Anti-PCSK9 Antibodies: A New Era in the Treatment of Dyslipidemia

Abstract

The serine protease proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low-density lipoprotein (LDL) receptor (LDLR) and directs it to lysosomal degradation. This results in decreased numbers of LDLR available on the cell surface to bind LDL particles and remove them from the circulation which in turn leads to an increase in circulating LDL-cholesterol (LDL-C) concentrations. Since the role PCSK9 plays in LDLC metabolism has been discovered in 2003 there have been major efforts in finding efficient and safe methods to inhibit it. Amongst those the fully human anti-PCSK9 antibodies alirocumab and evolocumab have been studied in a wide range of patients such as in those with statin intolerance, as add-on to statin therapy, as monotherapy and in patients with familial hypercholesterolemia and have been shown to decrease LDL-C overall by ~50-70%. Rates of achieving LDL-C goals, depending on individual risk, are up to 87 -98% of treated subjects. Multiple phase III studies with these drugs are already completed and cardiovascular endpoint trials are expected to be concluded by the end of 2016 and 2017 for evolocumab and alirocumab, respectively. In 2015 both alirocumab and evolocumab were approved for the treatment of hypercholesterolemia in the European Union and in the US. Preliminary data show an improvement in cardiovascular morbidity and mortality by ~50%. If the large ongoing endpoint trials confirm the cardiovascular efficacy and overall safety of these drugs, PCSK9 antibodies will revolutionarize lipid-lowering therapy.

Keywords: Alirocumab; PCSK9; anti-PCSK9 antibodies; evolocumab; hypercholesterolemia; statins.