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

  • BioDrugs. 2023 Sep;37(5):721-735. doi: 10.1007/s40259-023-00604-7.
Chen Li  #  1  2 ,  Haiyan Liu  #  2 ,  Yixiang Liao  2 ,  Yu Zhu  1 ,  Jingyuan Tian  1 ,  Xuan Wang  2 ,  Zhiqin Hu  1 ,  Yaoxuan Zhan  2 ,  Xianbo Li  2 ,  Xintong Liang  1 ,  Jin He  1 ,  Yongmei Li  1 ,  Dewei Shang  3 ,  Qingshan Zheng  4 ,  Tenghua Wang  5 ,  Haifeng Song  6 ,  Yi Fang  7
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.
  • 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.
  • 3. Department of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China.
  • 4. Center for Drug Clinical Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
  • 5. 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. [email protected].
  • 6. Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing, China. [email protected].
  • 7. Clinical Trial Institution Research Ward, Peking University People's Hospital, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 37278972 DOI: 10.1007/s40259-023-00604-7
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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