Wong Nathan D, Rosenblit Paul D, Greenfield Robert S
California Heart Associates, Fountain Valley, California, USA.
Cardiovasc Diagn Ther. 2017 Apr;7(Suppl 1):S11-S20. doi: 10.21037/cdt.2017.03.02.
In 2003, select families with familial hypercholesterolemia were first identified to have gain-of-function mutations for proprotein convertase subtilisin kexin type 9 (PCSK9) followed, in 2006, by the identification of those with lifelong low levels of LDL-C and lowered atherosclerotic cardiovascular disease (ASCVD) risk who had loss-of-function PCSK9 mutations. These discoveries led to the rapid development of PSCK9-targeted monoclonal antibody (PCSK9 mAb) therapies and, in 2015, 2 'fully-humanized' PCSK9 mAbs (alirocumab and evolocumab) were marketed in the United States, Europe, and other countries. In a wide range of high risk patients, with and without ASCVD, these PCSK9 mAbs, as once or twice monthly subcutaneous injections, potently reduce LDL-C 50-65% beyond levels achieved by maximally tolerated statin therapy; approximately one-third of patients achieve LDL-C levels <25 mg/dL. In the US, PCSK9 mAb therapy has current limited indications for persons with ASCVD or familial hypercholesterolemia requiring additional LDL-C reduction beyond maximally tolerated statin therapy. The first of the ASCVD outcomes-driven trials, the FOURIER trial has very recently shown in over 27,000 subjects randomized to evolocumab or placebo on top of moderate or high intensity statin therapy, a 15% risk reduction in the primary and 20% reduction in the secondary outcome over 2.2 years of treatment. Also of interest in patients with coronary artery disease on statin therapies, once-monthly evolocumab treatment, for only 76 weeks, resulted in significant plaque atheroma volume regression, as assessed by serial intravascular ultrasonography imaging, in approximately two-thirds of treated patients. Finally, in development is a highly durable RNA interference therapeutic inhibitor of PCSK9 synthesis which from a single dosage has been shown to maintain, for 6 months, a 75% reduction in PCSK9 levels and 50% reductions in LDL-C levels. The potential role of this vaccination-like product, as well as currently available PCSK9 mAb therapies, represents significant therapeutic advances to address ASCVD residual risk.
2003年，首次发现患有家族性高胆固醇血症的特定家族存在前蛋白转化酶枯草溶菌素9型（PCSK9）功能获得性突变，随后在2006年，又发现了那些低密度脂蛋白胆固醇（LDL-C）水平终生较低且动脉粥样硬化性心血管疾病（ASCVD）风险降低的人存在PCSK9功能丧失性突变。这些发现促使针对PCSK9的单克隆抗体（PCSK9 mAb）疗法迅速发展，2015年，两种“完全人源化”的PCSK9单克隆抗体（阿利西尤单抗和依洛尤单抗）在美国、欧洲及其他国家上市。在众多有或没有ASCVD的高危患者中，这些PCSK9单克隆抗体通过每月皮下注射一次或两次，能使LDL-C水平比最大耐受剂量他汀类药物治疗所达到的水平再强效降低50% - 65%；约三分之一的患者LDL-C水平降至<25 mg/dL。在美国，PCSK9单克隆抗体疗法目前对于患有ASCVD或家族性高胆固醇血症且需要在最大耐受剂量他汀类药物治疗基础上进一步降低LDL-C的患者的适应证有限。首个由ASCVD结局驱动的试验——FOURIER试验最近在超过27000名随机接受依洛尤单抗或安慰剂治疗（在中等强度或高强度他汀类药物治疗基础上）的受试者中显示，在2.2年的治疗期间，主要结局风险降低15%，次要结局风险降低20%。同样值得关注的是，对于接受他汀类药物治疗的冠心病患者，每月一次依洛尤单抗治疗仅76周，通过连续血管内超声成像评估，约三分之二接受治疗的患者出现显著的斑块粥样硬化体积消退。最后，一种高度持久的PCSK9合成RNA干扰治疗抑制剂正在研发中，单次给药已显示能在6个月内使PCSK9水平降低75%，LDL-C水平降低50%。这种类似疫苗的产品以及目前可用的PCSK9单克隆抗体疗法的潜在作用，代表了在解决ASCVD残余风险方面的重大治疗进展。
