Pfizer, Inc, South San Francisco, California.
Pfizer, Inc, San Diego, California.
Clin Ther. 2017 Nov;39(11):2243-2259.e5. doi: 10.1016/j.clinthera.2017.09.009. Epub 2017 Oct 14.
Monoclonal antibody inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) elicit significant reductions in serum LDL-C levels. However, little is known about their effects on lipoprotein particles. The purpose of this analysis was to evaluate the effect of PCSK9 inhibition with bococizumab (RN316/PF-04950615), a humanized monoclonal antibody to PCSK9, on LDL, VLDL, and HDL particle concentration and size in hypercholesterolemic subjects.
Data from 3 double-blind, placebo-controlled, randomized studies were analyzed. In study 1, a total of 67 hypercholesterolemic subjects received IV placebo or bococizumab 0.25, 0.5, 1, or 1.5 mg/kg weekly for 4 weeks. In studies 2 and 3, a total of 135 hypercholesterolemic subjects taking statins received IV placebo or bococizumab 0.25, 1, 3, or 6 mg/kg monthly for 12 weeks. Lipoprotein particle concentration and size were measured by using nuclear magnetic resonance spectroscopy.
Overall, the majority of subjects were men (51.9%) aged >50 years of age and of white ethnic origin. In total, 189 subjects with both baseline and 2-week posttreatment data were included in the analysis. After PCSK9 inhibition with bococizumab 0.5, 1, 1.5, 3, and 6 mg/kg, concentrations of total LDL, total small LDL, and small VLDL particles decreased significantly versus baseline and placebo (P < 0.05), whereas concentrations of HDL particles increased (P < 0.05). The size of the LDL, VLDL, and HDL particles increased after PCSK9 inhibition. Reductions in LDL-C and total LDL particle concentrations were highly correlated.
The effect of inhibiting PCSK9 with bococizumab on lipoprotein particle concentration and size are consistent with the general mechanism of PCSK9 inhibitors in blocking PCSK9-mediated downregulation of LDL receptors. PCSK9 inhibition has the potential to provide a clinical benefit through the modulation of atherogenic lipoprotein particles in addition to LDL-C lowering, and this effect will likely be assessed in future analyses of data from cardiovascular outcomes trials of PCSK9 monoclonal antibodies that are currently being conducted. ClinicalTrials.gov identifiers: NCT01243151, NCT01342211, and NCT01350141.
前蛋白转化酶枯草溶菌素 9（PCSK9）单克隆抗体抑制剂可显著降低血清 LDL-C 水平。然而，人们对其对脂蛋白颗粒的影响知之甚少。本分析的目的是评估 bococizumab（RN316/PF-04950615）对 PCSK9 的抑制作用对高胆固醇血症患者 LDL、VLDL 和 HDL 颗粒浓度和大小的影响。
分析了 3 项双盲、安慰剂对照、随机研究的数据。在研究 1 中，67 名高胆固醇血症患者每周接受静脉注射安慰剂或 bococizumab 0.25、0.5、1 或 1.5 mg/kg，共 4 周。在研究 2 和 3 中，135 名服用他汀类药物的高胆固醇血症患者每月接受静脉注射安慰剂或 bococizumab 0.25、1、3 或 6 mg/kg，共 12 周。使用核磁共振光谱法测量脂蛋白颗粒浓度和大小。
总体而言，大多数受试者为男性（51.9%），年龄>50 岁，为白种人。共有 189 名受试者同时具有基线和治疗后 2 周的数据，纳入分析。与基线和安慰剂相比，在用 bococizumab 0.5、1、1.5、3 和 6 mg/kg 抑制 PCSK9 后，总 LDL、总小 LDL 和小 VLDL 颗粒的浓度显著降低（P<0.05），而 HDL 颗粒的浓度增加（P<0.05）。LDL、VLDL 和 HDL 颗粒的大小在 PCSK9 抑制后增加。LDL-C 和总 LDL 颗粒浓度的降低与 PCSK9 抑制剂抑制 LDL 受体介导的 LDL-C 下调的一般机制一致。通过抑制 PCSK9 抑制 PCSK9 具有通过调节致动脉粥样硬化脂蛋白颗粒来提供临床益处的潜力，除了降低 LDL-C 之外，这一效果可能会在目前正在进行的 PCSK9 单克隆抗体心血管结局试验的数据的未来分析中进行评估。临床试验.gov 标识符：NCT01243151、NCT01342211 和 NCT01350141。
