Baruch Amos, Mosesova Sofia, Davis John D, Budha Nageshwar, Vilimovskij Alexandr, Kahn Robert, Peng Kun, Cowan Kyra J, Harris Laura Pascasio, Gelzleichter Thomas, Lehrer Josh, Davis John C, Tingley Whittemore G
Genentech, Inc., South San Francisco, California.
Genentech, Inc., South San Francisco, California.
Am J Cardiol. 2017 May 15;119(10):1576-1583. doi: 10.1016/j.amjcard.2017.02.020. Epub 2017 Mar 1.
RG7652 (MPSK3169A), a fully human immunoglobulin G1 (IgG1) monoclonal antibody directed against proprotein convertase subtilisin/kexin type 9 (PCSK9), blocks the interaction between PCSK9 and low-density lipoprotein (LDL) receptor. EQUATOR (ClinicalTrials.govNCT01609140), a randomized, double-blind, and dose-ranging phase 2 study, evaluated RG7652 in patients (1) at high risk for or (2) with coronary heart disease (CHD). The primary end point was change in LDL cholesterol (LDL-C) from baseline to day 169. Patients (n = 248; median age, 64 years; 57% men; 52% with established CHD; 82% on statins) with baseline LDL-C levels of 90 to 250 mg/dl (mean, 126 mg/dl) continuing on standard-of-care therapy were randomized to receive 1 of 5 RG7652 doses or placebo, subcutaneously every 4, 8, or 12 weeks for 24 weeks. Significant dose-dependent reductions in LDL-C levels from baseline to nadir (56 to 74 mg/dl [48% to 60%]) were observed in all RG7652-dosed patients; effects persisted to day 169 with the highest doses (reduction vs placebo up to 62 mg/dl [51%]) with no unexpected safety signals. RG7652 reduced apolipoprotein B and lipoprotein(a) levels. LDL-C subfraction analysis by nuclear magnetic resonance spectroscopy revealed a prominent decrease in large LDL-C and some decrease in small LDL particles. There was significant reduction in mean particle size of LDL-C on day 169 but no significant reductions in systemic markers of inflammation (high-sensitivity C-reactive protein, interleukin-6, and tumor necrosis factor-alpha). RG7652 reduced LDL-C levels and was well tolerated in patients at high risk for or with CHD on standard-of-care therapy. In conclusion, RG7562 treatment affected large LDL-C and, to a lesser extent, small LDL-C particles; RG7562 did not affect systemic circulating pro-inflammatory cytokines or high-sensitivity C-reactive protein.
RG7652（MPSK3169A）是一种完全人源化的免疫球蛋白G1（IgG1）单克隆抗体，靶向前蛋白转化酶枯草溶菌素/克新9型（PCSK9），可阻断PCSK9与低密度脂蛋白（LDL）受体之间的相互作用。EQUATOR（ClinicalTrials.gov编号：NCT01609140）是一项随机、双盲、剂量范围的2期研究，评估了RG7652在（1）具有高风险或（2）患有冠心病（CHD）的患者中的疗效。主要终点是从基线到第169天低密度脂蛋白胆固醇（LDL-C）的变化。基线LDL-C水平为90至250mg/dl（平均126mg/dl）且继续接受标准治疗的患者（n = 248；中位年龄64岁；57%为男性；52%患有确诊的CHD；82%正在服用他汀类药物）被随机分配接受5种RG7652剂量之一或安慰剂，每4、8或12周皮下注射一次，共24周。在所有接受RG7652治疗的患者中均观察到从基线到最低点LDL-C水平有显著的剂量依赖性降低（56至74mg/dl [48%至60%]）；最高剂量组的疗效持续到第169天（与安慰剂相比降低高达62mg/dl [51%]），且未出现意外的安全信号。RG7652降低了载脂蛋白B和脂蛋白（a）水平。通过核磁共振波谱法进行的LDL-C亚组分分析显示，大LDL-C显著减少，小LDL颗粒略有减少。在第169天，LDL-C的平均颗粒大小显著减小，但炎症的全身标志物（高敏C反应蛋白、白细胞介素-6和肿瘤坏死因子-α）没有显著降低。RG7652降低了LDL-C水平，并且在接受标准治疗的具有高风险或患有CHD的患者中耐受性良好。总之，RG7562治疗影响了大LDL-C，在较小程度上也影响了小LDL-C颗粒；RG7562不影响全身循环的促炎细胞因子或高敏C反应蛋白。
