Lancet：降低坏胆固醇的新药

　　

生物通报道：对于许多胆固醇高的人来说，他​​汀类药物（statins serve） 往往是治疗的第一选择。然而，一些患者在使用此类药物时无法有效地降低低密度脂蛋白胆固醇（LDL cholesterol），或称为“坏胆固醇”的浓度，因为他们的身体无法对这些药物做出足够的反应。

来自Brigham and Women's Hospital 的研究人员近期研发了一种新型药物：AMG145，如果病患在使用他汀类药物的同时加入这种药物，能在12周后有效降低LDL胆固醇水平66％。这一研究结果在今年的美国心脏协会年会上公布，并发表于11月6日Lancet杂志。

研究人员在一项双盲，广剂量范围，并带有安慰剂对照的试验中，分析了631位年龄介于18岁到80岁之间的患者，他们胆固醇高并稳定使用一定剂量的他汀类药物（或有或无 ezetimibe），研究人员将患者随机分成两组，一组接受六种不同AMG145剂量的治疗，另外一组则使用安慰剂，之后每两个星期或每四个星期进行皮下注射，共十二周分析药效。

对于每两周接受一次AMG145治疗的患者，研究人员发现到这十二周结束的时候，相比于安慰剂组，这种药物能以剂量依赖方式降低42％至66％的LDL胆固醇。

而每四周接受一次AMG145治疗的患者，则相比于安慰剂组，LDL胆固醇降低了42％至50％。而且，在短短的一个星期的药物治疗后，研究人员就发现了高达85％的LDL胆固醇降低。

“我们观察到的LDL胆固醇水平降低疗效非常引人注目，尤其是那些进行他汀类药物治疗的患者，”文中的第一作者，BWH心血管科 Robert Giugliano说。

每两周注射一次最高剂量的患者也出现了93.5％的最高降低水平，此外研究人员也指出在利用AMG145治疗的患者没有出现严重不良反应。

“这些数据令人兴奋，为降低LDL胆固醇提出了一种新的范例，下一步将是进行大规模的，长期的心血管检测试验，”文章的通讯作者，TIMI研究组主任Marc Sabatine说。

AMG145是一种单克隆抗体，它能结合到一种促进LDL胆固醇受体被降解的蛋白上，通过阻断这种蛋白的作用，AMG145保护受体免遭降解，从而增加了肝脏表面上的LDL胆固醇受体数量，帮助血液中LDL胆固醇的代谢。

这项研究由Amgen公司资助，Amgen公司相关研究人员也参与了研究设计和数据收集。数据分析和解释是由BWH研究组成员单独进行。

（生物通：张迪）

原文摘要：

Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study

Summary
Background
LDL cholesterol (LDL-C) is a well established risk factor for cardiovascular disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds LDL receptors, targeting them for degradation. We therefore assessed the efficacy, safety, and tolerability of AMG 145, a human monoclonal IgG2 antibody against PCSK9, in stable patients with hypercholesterolemia on a statin.
Methods
In a phase 2, dose-ranging study done in 78 centres in the USA, Canada, Denmark, Hungary, and Czech Republic, patients (aged 18—80 years) with LDL-C greater than 2·2 mmol/L on a stable dose of statin (with or without ezetimibe), were randomly assigned equally, through an interactive voice response system, to subcutaneous injections of AMG 145 70 mg, 105 mg, or 140 mg, or matching placebo every 2 weeks; or subcutaneous injections of AMG 145 280 mg, 350 mg, or 420 mg, or matching placebo every 4 weeks. Everyone was masked to treatment assignment within the every 2 weeks and every 4 weeks schedules. The primary endpoint was the percentage change in LDL-C concentration from baseline after 12 weeks. Analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01380730.
Findings
631 patients with hypercholesterolaemia were randomly assigned to AMG 145 70 mg (n=79), 105 mg (n=79), or 140 mg (n=78), or matching placebo (n=78) every 2 weeks; or AMG 145 280 mg (n=79), 350 mg (n=79), and 420 mg (n=80), and matching placebo (n=79) every 4 weeks. At the end of the dosing interval at week 12, the mean LDL-C concentrations were reduced generally dose dependently by AMG 145 every 2 weeks (ranging from 41·8% to 66·1%; p<0·0001 for each dose vs placebo) and AMG 145 every 4 weeks (ranging from 41·8% to 50·3%; p<0·0001). No treatment-related serious adverse events occurred. The frequencies of treatment-related adverse events were similar in the AMG 145 and placebo groups (39 [8%] of 474 vs 11 [7%] of 155); none of these events were severe or life-threatening.
Interpretation
The results suggest that PCSK9 inhibition could be a new model in lipid management. Inhibition of PCSK9 warrants assessment in phase 3 clinical trials.
Funding
Amgen.