The efficacy of anti-PCSK9 antibodies: Results from recent trials

The serine protease proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low-density lipoprotein (LDL) receptor (LDLR) and directs it to the lysosome for degradation. This results in decreased numbers of LDLR available on the cell surface to bind LDL particles and remove them from the circulation and a subsequent increase in circulating LDL-cholesterol (LDL-C) concentrations. Since the role PCSK9 plays in LDL-C 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 PCSK9 antibodies evolocumab and alirocumab 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 they have been shown to decrease LDL-C by ∼50 to 70%. Rates of achieving LDL-C goals are up to 87-98% of treated subjects. Multiple phase 3 studies with these drugs are already completed and cardiovascular endpoint trials are expected to be concluded by the end of 2016. Both, alirocumab and evolocumab have been approved in 2015 for the treatment of hypercholesterolemia in the European Union and in the United States. Preliminary meta-analytic 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.