Alirocumab for hyperlipidemia: physiology of PCSK9 inhibition, pharmacodynamics and Phase I and II clinical trial results of a PCSK9 monoclonal antibody.
Statins have been the cornerstone of lipid therapy for the last two decades, but despite significant clinical efficacy in the majority of patients, a large residual risk remains for the development of initial or recurrent atherosclerotic cardiovascular disease. In addition, owing to side effects, a significant percentage of patients cannot tolerate any statin dose or a high enough statin dose to reach their recommended LDL cholesterol goals. Monoclonal antibodies (mAbs) to PCSK9 have recently been shown to be highly efficacious in lowering LDL cholesterol, while demonstrating a favorable adverse event profile in early clinical trials. This review of alirocumab (formerly REGN727/SAR236553) explains the physiology and pharmacodynamics of PCSK9 inhibition with a mAb, as well as the Phase I and II clinical trial results of alirocumab and the ongoing Phase III trial designs. Several mAbs to PCSK9 are currently in development and approval may be 1-3 years away. We will focus this review on alirocumab, but mAbs to PCSK9 are the most promising cholesterol-lowering medication since statins and have the potential to significantly reduce further the occurrence of atherosclerotic cardiovascular disease.
Sterling Research Group, 375 Glensprings Drive, 2nd Floor, Cincinnati, OH 45246, USA.
Eli M
EM
Roth
Philip
P
Diller
D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D008078:Cholesterol, LDL / Q000097:blood; D002986:Clinical Trials as Topic; D015536:Down-Regulation; D006801:Humans; D006949:Hyperlipidemias / Q000188:drug therapy*; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011973:Receptors, LDL / Q000187:drug effects / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D008078:Cholesterol, LDL; D011973:Receptors, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C571059:alirocumab