PCSK9 antibodies for the treatment of hypercholesterolemia

Abstract

Abstract:The serine protease proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low-density lipoprotein (LDL) receptor (LDLR) and directs it to lysosomes for intracellular degradation. This results in decreased numbers of LDLR available on the hepatic cell surface to bind LDL particles and remove them from the circulation and therefore to a subsequent increase in circulating LDL-cholesterol (LDL-C) plasma levels. Since 2003, when the role of PCSK9 in LDL-C metabolism was discovered, there have been major efforts to develop efficient and safe methods to inhibit it. Amongst those, monoclonal antibodies against PCSK9 are the furthest in development, with multiple phase 3 trials already published and with cardiovascular endpoint trials currently underway. Two fully human monoclonal antibodies, evolocumab (AMG 145) and alirocumab (REGN727/SAR236553), have been extensively studied in a wide range of subjects, such as those with statin intolerance, as an add-on to statin therapy, as a monotherapy and in patients with familial hypercholesterolemia. PCSK9 antibodies result in a consistent and robust decrease in LDL-C plasma levels ranging from 40% to 70%, either on top of statins or as a monotherapy. If the safety data from the on-going phase 3 trials remain as reassuring as the data available till now, PCSK9 antibodies will offer a novel, powerful therapeutic option to decrease LDL-C plasma levels and, hopefully, cardiovascular risk.

Effect of statin therapy on plasma proprotein convertase subtilisin kexin 9 (PCSK9) concentrations: a systematic review and meta‐analysis of clinical trials

“…This is a limitation of statin therapy, especially for the reduction of severe dyslipidaemias such as familial hypercholesterolaemia, as increasing the intensity of statin therapy may predispose the patients to myopathies. The role of a statin-induced increase in PCSK9 levels, as confirmed in the present meta-analysis has been noticed to justify the limitations of statin therapy in attaining the targets recommended by the guidelines; however, recent findings in non-familial hypercholesterolemic patients have not shown any improvement of the log-linear LDL-lowering effect of statins after combination with PCSK9 monoclonal antibodies, evolocumab [43,44] and alirocumab [45]. In spite of these results, further trials are still required to confirm the lack of synergistic effect of PCSK9 inhibition on the statins' dose response in patients with familial hypercholesterolaemia.…”

Effects of proprotein convertase subtilisin/kexin type 9 and nilotinib plasma concentrations on nilotinib‐induced hypercholesterolaemia in patients with chronic myeloid leukaemia

“…Pearson's product moment correlation coefficient test was used to assess correlations in continuous values between groups, and all results were expressed as correlation coefficients ( r values). Because the efficacy of PCSK9‐inhibiting monoclonal antibodies has been shown to decrease LDL cholesterol by more than 40%, 21,22 a change rate of 40% in PCSK9 after therapy was set as the cut‐off in the current study. Results with P values of <.05 were considered statistically significant.…”