleotide

Familial chylomicronemia syndrome (FCS) is a rare, typically debilitating genetic disorder of extreme hypertriglyceridemia associated with high triglyceride levels and elevated risk for recurrent acute pancreatitis. Diagnosis of FCS is frequently delayed due to its rarity, and treatment options are limited. Patients often report history of acute pancreatitis or associated symptoms, including chronic or recurrent abdominal pain, weakness, and fatigue. The hallmark of chylomicronemia (extreme hypertriglyceridemia) syndromes, including FCS, is extremely high triglyceride levels ≥880 mg/dL (10 mmol/L) resistant to conventional triglyceride-lowering medications including statins, fibrates, and omega-3 fatty acids. Validated clinical scoring tools or genetic testing can support diagnosis. Patients must follow a strict FCS-specific diet <15 to 20 g fat/day. Failure to adhere increases the possibility of recurrent acute and chronic pancreatitis and pancreatic dysfunction. Dietary adherence and long-term disease management are extremely challenging for patients. Multidisciplinary clinical teams can improve patient outcomes and quality of life. Therapies that reduce apolipoprotein C-III, a regulator of triglyceride metabolism, offer an FCS treatment option. Olezarsen, a hepatic-targeted APOC3 antisense oligonucleotide, is the first US Food and Drug Administration–approved therapy specifically for FCS treatment, indicated as an adjunct to diet to reduce triglycerides in adult patients with FCS; olezarsen is also European Medicines Agency-approved. Combining olezarsen with the low-fat FCS diet may prevent acute pancreatitis and improve long-term patient outcomes. Plozasiran, a small interfering RNA therapy targeting APOC3 , is in late-stage clinical development. This article describes the updated diagnosis and clinical management of FCS and practical considerations for APOC3 -targeting treatment.