Ballantyne Christie M, Neutel Joel, Cropp Anne, Duggan William, Wang Ellen Q, Plowchalk David, Sweeney Kevin, Kaila Nitin, Vincent John, Bays Harold
Section of Cardiovascular Research, Division of Atherosclerosis, Department of Medicine, Baylor College of Medicine, Houston, Texas; Center for Cardiovascular Research, Houston Methodist DeBakey Heart and Vascular Center, Houston, Texas.
Orange County Research Center, Tustin, California.
Am J Cardiol. 2015 May 1;115(9):1212-21. doi: 10.1016/j.amjcard.2015.02.006. Epub 2015 Feb 12.
Bococizumab is a humanized monoclonal antibody binding proprotein convertase subtilisin/kexin type 9, which may be a potential therapeutic option for reducing low-density lipoprotein cholesterol (LDL-C) levels in patients with hypercholesterolemia. In this 24-week, multicenter, double-blind, placebo-controlled, dose-ranging study (NCT01592240), subjects with LDL-C levels≥80 mg/dl on stable statin therapy were randomized to Q14 days subcutaneous placebo or bococizumab 50, 100, or 150 mg or Q28 days subcutaneous placebo or bococizumab 200 or 300 mg. Doses of bococizumab were reduced if LDL-C levels persistently decreased to ≤25 mg/dl. The primary end point was the absolute change in LDL-C levels from baseline to week 12 after placebo or bococizumab administration. Continuation of bococizumab administration through to week 24 enabled the collection of safety data over an extended period. Of the 354 subjects randomized, 351 received treatment (placebo [n=100] or bococizumab [n=251]). The most efficacious bococizumab doses were 150 mg Q14 days and 300 mg Q28 days. Compared with placebo, bococizumab 150 mg Q14 days reduced LDL-C at week 12 by 53.4 mg/dl and bococizumab 300 mg Q28 days reduced LDL-C by 44.9 mg/dl; this was despite dose reductions in 32.5% and 34.2% of subjects at week 10 or 8, respectively. Pharmacokinetic/pharmacodynamic model-based simulation assuming no dose reductions predicted that bococizumab would lower LDL-C levels by 72.2 and 55.4 mg/dl, respectively. Adverse events were similar across placebo and bococizumab groups. Few subjects (n=7; 2%) discontinued treatment because of treatment-related adverse events. In conclusion, bococizumab significantly reduced LDL-C across all doses despite dose reductions in many subjects. Model-based simulations predicted greater LDL-C reduction in the absence of bococizumab dose reduction. The Q14 days regimen is being evaluated in phase 3 clinical trials.
波考izumab是一种人源化单克隆抗体，可结合前蛋白转化酶枯草溶菌素/kexin 9型，它可能是降低高胆固醇血症患者低密度脂蛋白胆固醇（LDL-C）水平的一种潜在治疗选择。在这项为期24周的多中心、双盲、安慰剂对照、剂量范围研究（NCT01592240）中，接受稳定他汀类药物治疗且LDL-C水平≥80mg/dl的受试者被随机分为每14天皮下注射安慰剂或50、100或150mg波考izumab，或每28天皮下注射安慰剂或200或300mg波考izumab。如果LDL-C水平持续降至≤25mg/dl，则降低波考izumab的剂量。主要终点是安慰剂或波考izumab给药后第12周时LDL-C水平相对于基线的绝对变化。将波考izumab给药持续至第24周能够在更长时间内收集安全性数据。在随机分组的354名受试者中，351名接受了治疗（安慰剂[n = 100]或波考izumab[n = 251]）。波考izumab最有效的剂量是每14天150mg和每28天300mg。与安慰剂相比，每14天150mg波考izumab在第12周时使LDL-C降低了53.4mg/dl，每28天300mg波考izumab使LDL-C降低了44.9mg/dl；尽管在第10周或第8周时分别有32.5%和34.2%的受试者降低了剂量。基于药代动力学/药效学模型的模拟假设未降低剂量，预测波考izumab将分别使LDL-C水平降低72.2和55.4mg/dl。安慰剂组和波考izumab组的不良事件相似。很少有受试者（n = 7；2%）因治疗相关不良事件而停药。总之，尽管许多受试者降低了剂量，但波考izumab在所有剂量下均显著降低了LDL-C。基于模型的模拟预测在不降低波考izumab剂量的情况下LDL-C降低幅度更大。每14天给药方案正在3期临床试验中进行评估。
