Emerging biologic therapies for hypercholesterolaemia

ABSTRACT

Introduction: LDL-cholesterol (LDL-C) is one of the most well-established risk factors for CV disease. Indeed, therapies that decrease LDL-C are proven to effectively reduce the risk of atherosclerotic CV disease. Monoclonal antibodies (mAbs) that target proprotein convertase subtilisin/kexin type 9 (PCSK9) have recently gained traction as a promising therapeutic strategy.

Areas covered: In this review, the authors discuss the effectiveness of mAbs against PCSK9 in lowering low-density lipoprotein cholesterol (LDL-C) and other atherogenic lipid fractions. The discontinuation in the development of bococizumab due to efficacy and safety concerns, and the initial promising data about inclisiran, a long-acting small inhibiting RNA molecule against PCSK9 synthesis, is also discussed.

Expert opinion: Initial data about cardiovascular (CV) outcomes in large scale, long-term studies suggest a possible further therapeutic pathway for LDL-C reduction, and currently support the notion that further LDL-C reduction, obtained with PCSK9 inhibition on top of best available therapy, provides increased CV protection in subjects at very high CV risk. The development and marketing of mAbs against PCSK9 could help to redefine current therapeutic strategies aimed at reducing cardiovascular (CV) morbidity and risk, through the reduction of LDL-C concentrations. The cost-effectiveness of these emerging drugs is yet to be established.

KEYWORDS:

• Hypercholesterolemia
• dyslipidemia
• biologic therapy
• proprotein convertase subtilisin/kexin type 9 inhibitors
• alirocumab
• evolocumab
• LDL cholesterol
• lipoproteins
• cardiovascular disease
• cardiovascular risk
• PCSK9

Article highlights

• Anti-PCSK9 inhibitors represent the most recent development in the treatment of severe hypercholesterolemia

• Alirocumab and evolocumab are overall safe, optimally tolerated and efficacious in a large kind of high-risk patients

• Anti-PCSK9 inhibitors are able to dramatically reduce LDL-C in statin and ezetimibe treated patients, so being useful in reaching the desired LDL-C target in high and very high risk patients

• PCKS9 inhibitors are also able to significantly reduce serum Total and non-HDL cholesterol, ApoB, Lipoprotein(a) and Triglycerides, and increase HDL-cholesterol and Apolipoprotein A1 levels.

• The cost:efficacy ratio of PCKS9 inhibitors has yet to be clearly defined.

This box summarizes key points contained in the article.

Acknowledgments

The authors would express their profound gratitude to Professor Giuseppe Schillaci, who substantially and brilliantly contributed to the preparation of the present manuscript, and prematurely passed away before its publication. The present article is dedicated to his memory.

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.

Additional information

Funding

The position of Giacomo Pucci as an Adjunct Assistant Professor at the University of Perugia is funded by a grant from the Fondazione Cassa di Risparmio di Terni e Narni, Italy.