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Proprotein convertase subtilisin/kexin type 9 inhibition

Marais, David A.; Blom, Dirk J.; Petrides, Francine; Gouëffic, Yann; Lambert, Gilles

doi: 10.1097/MOL.0b013e3283587563
THERAPY AND CLINICAL TRIALS: Edited by Anton F. Stalenhoef and John Kastelein

Purpose of review There are now ample data that demonstrate that inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9) can safely lower LDL cholesterol synergistically with statins. Considering that PCSK9 was first identified less than a decade ago, the last few years have shown rapid and remarkable advancements in our understanding and knowledge of the structure and function of PCSK9.

Recent findings Therapeutic developments have not lagged far behind with some monoclonal antibodies currently entering phase III trials. Of the many approaches to PCSK9 inhibition, these compounds are the furthest advanced in their clinical development while small molecule oral inhibitors seem a distant prospect.

Summary This review summarizes the discovery and history of PCSK9 and in particular its mode of action as an inhibitor of the LDL receptor. It also recapitulates key studies that have demonstrated the potential of inhibiting PCSK9 to further decrease LDL-cholesterol levels safely and synergistically with statins. Finally, we review the strategies that are currently in development to inhibit PCSK9, with a special emphasis on the spectacular results from recent phase-I and phase-II clinical trials.

aDepartment of Chemical Pathology

bDepartment of Medicine, University of Cape Town, Cape Town, South Africa

cThe Heart Research Institute, Lipid Research Group, Sydney, New South Wales, Australia

dCHU Nantes, I’Institut du Thorax, Service de Chirurgie Vasculaire

eFaculté de Médecine, Université de Nantes

fLaboratoire Inserm UMR957, Nantes, France

Correspondence to Gilles Lambert, Laboratoire Inserm UMR957, Faculté de Médecine, 1 Rue Gaston Veil, 44000 Nantes, France. Tel: +33 2 4041 2960; fax: +33 2 4041 2860; e-mail:

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