Volanesorsen for treatment of familial chylomicronemia syndrome

ABSTRACT

Introduction

Familial chylomicronemia syndrome (FCS) is a rare subtype of severe hypertriglyceridemia that affects ~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.

Keywords:

• antisense ribonucleic acid
• apolipoprotein C-III
• type 1 hyperlipoproteinemia
• pancreatitis
• triglycerides
• lipoprotein lipase
• multifactorial chylomicronaemia
• familial chylomicronemia syndrome

Article highlights box

• Fasting triglyceride (TG) levels >10 mmol/L are a marker for chylomicronemia; a small subset of these patients have familial chylomicronemia syndrome (FCS), which is a rare monogenic syndrome associated with complete lack of plasma lipolytic capacity.

• Severe hypertriglyceridemia is associated with an increased risk of acute pancreatitis; maintaining lower plasma TG levels (typically <5 mmol/L) attenuates the risk of pancreatitis.

• The only treatment available for FCS that shows even moderate efficacy is a low fat diet, which usually impairs the quality of life of these patients.

• Individuals with naturally occurring human genetic variants that interfere with apo C-III synthesis or secretion have reduced TG levels, which would theoretically help prevent pancreatitis in those with FCS.

• Volanesorsen is an antisense RNA drug (ASO) administered subcutaneously that knocks down apo C-III, resulting in dramatic reductions in TG levels.

• Volanesorsen’s benefits are offset by drug-induced thrombocytopenia observed in clinical trials, which appears not to be a class effect; the development of a next-generation N-acetylgalactosamine (GalNac)–conjugated ASO targeting apo C-III may eliminate this risk.

Declaration of interest

RA Hegele reports consulting fees from Acasti, Aegerion, Akcea/Ionis, Amgen, and Sanofi. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosure

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

J Lazarte is supported by the Canadian Institutes of Health Research (Doctoral Research Award) and the Schulich School of Medicine and Dentistry (Cobban Student Award in Heart and Stroke Research). RA Hegele is supported by the Jacob J. Wolfe Distinguished Medical Research Chair, the Edith Schulich Vinet Canada Research Chair in Human Genetics, the Martha G. Blackburn Chair in Cardiovascular Research, and operating grants from the Canadian Institutes of Health Research (Foundation Grant) and the Heart and Stroke Foundation of Ontario.