New developments in atherosclerosis: clinical potential of PCSK9 inhibition

Vascular Health and Risk Management
Ilaria Giunzioni, Hagai Tavori

Abstract

Pro-protein convertase subtilisin/kexin type 9 (PCSK9) is a secreted 692-amino acid protein that binds surface low-density lipoprotein (LDL) receptor (LDLR) and targets it toward lysosomal degradation. As a consequence, the number of LDLRs at the cell surface is decreased, and LDL-cholesterol (LDL-C) clearance is reduced, a phenomenon that is magnified by gain-of-function mutations of PCSK9. In contrast, loss-of-function mutations of PCSK9 result in increased surface LDLR and improved LDL-C clearance. This provides the rationale for targeting PCSK9 in hypercholesterolemic subjects as a means to lower LDL-C levels. Monoclonal antibodies (mAbs) against PCSK9 that block its interaction with the LDLR have been developed in the past decade. Two companies have recently received the approval for their anti-PCSK9 mAbs by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) Regeneron/Sanofi, with alirocumab (commercial name--PRALUENT(®)) and, Amgen with evolocumab (commercial name--Repatha™). The introduction of anti-PCSK9 mAbs will provide an alternative therapeutic strategy to address many of the unmet needs of current lipid-lowering therapies, such as inability to achieve goal LDL-C level, or intolerance ...Continue Reading

Citations

Mar 31, 2016·Biopharmaceutics & Drug Disposition·Harvey Wong, Matthew R Wright
Jul 31, 2018·Hormone Molecular Biology and Clinical Investigation·Mohsen KhosraviMohammad Najafi

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Methods Mentioned

BETA
transgenic

Clinical Trials Mentioned

NCT01764633
NCT01663402
NCT01975376
NCT01975389
NCT02207634

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