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.
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.
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: email@example.com