A randomized trial comparing LY01011, biosimilar candidate, with the reference product denosumab (Xgeva®) in healthy Chinese subjects.

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 (Cmax) and area under the concentration-time curve from time zero to last quantifiable concentration (AUC0→t), were collected and measured for evaluation. Other secondary PK parameters included AUC0- ∞, Tmax, CL/F, λz, t1/2, Vd/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 Cmax and AUC0→t 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 AUEC0→t and Emax 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 AUC0→∞ 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.

Ding Y ，Liu Y ，Dou C ，Guo S ... -  《Journal of Bone Oncology》

The similarity of pharmacokinetics, pharmacodynamics, safety, and immunogenicity between recombinant fully human anti-RANKL monoclonal antibody injection (MW032) and denosumab (Xgeva®) in healthy Chinese subjects: A single-center, randomized, double-blind

To compare the pharmacokinetics (PK), pharmacodynamics (PD), safety and immunogenicity between MW032 (denosumab biosimilar) and Xgeva® (denosumab) in healthy Chinese subjects. In this single-center, randomized, double-blind, single-dose, parallel-controlled design study, 120 healthy male subjects were randomized 1:1 to receive a single dose subcutaneous injection of 120 mg MW032 or Xgeva®, with an observation period of 161 days. The primary endpoint was the bioequivalence of PK parameters (Cmax, AUC0-t), and secondary endpoints including PD parameters, safety, and immunogenicity. One hundred and twelve subjects completed the study, including 56 subjects in each group. The geometric mean ratio and 90% CI for AUC0-t and Cmax were 1.117 (1.034, 1.205) and 1.060 (0.984, 1.142), respectively, which were both within the equivalence interval (0.8, 1.25). The inter-subject variation ranged from 21.37% to 27.37%. The PD parameters between MW032 and Xgeva® were similar. There was no statistically significant difference in the positive incidence of anti-drug antibody test between the two groups. Both MW032 and Xgeva® appeared to be well-tolerated and no Grade 3 or above serious adverse reactions occurred. The adverse reactions observed in the study were reported for denosumab generally. Moreover, there were no high-incidence or previously unreported adverse reactions. This study evidenced that the PK profiles of MW032, a denosumab biosimilar, and Xgeva® were bioequivalent. We also found that the PDs, safety, and immunogenicity were similar between the two drugs. Therefore, our results supported the next confirmatory studies for the development of MW032.

Hou J ，Hu Z ，Xu W ，Di Y ，Song C ，Wu F ，Liu J ，Guo Y ... -  《-》

Biosimilarity of HS-20090 to Denosumab in healthy Chinese subjects: a randomized, double-blinded, pharmacokinetics/pharmacodynamics study.

Lin Y ，Yang H ，Yang X ，Guo C ，Yang S ，Yang G ，Wu Q ，Pan C ，Sun C ，Li C ，He L ，Huang J ，Pei Q ... -  《-》

Pharmacokinetics and pharmacodynamics of the proposed biosimilar denosumab GP2411 and reference denosumab in healthy males.

Vogg B ，Poetzl J ，El Galta R ，Fuhr R ，Schwebig A ，Sekhar S ... -  《-》

A Phase I, Randomized, Single-Dose Study to Evaluate the Biosimilarity of QL1206 to Denosumab Among Chinese Healthy Subjects.

This study was conducted to explore the tolerance, variability, pharmacokinetics (PK), and pharmacodynamics (PD) of denosumab biosimilar (QL1206) in healthy Chinese subjects. This is a randomized, double-blind, two-arm, parallel study performed to examine the bioequivalence of denosumab biosimilar, QL1206, with that of Xgeva® (Denosumab) as a reference drug. A single dose of 120 mg/kg of the denosumab biosimilar or Xgeva® was administered to the subjects, who were followed up for 134 days. Similar PK properties as those of Xgeva® were exhibited by QL1206. When compared to QL1206 with Xgeva®, the 90% confidence intervals of the ratios for Cmax, AUC0-t, and AUC0-∞ were observed to be within 80-125%. The inter-subject variability (inter-CV) ranged from 29% to 39.5%. Six and three subjects in the QL1206 and Xgeva® groups were found to be positive for the ADA and negative for the NAb, respectively. The CTX1 concentration-time profiles appeared similar (about 80% decrease from 48 hours to134 days) between the QL1206 and Xgeva® groups. Adverse events (AEs) were observed in 92.6% and 93.4% of subjects in the QL1206 and Xgeva® groups, respectively. Reduction in blood calcium level was found to be the most common AE recorded, with an incidence of 72.8% versus 72.4% in the QL1206 and Xgeva® groups, respectively. Similar PK and PD characteristics were exhibited by QL1206 as compared to those of Xgeva®. The inter-CV was slightly large. The safety profiles of denosumab biosimilars and Xgeva® were found to be similar.

Zhang H ，Wu M ，Zhu X ，Li C ，Li X ，Sun J ，Liu C ，Liu Q ，Wei W ，Niu J ，Ding Y ... -  《-》