Targeting low‐density lipoprotein cholesterol with PCSK9 inhibitors

Abstract

Over the past quarter century, clinical trials have consistently demonstrated that lowering levels of low-density lipoprotein cholesterol (LDL-C) with statins reduces the rate of major adverse cardiovascular events. However, the findings that many patients continue to experience events or harbour inappropriately high LDL-C levels despite intensive statin therapy and the clinical reality of statin intolerance suggests that additional therapeutic strategies are required in order to achieve more effective reductions in cardiovascular risk. The emergence of inhibitory monoclonal antibodies targeted against proprotein convertase subtilisin kexin type 9 (PCSK9) provides a novel approach to reducing LDL-C levels. The current experience of PCSK9 inhibitors and implications for clinical use and cost effectiveness will be reviewed.

The effects of single‐ and multiple‐dose administration of bococizumab (RN316/PF‐04950615), a humanized IgG2Δa monoclonal antibody binding proprotein convertase subtilisin/kexin type 9, in hypercholesterolemic subjects treated with and without atorvastatin: Results from four phase I studies

“…Identified as the ninth member of the proteinase K subfamily of subtilases, proprotein convertase subtilisin/kexin type 9 (PCSK9) is one of the most exciting new targets in cholesterol metabolism to emerge since the identification of 3‐hydroxy‐3‐methyl‐glutaryl‐CoA reductases. In its primary role, PCSK9 binds to and induces degradation of the low‐density lipoprotein receptor (LDLR), particularly in the liver, resulting in diminished hepatic clearance and increased plasma concentration of low‐density lipoprotein cholesterol (LDL‐C) . Additional roles for PCSK9 in lipoprotein metabolism and in extra‐hepatic tissues have also been identified …”

Management of Severe Dyslipidaemia: Role of PCSK9 Inhibitors

“…Proprotein convertase subtilisin/kexin type 9 (PCSK9) was discovered in 2003 and plays an important role in the regulation of lipid metabolism. 9 PCSK9 is a factor, synthesised within the hepatocyte and secreted into the circulation, where it binds to the complex between LDL particles and the LDL receptor. Within the hepatocyte, the presence of PCSK9 prevents dissociation of the LDL particle from the receptor, which directs both to lysosomal degradation.…”

“…hypercholesterolaemia. 10 In addition, a number of polymorphisms have been identified that result in reduced PCSK9 and are associated with both lower LDL-C levels and lower rates of cardiovascular events. 11,12 Mendelian randomisation studies have provided further evidence linking low levels of PCSK9 activity with both lower lipid levels and cardiovascular risk.…”

Comparative Pharmacokinetics and Pharmacodynamics of Bococizumab Following a Single Subcutaneous Injection Using Drug Substance Manufactured at Two Sites or Administration via Two Different Devices

“…Monoclonal antibodies (mAbs) against proprotein convertase subtilisin/kexin type 9 (PCSK9) have become the focus of much research in recent years as a new approach to lipid management . PCSK9 binds to the low‐density lipoprotein (LDL) receptor leading to its degradation, which results in an increase in circulating levels of LDL‐cholesterol (LDL‐C) .…”