Volanesorsen for treatment of familial chylomicronemia syndrome

Introduction: Familial chylomicronemia syndrome (FCS) is a rare subtype of severe hypertriglyceridemia that affects similar to 1 in 100, 000 to 1,000,000 individuals. The major risk to health is acute pancreatitis. FCS is defined by biallelic loss-of-function mutations in one of five canonical genes that encode proteins critical to lipolysis of large triglyceride-rich lipoprotein particles. Unlike the vast majority of patients with severe hypertriglyceridemia, FCS patients lack any lipolytic capacity and are thus resistant to standard medications. Areas covered: This review focuses on a mechanism that effectively reduces elevated triglyceride levels in FCS, namely interference of synthesis of apolipoprotein (apo) C-III. Volanesorsen is an antisense RNA drug administered subcutaneously that knocks down apo C-III, resulting in dramatic reductions in triglyceride levels both in FCS patients and in the wider population of subjects with severe hypertriglyceridemia. Expert opinion: Volanesorsen is a highly effective treatment to reduce elevated triglycerides in FCS patients, providing proof-of-concept of the validity of targeting apo C-III. However, off target effects of volanesorsen, including thrombocytopenia, may ultimately limit its use. Nonetheless, building on the knowledge derived from the volanesorsen experience, there is intensified interest in promising newer agents that also target apo C-III but have technical modifications that limit potential off target adverse effects.

Automated summary

FCS is a rare subtype of severe hypertriglyceridemia caused by genetic mutations, resulting in a lack of lipolytic capacity in patients. Volanesorsen is an effective treatment that reduces triglyceride levels by interfering with apo C-III synthesis. However, off-target effects, such as thrombocytopenia, may limit its use, leading to the search for newer agents targeting apo C-III with fewer adverse effects.