Are PCSK9 Inhibitors the Next Breakthrough in the Cardiovascular Field?

Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low-density lipoprotein receptor, escorting it to its destruction in the lysosome and thereby preventing the recirculation of the low-density lipoprotein receptor to the hepatocyte cell surface. Both gain-of-function mutations in PCSK9 (causing marked increases in low-density lipoprotein cholesterol [LDL-C] concentration and premature atherosclerosis) and loss-of-function mutations (causing modest LDL-C reduction with low rates of coronary heart disease) have been described. Several monoclonal antibodies to PCSK9 have achieved LDL-C reductions of 50% to 70% across various patient populations and background lipid therapies. Phase 2/3 trials have demonstrated good tolerability without clear drug-related toxicity, although the number and duration of patients treated to date is modest. Currently, 4 phase 3 trials involving >70,000 patients are testing whether these drugs reduce cardiovascular events. The U.S. Food and Drug Administration is currently reviewing the existing data to determine whether these agents could be made available prior to the completion of these cardiovascular endpoint trials expected in 2018.