Experimental therapies targeting apolipoprotein C-III for the treatment of hyperlipidemia – spotlight on volanesorsen

ABSTRACT

Introduction: Despite the substantial reduction in cardiovascular morbidity and mortality after the management of dyslipidemia with statins, residual risk remains even after achieving low-density lipoprotein cholesterol targets. This residual risk appears to be partly attributed to low levels of high-density lipoprotein cholesterol (HDL-C) and high levels of triglycerides (TG). Apolipoprotein C3 (APOC3) is a key regulator of TG metabolism and its targeting may reduce TG levels and cardiovascular risk.

Areas covered: We discuss APOC3-targeted experimental treatments for dyslipidemia. There is an emphasis on volanesorsen because it the agent in the most advanced stage of development. M580, a retinoic acid receptor-α specific agonist, an agent in early-stage development is briefly covered. Preclinical data suggest that this agent decreases APOC3 mRNA levels and reduces total cholesterol, TG levels and hepatic lipid accumulation.

Expert opinion: The effects of this novel therapeutic approach on cardiovascular morbidity and mortality should be determined in randomized controlled trials. The cost of volanesorsen, the unfavorable safety profile and the need for subcutaneous administration present barriers to long-term use. AM580 may hold promise in the management of hypertriglyceridemia but further investigations are necessary to evaluate safety and efficacy.

Trial registration: ClinicalTrials.gov identifier: NCT02527343.

KEYWORDS:

• Apolipoprotein C3
• volanesorsen
• residual risk
• triglycerides
• very-low density lipoproteins
• AM580

Article Highlights

• Elevated triglyceride (TG) levels appear to be associated with increased cardiovascular risk

• Apolipoprotein C3 (APOC3) is a key regulator of TG metabolism

• Loss of function mutations in the gene encoding APOC3 are associated with lower TG levels and lower risk for cardiovascular events

• Volanesorsen, an antisense oligonucleotide inhibiting apolipoprotein C3, is the APOC3 inhibitor in the most advanced stage of development and induces substantial reductions in TG levels

• Volanesorsen also appears to increase high-density lipoprotein cholesterol levels and to improve insulin sensitivity

• Preliminary preclinical data suggest that AM580, a retinoic acid receptor-α specific agonist, also decreases APOC3 mRNA and protein levels resulting in a reduction in total cholesterol and TG levels as well as in body weight and hepatic lipid accumulation

• Larger studies are needed to evaluate the safety of volanesorsen in patients with hypertriglyceridemia and to assess its effects on cardiovascular morbidity and mortality

• More studies are also needed to evaluate the safety and efficacy of AM580

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Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

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

Additional information

Funding

This paper was not funded.