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New Pharmacological Approaches to Target PCSK9

  • Nonstatin Drugs (M. Vrablik, Section Editor)
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Current Atherosclerosis Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Proprotein convertase subtilisin kexin 9 (PCSK9) plays a crucial role in regulating circulating levels of LDL-C as a consequence of its ability to inhibit LDL receptor recycling in the liver. Loss of function variants in the PCSK9 gene result in low LDL-C levels and associate with reduced cardiovascular risk, whereas gain of-function variants associate with hypercholesterolemia and increased risk of early cardiovascular events. Thus, PCSK9 inhibition has been established as an additional approach for the treatment of hypercholesterolemia. The aim of this review is to provide a brief overview of current strategies targeting PCSK9 and discuss clinical results of the emerging approaches.

Recent Findings

Two monoclonal antibodies targeting circulating PCSK9 (evolocumab and alirocumab) have been approved for the treatment of hypercholesterolemia and cardiovascular disease. Later, a gene silencing approach (inclisiran), which inhibits hepatic PCSK9 synthesis, was shown to be as effective as monoclonal antibodies but with a twice a year injection and is currently under evaluation for approval. Due to the elevated costs of such therapies, several other approaches have been explored, including peptide-based anti PCSK9 vaccination, and small oral PCSK9 inhibitors, which are still in preclinical phase.

Summary

In the coming years, we will assist to a progressive introduction of novel anti-PCSK9 approaches in the clinical practice for the treatment of patients with hypercholesterolemia as well as patients at high cardiovascular risk.

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Acknowledgments

Authors are supported by Fondazione Cariplo [2016-0852 to GDN]; Telethon Foundation [grant numbers GGP19146 to GDN]; PRIN 2017H5F943 to ALC, and PRIN 2017K55HLC to GDN.

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Authors and Affiliations

  1. Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy

    Alberico L. Catapano & Giuseppe D. Norata

  2. IRCCS MultiMedica, Sesto S. Giovanni, Milan, Italy

    Alberico L. Catapano & Angela Pirillo

  3. Center for the Study of Atherosclerosis, E. Bassini Hospital, Cinisello Balsamo, Milan, Italy

    Angela Pirillo & Giuseppe D. Norata

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  1. Alberico L. Catapano
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Correspondence to Giuseppe D. Norata.

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Conflict of Interest

ALC reports grants from Sanofi, Regeneron, Merck, and Mediolanum; grants from SigmaTau, Menarini, Kowa, Recordati, and Eli Lilly; personal fees from Merck, Sanofi, Regeneron, AstraZeneca, Amgen, Sigma Tau, Recordati, Aegerion, Kowa, Menarini, Eli Lilly, and Genzyme, outside the submitted work. AP has nothing to disclose. GDN reports grants from Pfizer and Amgen and personal fees from Sanofi, Amgen, Alnylam, and Novartis, outside the submitted work.

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Catapano, A.L., Pirillo, A. & Norata, G.D. New Pharmacological Approaches to Target PCSK9. Curr Atheroscler Rep 22, 24 (2020). https://doi.org/10.1007/s11883-020-00847-7

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