Proprotein convertase subtilisin/kexin 9 (PCSK9) inhibition in patients with or at high risk of coronary heart disease

Abstract

Proprotein convertase subtilisin/kexin 9 (PCSK9) is an enzyme that binds and inactivates the low-density lipoprotein (LDL) receptor onhepatocytes, leading to higher levels of serum LDL cholesterol (LDL-C). Individuals with 'loss of function' mutations in the PCSK9 gene havelower LDL-C levels and are at decreased risk of coronary heart disease. In light of this, inhibition of PCSK9 activity has become a target forreducing LDL-C levels, with approaches including monoclonal antibodies, antisense oligonucleotides, and RNA interference technology. Twomonoclonal antibodies to PCSK9, alirocumab and evolocumab, have recently been FDA approved. Although large-scale clinical trials to assesscardiovascular outcomes are awaited, reductions in LDL-C levels have been demonstrated, with no increase in muscle-related adverse effects.In addition to these monoclonal antibody approaches, inclisiran - a molecule that inhibits PCSK9 synthesis by RNA interference - is currentlyunder development. Phase 1 and 2 studies indicate an LDL-C-lowering effect comparable to that of monoclonal antibodies, with effectspersisting to as long as 180 days. Phase 3 studies are planned investigating dose administration two to three times per year. The aim of this report is to summarize the role of PCSK9 inhibition in the lowering of LDL-C. Approaches to PCSK9 inhibition are discussed, and an up-todate insight into current developments in the field is provided.