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

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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 (Tmax) 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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Acknowledgments

The authors are indebted to Lun Ou for skillfully performing the ELISA and ECLIA assays.

Author information

Author notes

  1. Chen Li and Haiyan Liu contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacy, Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

    Chen Li, Yu Zhu, Jingyuan Tian, Zhiqin Hu, Xintong Liang, Jin He, Yongmei Li & Tenghua Wang

  2. Phase I Clinical Research Center, Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

    Chen Li, Haiyan Liu, Yixiang Liao, Xuan Wang, Yaoxuan Zhan & Xianbo Li

  3. Department of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China

    Dewei Shang

  4. Center for Drug Clinical Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China

    Qingshan Zheng

  5. Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing, China

    Haifeng Song

  6. Clinical Trial Institution Research Ward, Peking University People’s Hospital, Beijing, China

    Yi Fang

Authors
  1. Chen Li
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Corresponding authors

Correspondence to Tenghua Wang, Haifeng Song or Yi Fang.

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Funding

This work was primarily supported by the Major Project of National Science and Technology ‘Creation of Major New Drugs’ (2020ZX09201026), the Guangzhou Health Science and Technology Project (2021A031005), and the General Guidance Project of Guangzhou Municipal Health Commission (20231A010063).

Conflicts of Interest

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, and Yi Fang declare that they have no conflicts of interest.

Data Availability

Data are available from the corresponding author on reasonable request.

Ethics Approval

This study was approved by the Ethics Committee of the Fifth Affiliated Hospital of Guangzhou Medical University (No. 201802010) and was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments.

Consent to Participate

All participants provided written informed consent for this study.

Consent for Publication

Not applicable.

Code Availability

Code is available from the corresponding author on reasonable request.

Author Contributions

YF, HS, TW, and QZ contributed to the design of the study; HL, XW, XL, JH, and YL contributed to the monitoring of the study; YZ contributed to the subjects’ blood drawing; ZH contributed to the drug preparation; YL, YZ, JT and XL contributed to the blood sample collection and treatment; CL, HL, YL, and YZ contributed to the analysis and interpretation of the results; CL and DS contributed to the modeling; and CL contributed to the manuscript writing. All authors contributed to the manuscript and approved its publication.

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Li, C., Liu, H., Liao, Y. et al. Phase I, Randomized, Placebo-Controlled, Dose-Escalation Study of GB223, a Fully-Humanized Monoclonal Antibody to RANKL, in Healthy Chinese Adults. BioDrugs 37, 721–735 (2023). https://doi.org/10.1007/s40259-023-00604-7

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