Farnier Michel
Point médical, rond point de la nation, 21000 Dijon, France.
Arch Cardiovasc Dis. 2014 Jan;107(1):58-66. doi: 10.1016/j.acvd.2013.10.007. Epub 2013 Dec 27.
The proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates cholesterol metabolism mainly by targeting the low-density lipoprotein receptor (LDLR) for degradation in the liver. Gain-of-function mutations in PCSK9 are one of the genetic causes of autosomal dominant hypercholesterolaemia. Conversely, loss-of-function mutations are associated with lower concentrations of LDL cholesterol (LDL-C) and reduced coronary heart disease. As these loss-of-function mutations are not associated with apparent deleterious effects, PCSK9 inhibition is an attractive new strategy for lowering LDL-C concentration. Among the various approaches to PCSK9 inhibition, human data are only available for inhibition of PCSK9 binding to LDLR by monoclonal antibodies. In phase II studies, the two most advanced monoclonal antibodies in development (alirocumab and evolocumab) decreased atherogenic lipoproteins very effectively and were well tolerated. A dramatic decrease in LDL-C up to 70% can be obtained with the most efficacious doses. Efficacy has been evaluated so far in addition to statins in hypercholesterolaemic patients with or without familial hypercholesterolaemia, in patients with intolerance to statin therapy and in monotherapy. Large phase III programmes are ongoing to evaluate the long-term efficacy and safety of these very promising new agents.
前蛋白转化酶枯草溶菌素/kexin 9型（PCSK9）主要通过靶向肝脏中的低密度脂蛋白受体（LDLR）进行降解来调节胆固醇代谢。PCSK9的功能获得性突变是常染色体显性高胆固醇血症的遗传病因之一。相反，功能丧失性突变与较低的低密度脂蛋白胆固醇（LDL-C）浓度以及冠心病风险降低相关。由于这些功能丧失性突变未显示出明显的有害影响，抑制PCSK9成为一种降低LDL-C浓度的颇具吸引力的新策略。在抑制PCSK9的各种方法中，仅有人用单克隆抗体抑制PCSK9与LDLR结合的数据。在II期研究中，两种研发进展最为领先的单克隆抗体（阿利西尤单抗和依洛尤单抗）能非常有效地降低致动脉粥样硬化脂蛋白，且耐受性良好。使用最有效剂量可使LDL-C显著降低达70%。迄今为止，已在患有或未患有家族性高胆固醇血症的高胆固醇血症患者、对他汀类药物治疗不耐受的患者以及单药治疗中评估了其除他汀类药物之外的疗效。大型III期项目正在进行中，以评估这些极具前景的新药的长期疗效和安全性。
