PCSK9 (Proprotein convertase subtilisin/kexin type 9) inhibitors: past, present, and the future.

Reduction in low-density lipoprotein cholesterol (LDL-C), mainly with statins, has decreased the risk of cardiovascular events over the last few decades. However, there are several patient populations that warrant further decrease in LDL-C by additional cholesterol-lowering therapy other than statins. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are a new class of drugs that have been shown to further decrease LDL-C by 50-70% when administered as a monotherapy or on a background therapy with statins. Proprotein convertase subtilisin/kexin type 9 inhibitors are also an excellent example of drug development in which discovery of gene mutations and its clinical effects have rapidly progressed into successful preclinical and clinical studies with multiple Phases 1-3 clinical trials completed or ongoing to date. This review summarizes the rapid evolution of the drug from genetic discovery to identification of targets for the drugs, to animal and human testing, and to large clinical outcomes trials, followed by discussion on foreseeable challenges of PCSK9 inhibitors.