Progress and prospects of biological approaches targeting PCSK9 for cholesterol-lowering, from molecular mechanism to clinical efficacy

ABSTRACT

Introduction

Cardiovascular disorders are one of the leading causes of mortality and morbidity worldwide. Recent advances showed a promising role of proprotein convertase subtilisin/kexin type 9 (PCSK9) as a critical player in regulating plasma LDL levels and lipid metabolism.

Areas covered

This review addresses the molecular functions of PCSK9 with a vision on the clinical progress of utilizing monoclonal antibodies and other biological approaches to block PCSK9 activity. The successful clinical trials with monoclonal antibodies are reviewed. Recent advances in (pre)clinical trials of other biological approaches, such as small interfering RNAs, are also discussed.

Expert opinion

Discovery of PCSK9 and clinical use of its inhibitors to manage lipid metabolism is a step forward in hypolipidaemic therapy. A better understanding of the molecular activity of PCSK9 can help to identify new approaches in the inhibition of PCSK9 expression/activity. Whether if PCSK9 plays a role in other cardiometabolic conditions may provide grounds for further development of therapies.

KEYWORDS:

• PCSK9
• monoclonal antibodies
• cholesterol-lowering
• metabolic regulation

Article highlights

• PCSK9 is a small protein produced mainly by hepatocytes, which has a crucial role in modulating the clearance of LDL from plasma.

• The LDL receptors (LDLR) that have PCSK9 bound will be degraded in lysosomes, and this reduction of LDLR increases the levels of LDL in plasma.

• Blocking PCSK9 either in function (with monoclonal antibodies) or at its expression level (with small RNAs or other biological agents) can significantly reduce the plasmatic LDL-C levels and, therefore, cardiovascular risks.

• The translation from bench to clinical usage of monoclonal antibodies to block PCSK9 is one of the fastest in the history of drug development, due to its efficient and specific function on LDLR turnover.

This box summarizes key points contained in the article.

Declaration of interest

AL Catapano has received honoraria, lecture fees, or research grants from: Akcea, Amgen, Astrazeneca, Eli Lilly, Genzyme, Kowa, Mediolanum, Menarini, Merck, Pfizer, Recordati, Sanofi, Sigma Tau, Medco and Amryt. 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

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

Additional information

Funding

The work of AL Catapano cited in this paper is supported in part by: Fondazione Cariplo [2015-0524 and 2015-0564]; H2020 REPROGRAM [PHC-03-2015/667837-2]; ERANET ER-2017-2364981; PRIN 2017H5F943; Ministry of Health-IRCCS MultiMedica [GR-2011-02346974]; SISA Lombardia and Fondazione SISA; European Union’s Horizon 2020 research and innovation program under the [ERA-Net Cofund action N° 727565 (OCTOPUS project)]. This work has been supported by funds from the Italian Ministry of Health to IRCCS Multimedica (Ricerca Corrente).