New developments in atherosclerosis: clinical potential of PCSK9 inhibition

Ilaria Giunzioni, Hagai Tavori Knight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health and Science University, Portland, OR, USA 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 and aversion to statins. This review will focus on the kinetics of PCSK9, pharmacokinetics and pharmacodynamics of anti-PCSK9 mAbs, and recent data linking PCSK9 and anti-PCSK9 mAbs to cardiovascular events. Moreover, it will highlight the unanswered questions that still need to be addressed in order to understand the physiologic function, kinetics, and dynamics of PCSK9. Keywords: PCSK9, LDLR, monoclonal antibodies, pharmacokinetics, cardiovascular ris

Threshold Effects of Circulating Angiopoietin-like 3 Levels on Plasma Lipoproteins

Context: Angiopoietin-like 3 (ANGPTL3) deficiency in plasma due to loss-of-function (LOF) gene mutations causes familial combined hypobetalipoproteinemia (FHBL) type 2 in homozygotes. However, the lipid phenotype in heterozygotes is much milder and does not appear to relate directly to ANGPTL3 levels. Furthermore, the low LDL phenotype in carriers of ANGPTL3 mutations is unexplained. Objective: To determine whether a reduction below a critical threshold in plasma ANGPTL3 levels is a determinant of lipoprotein metabolism in FHBL2, and to study the whether PCSK9 is involved in determining low LDL levels in this condition. Design: We studied subjects from 19 families with ANGPTL3 mutations, and subjects with FHBL type 1 due to truncated apolipoprotein B (apoB) species. Results: Total cholesterol, HDL-c, triglycerides, and HDL and LDL particle concentration correlated with plasma ANGPTL3 levels, but only when this was below 25% of normal (<60 ng/ml); (ii) VLDL particle concentration strongly correlated with plasma ANGPTL3 when this was below 58% of normal; (iii) both FHBL1 and FHBL2 subjects showed low levels of mature and LDL-bound PCSK9, and higher levels of its furin-cleaved form; and (iv) LDL-bound PCSK9 is protected from cleavage by furin, and binds to the LDL receptor more strongly compared to apoB-free PCSK9. Conclusion: Our studies suggest that the hypolipidemic effects of ANGPTL3 mutations in FHBL2 are dependent on threshold plasma ANGPTL3 levels, with differential effects on various lipoprotein particles. The increased inactivation of PCSK9 by furin in FHBL1 and FHBL2 is likely to cause increased LDL clearance and suggests novel therapeutic avenues