替伏西单抗治疗中国非家族性高胆固醇血症患者（CREDIT-1）：一项为期48周的随机、双盲、安慰剂对照3期试验。
Tafolecimab in Chinese patients with non-familial hypercholesterolemia (CREDIT-1): a 48-week randomized, double-blind, placebo-controlled phase 3 trial.
作者信息
Huo Yong, Chen Beijian, Lian Qiufang, Wang Shuqing, Liu Lu, Lu Di, Qu Yanling, Zheng Guanzhong, Li Lipeng, Ji Yuan, Yin Guotian, Huang Wenjun, Xie Ying, Yang Xinchun, Gao Xiufang, An Pei, Xue Fengtai, Li Haoyu, Deng Huan, Li Li, Pei Lijuan, Qian Lei
机构信息
Department of Cardiology, Peking University First Hospital, Beijing, China.
Department of Cardiology, Heze Municipal Hospital, Heze, China.
出版信息
Lancet Reg Health West Pac. 2023 Sep 28;41:100907. doi: 10.1016/j.lanwpc.2023.100907. eCollection 2023 Dec.
BACKGROUND
Tafolecimab, a fully human proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibody developed for the treatment of hypercholesterolemia, demonstrated robust lipid-lowering efficacy and favorable safety in previous short-term studies. We aimed to assess the long-term efficacy and safety of tafolecimab in Chinese non-familial hypercholesterolemia (non-FH) patients.
METHODS
Non-FH patients at high or very-high cardiovascular risk with screening low-density lipoprotein cholesterol (LDL-C) level ≥1.8 mmol/L or non-FH patients with screening LDL-C level ≥3.4 mmol/L and on stable lipid-lowering therapy for at least 4 weeks, were randomized in a 2:2:1:1 ratio to receive subcutaneous tafolecimab 450 mg Q4W, tafolecimab 600 mg Q6W, placebo 450 mg Q4W, or placebo 600 mg Q6W, respectively, in the 48-week double-blind treatment period. The primary endpoint was the percent change from baseline to week 48 in LDL-C levels.
FINDINGS
A total of 618 patients were randomized and 614 patients received at least one dose of tafolecimab (n = 411) or placebo (n = 203). At week 48, tafolecimab induced significant reductions in LDL-C levels (treatment differences versus placebo [on-treatment estimand]: -65.0% [97.5% CI: -70.2%, -59.9%] for 450 mg Q4W; -57.3% [97.5% CI: -64.0%, -50.7%] for 600 mg Q6W; both < 0.0001). Significantly more patients treated with tafolecimab achieved ≥50% LDL-C reductions, LDL-C < 1.8 mmol/L, and LDL-C < 1.4 mmol/L than placebo group at both dose regimens (all < 0.0001). Furthermore, tafolecimab significantly reduced non-HDL-C, apolipoprotein B, and lipoprotein(a) levels. The most commonly-reported treatment emergent adverse events in the tafolecimab groups included upper respiratory infection, urinary tract infection and hyperuricemia.
INTERPRETATION
Tafolecimab dosed at 450 mg Q4W and 600 mg Q6W was safe and showed superior lipid-lowering efficacy versus placebo, providing a novel treatment option for Chinese hypercholesterolemia patients.
FUNDING
This study was sponsored by Innovent Biologics, Inc.
背景
他伏西单抗是一种开发用于治疗高胆固醇血症的全人源前蛋白转化酶枯草溶菌素/克新9型（PCSK9）单克隆抗体，在既往短期研究中显示出强大的降脂疗效和良好的安全性。我们旨在评估他伏西单抗在中国非家族性高胆固醇血症（非FH）患者中的长期疗效和安全性。
方法
心血管风险高或极高的非FH患者，筛查低密度脂蛋白胆固醇（LDL-C）水平≥1.8 mmol/L，或筛查LDL-C水平≥3.4 mmol/L且接受稳定降脂治疗至少4周的非FH患者，按2:2:1:1比例随机分组，在48周双盲治疗期分别接受皮下注射他伏西单抗450 mg每4周一次、他伏西单抗600 mg每6周一次、安慰剂450 mg每4周一次或安慰剂600 mg每6周一次。主要终点是从基线到第48周LDL-C水平的变化百分比。
结果
共618例患者随机分组，614例患者接受了至少一剂他伏西单抗（n = 411）或安慰剂（n = 203）。在第48周时，他伏西单抗使LDL-C水平显著降低（与安慰剂相比的治疗差异[治疗中估计值]：450 mg每4周一次为-65.0%[97.5%CI：-70.2%，-59.9%]；600 mg每6周一次为-57.3%[97.5%CI：-64.0%，-50.7%]；均P < 0.0001）。在两种剂量方案下接受他伏西单抗治疗的患者中，实现LDL-C降低≥50%、LDL-C < 1.8 mmol/L和LDL-C < 1.4 mmol/L的患者显著多于安慰剂组（均P < 0.0001）。此外，他伏西单抗显著降低了非HDL-C、载脂蛋白B和脂蛋白（a）水平。他伏西单抗组最常报告的治疗中出现的不良事件包括上呼吸道感染、尿路感染和高尿酸血症。
解读
每4周一次给予450 mg和每6周一次给予600 mg剂量的他伏西单抗是安全的，且与安慰剂相比显示出卓越的降脂疗效，为中国高胆固醇血症患者提供了一种新的治疗选择。
资助
本研究由信达生物制药（苏州）有限公司赞助。
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