Ding Yanhua, Liu Yusi, Dou Changlin, Guo Shuren
The Phase I Clinical Trial Unit of The First Hospital of Jilin University, Changchun, China.
Shandon Boan Biotechnology Co., Ltd., Yantai, China.
J Bone Oncol. 2023 Sep 1;42:100499. doi: 10.1016/j.jbo.2023.100499. eCollection 2023 Oct.
Complications of bone metastases such as skeletal-related events lead to the impaired functional status and quality of life including death in patients with bone metastasis from solid tumors. Denosumab (XGEVA®) is indicated for the prevention of skeletal-related events in bone metastasis patients with solid tumors. The biosimilar product LY01011, a fully human anti-receptor activator of nuclear factor kappa-B ligand monoclonal antibody, was developed to be compared with the reference product denosumab.
A randomized, double-blind, single-dose, parallel-controlled phase 1 study was conducted in healthy Chinese subjects. A total of 168 enrolled subjects were randomly assigned in a 1:1 ratio to receive a single 120 mg dose of LY01011 (n = 85) or denosumab (n = 83) subcutaneously. The primary pharmacokinetic (PK) parameters, including maximum plasma concentration (C) and area under the concentration-time curve from time zero to last quantifiable concentration (AUC), were collected and measured for evaluation. Other secondary PK parameters included AUC, T, CL/F, λ, t, V/F, etc. Pharmacodynamics (PD), safety and immunogenicity profiles were also accounted for data analysis.
The geometric mean ratios (GMRs) of LY01011 and denosumab for the primary PK parameters such as C and AUC were 98.13% and 100.32%. The 90% confidence intervals (CIs) were all within the acceptance range of 80%-125%. The GMRs of the PD parameters including AUEC and E were 98.71% and 99.80%, which fell within the pre-defined acceptance range of 80%-125%. The results also demonstrated PK similarity even if Cmax and AUC had been used as primary endpoints. Safety profiles were tolerable and similar between groups. 4 (4.7%) and 2 (2.4%) subjects had experienced Grade 3 or above treatment-emergent adverse events (TEAEs) in LY01011 group and denosumab group. 3 subjects were reported to have serious adverse events (SAEs). None of the Grade 3 or above TEAEs and SAEs were related to the study drug, LY01011. No subject was tested anti-drug antibody (ADA) positive in both groups prior to the study drug administration. Following the study drug administration, only one subject in denosumab group was tested ADA positive, whereas no subject with ADA positive was reported in LY01011 group. No neutralizing antibody (Nab) was detected in either group throughout the study.
The study demonstrated PK and PD similarity of LY01011, a denosumab biosimilar, to denosumab in healthy Chinese subjects, with comparable safety and immunogenicity profiles.
骨转移的并发症，如骨相关事件，会导致实体瘤骨转移患者的功能状态受损和生活质量下降，甚至死亡。地诺单抗（XGEVA®）被用于预防实体瘤骨转移患者的骨相关事件。生物类似药LY01011是一种全人源抗核因子κB受体活化因子配体单克隆抗体，旨在与参比产品地诺单抗进行对比。
在健康中国受试者中开展了一项随机、双盲、单剂量、平行对照的1期研究。总共168名入组受试者按1:1比例随机分配，皮下注射单次120mg剂量的LY01011（n = 85）或地诺单抗（n = 83）。收集并测量主要药代动力学（PK）参数，包括最大血浆浓度（C）和从零时到最后可定量浓度的浓度-时间曲线下面积（AUC），以进行评估。其他次要PK参数包括AUC、T、CL/F、λ、t、V/F等。药效学（PD）、安全性和免疫原性概况也纳入数据分析。
LY01011与地诺单抗的主要PK参数如C和AUC的几何平均比值（GMRs）分别为98.13%和100.32%。90%置信区间（CIs）均在80%-125%的可接受范围内。包括AUEC和E在内的PD参数的GMRs分别为98.71%和99.80%，落在预先定义的80%-125%可接受范围内。即使将Cmax和AUC用作主要终点，结果也显示出PK相似性。两组的安全性概况均可耐受且相似。LY01011组和地诺单抗组分别有4名（4.7%）和2名（2.4%）受试者发生3级或以上治疗中出现的不良事件（TEAEs）。报告有3名受试者发生严重不良事件（SAEs）。所有3级或以上TEAEs和SAEs均与研究药物LY01011无关。在给予研究药物之前，两组均无受试者抗药抗体（ADA）检测呈阳性。给予研究药物后，地诺单抗组仅有一名受试者ADA检测呈阳性，而LY01011组未报告有ADA阳性受试者。在整个研究过程中，两组均未检测到中和抗体（Nab）。
该研究证明了生物类似药LY01011与地诺单抗在健康中国受试者中的PK和PD相似性，安全性和免疫原性概况相当。
