Evaluation of efficacy and safety of antisense inhibition of apolipoprotein C-III with volanesorsen in patients with severe hypertriglyceridemia

ABSTRACT

Introduction

Severe hypertriglyceridemia (sHTG) is a complex disorder of lipid metabolism characterized by plasma levels of triglyceride (TG) greater than 885 mg/dl (>10 mmol/L). The treatment of sHTG syndromes is challenging because conventional treatments are often ineffective in reducing TG under the threshold to prevent acute pancreatitis (AP). The inhibition of APOC3, which encodes a protein involved in triglyceride (TG)-rich lipoproteins (TGRLs) removal, has been reported to be a novel target for the treatment of sHTG. Volanesorsen is a second-generation antisense oligonucleotide inhibiting apoC-III transcription/translation that has been recently approved in Europe for Familial Chylomicronemia Syndrome (FCS) treatment.

Areas covered

This review summarizes the evidences on the efficacy and safety of volanesorsen for the treatment of sHTG syndromes.

Expert opinion

Volanesorsen effectively reduces TG in sHTG through a mechanism that is mainly LPL-independent, potentially decreasing the risk of AP. Some safety concerns have been raised with the use of volanesorsen, mainly represented by the occurrence of thrombocytopenia. Due to the potential severity of side effects, some caution is needed before affirming the long-term utility of this drug. Despite this, volanesorsen currently remains the only drug that has been demonstrated effective in FCS, which otherwise remains an untreatable disease.

KEYWORDS:

• Apo c-III
• antisense oligonucleotides
• clinical trials
• familial chylomicronemia syndrome
• severe hypertriglyceridemia
• orphan drug
• treatment
• volanesorsen

Box 1. Drug summary box

Table

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Declaration of interest

L D’Erasmo has received personal fees for public speaking, consultancy, and/or grant support from Amryt Pharma, Akcea Therapeutics, Pfizer Inc, and Sanofi. M Arca has received research grant support from Amryt Pharma, Amgen Inc, Ionis, Akcea Therapeutics, Pfizer Inc, and Sanofi. He has also served as a consultant for Amgen Inc, Aegerion, Akcea Therapeutics, Regeneron, Sanofi, and Alfasigma and has received lecturing fees from Amgen Inc, Amryt Pharma, Pfizer Inc, Sanofi, and Alfasigma. A Gallo has received personal fees from public speaking or consultancy support from Akcea Therapeutics, Amgen Inc, Novartis, Sanofi, Regeneron, and Unilever. Finally, E Bruckert has received honoraria from Amgen Inc, Merck Sharp and Dohme, Sanofi, Regeneron, Unilever, Danone, Aegerion, Chiesi Farmaceutici Rattapharm-Meda, Servier, Ionis Pharmaceuticals, Akcea Therapeutics, and Mylan. 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 disclosures

One referee was a site investigator for Akcea Therapeutics and Regeneron while another referee was a consultant for Akcea Therapeutics and 89bio. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This manuscript has not been funded.