Li Nanyang, Chu Nannan, Zhu Leilei, Wu Xiaojie, Wei Qiong, Wang Jiahui, Hu Xuhui, Yu Haoyu, Wang Qingyu, Yuan Wei'an, Huang Kai, Zhang Jing
Clinical Pharmacology Research Center, Huashan Hospital, Fudan University, Shanghai, China.
Phase I Clinical Research Center, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China.
Clin Transl Sci. 2024 Dec;17(12):e70089. doi: 10.1111/cts.70089.
Denosumab is a human IgG2 monoclonal antibody against receptor activator of nuclear factor kappa-B ligand (RANKL) for the treatment of osteoporosis and bone loss. HLX14 is a proposed biosimilar of denosumab. This randomized, parallel-group, two-part, phase I study aimed to compare the pharmacokinetics, pharmacodynamics, safety, and immunogenicity of HLX14 with reference denosumab in Chinese healthy adult male participants. In Part 1, participants were randomized 1:1 and given HLX14 or reference denosumab sourced from the European Union (EU). In double-blind Part 2, participants were randomized 1:1:1:1 to receive HLX14 or denosumab sourced from the United States, EU, or China. All study drugs were administered via subcutaneous injection at a single dose of 60 mg. The primary endpoints were area under the serum drug concentration-time curve from time 0 to the last concentration-quantifiable time t (AUC), maximum serum drug concentration (C), and area under the serum drug concentration-time curve from time 0 to infinity (AUC). Twenty-four participants were randomized in Part 1 and 228 in Part 2. The 90% confidence intervals of geometric mean ratio of AUC, C, and AUC between HLX14 and denosumab from different sources fell within the pre-specified similarity margins of 0.80-1.25 (AUC, 0.91-1.13; C, 0.91-1.13; AUC, 0.91-1.12), demonstrating pharmacokinetic similarity. No notable difference was observed among treatment groups in pharmacodynamics, safety, or immunogenicity. HLX14 demonstrated highly similar pharmacokinetic characteristics with comparable pharmacodynamics, safety, and immunogenicity to denosumab, supporting its further investigation as a potential denosumab biosimilar.
地诺单抗是一种抗核因子κB受体活化因子配体（RANKL）的人IgG2单克隆抗体，用于治疗骨质疏松症和骨质流失。HLX14是一种拟用地诺单抗生物类似药。这项随机、平行组、两部分的I期研究旨在比较HLX14与参比地诺单抗在中国健康成年男性受试者中的药代动力学、药效学、安全性和免疫原性。在第1部分中，受试者按1:1随机分组，给予HLX14或源自欧盟（EU）的参比地诺单抗。在双盲的第2部分中，受试者按1:1:1:1随机分组，接受HLX14或源自美国、欧盟或中国的地诺单抗。所有研究药物均通过皮下注射给药，单剂量为60mg。主要终点为从时间0至最后一个可定量浓度时间t的血清药物浓度-时间曲线下面积（AUC）、血清药物最高浓度（C）以及从时间0至无穷大的血清药物浓度-时间曲线下面积（AUC）。第1部分有24名受试者随机分组，第2部分有228名。HLX14与不同来源地诺单抗之间AUC、C和AUC的几何平均比的90%置信区间落在预先设定的0.80 - 1.25相似性范围内（AUC为0.91 - 1.13；C为0.91 - 1.13；AUC为0.91 - 1.12），表明药代动力学相似。各治疗组在药效学、安全性或免疫原性方面未观察到显著差异。HLX14表现出与地诺单抗高度相似的药代动力学特征，在药效学、安全性和免疫原性方面相当，支持其作为潜在地诺单抗生物类似药进行进一步研究。
