Phase I, Randomized, Placebo-Controlled, Dose-Escalation Study of GB223, a Fully-Humanized Monoclonal Antibody to RANKL, in Healthy Chinese Adults.

IF 5.4 2区医学 Q1 IMMUNOLOGY BioDrugs Pub Date : 2023-09-01 DOI:10.1007/s40259-023-00604-7

Chen Li, Haiyan Liu, Yixiang Liao, Yu Zhu, Jingyuan Tian, Xuan Wang, Zhiqin Hu, Yaoxuan Zhan, Xianbo Li, Xintong Liang, Jin He, Yongmei Li, Dewei Shang, Qingshan Zheng, Tenghua Wang, Haifeng Song, Yi Fang

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Abstract

Background: GB223 is a novel, fully-humanized monoclonal antibody against the receptor activator of nuclear factor-kappa B ligand (RANKL). In this phase I study, the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of GB223 were investigated.

Patients and methods: This was a randomized, double-blinded, placebo-controlled, single-dose escalation study conducted in 44 healthy Chinese adults. Participants were randomly assigned to receive a single subcutaneous injection dose of 7, 21, 63, 119, or 140 mg of GB223 (n = 34) or placebo (n = 10) and were followed up for 140-252 days.

Results: The results of noncompartmental analysis showed that GB223 was slowly absorbed after dosing, with a time to reach maximum concentration (T_max) ranging from 5 to 11 days. Serum GB223 concentrations decreased slowly, with a long half-life ranging from 7.91 to 19.60 days. A two-compartment Michaelis-Menten model was found to best describe the pharmacokinetics of GB223, and the absorption rate of GB223 differed between males (0.0146 h^-1) and females (0.0081 h^-1). Serum C-terminal telopeptide of type I collagen decreased significantly postdose, and the inhibition lasted 42-168 days. No deaths or drug-related serious adverse events occurred. The most frequent adverse events were blood parathyroid hormone increased (94.1%), blood phosphorus decreased (67.6%) and blood calcium decreased (58.8%). In the GB223 group, 44.1% (15/34) of subjects were antidrug antibody positive after dosing.

Conclusion: In this study, we demonstrated for the first time that a single subcutaneous injection of GB223, from 7 to 140 mg, is safe and well tolerated in healthy Chinese subjects. GB223 has a nonlinear pharmacokinetic profile, and sex was a potential covariate that may affect the absorption rate of GB223.

Clinical trial registration: NCT04178044 and ChiCTR1800020338.

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GB223 (RANKL的全人源单克隆抗体)在中国健康成人中的随机、安慰剂对照、剂量递增的I期研究

背景:GB223是一种新型的、完全人源化的抗核因子κ B配体受体激活剂(RANKL)的单克隆抗体。在本一期研究中，研究了GB223的安全性、耐受性、药代动力学、药效学和免疫原性。患者和方法:这是一项随机、双盲、安慰剂对照、单剂量递增的研究，在44名健康的中国成年人中进行。参与者被随机分配接受单次皮下注射剂量为7、21、63、119或140 mg的GB223 (n = 34)或安慰剂(n = 10)，随访140-252天。结果:非室区分析结果显示，GB223给药后吸收缓慢，达到最大浓度(Tmax)时间为5 ~ 11天。血清GB223浓度下降缓慢，半衰期较长，为7.91 ~ 19.60天。双室Michaelis-Menten模型最能描述GB223的药代动力学，男性和女性对GB223的吸收率分别为0.0146 h-1和0.0081 h-1。给药后血清I型胶原c端端肽明显降低，抑制持续42 ~ 168 d。未发生死亡或与药物相关的严重不良事件。最常见的不良事件为血甲状旁腺激素升高(94.1%)、血磷降低(67.6%)、血钙降低(58.8%)。GB223组给药后抗药抗体阳性的占44.1%(15/34)。结论:在本研究中，我们首次证明了GB223单次皮下注射7 ~ 140 mg在中国健康受试者中是安全且耐受性良好的。GB223具有非线性药代动力学特征，性别是影响GB223吸收率的潜在协变量。临床试验注册:NCT04178044和ChiCTR1800020338。

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来源期刊

BioDrugs 医学-免疫学

CiteScore

12.60

自引率

2.90%

发文量

审稿时长

>12 weeks

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