A phase 1 randomized study compare the pharmacokinetics, safety and immunogenicity of HLX04 to reference bevacizumab sourced from the United States, the European Union, and China in healthy Chinese male volunteers

Xiaoxue Zhu, Hongjie Qian, Jixuan Sun, Min Wu, Chen Yu, Yanhua Ding, Xiaodi Zhang, Katherine Chai, Xiaojiao Li, Xiaoxue Zhu, Hongjie Qian, Jixuan Sun, Min Wu, Chen Yu, Yanhua Ding, Xiaodi Zhang, Katherine Chai, Xiaojiao Li

Abstract

Purpose: To compare the pharmacokinetic profiles, safety and immunogenicity of proposed bevacizumab biosimilar HLX04 with reference bevacizumab in healthy Chinese males.

Methods: In this double-blind Phase 1 study, healthy volunteers (N = 208) were randomized 1:1:1:1 to a single 3 mg/kg intravenous infusion of HLX04 or reference bevacizumab sourced from the United States (bevacizumab-US), the European Union (bevacizumab-EU) or China (bevacizumab-CN). Co-primary endpoints were area under the serum concentration-time profile (AUC) from time zero extrapolated to infinity (AUC0-inf) and from zero to last quantifiable concentration (AUClast). Secondary endpoint was the maximum serum drug concentration (Cmax). Study participants were monitored for treatment-emergent adverse events (TEAEs) and samples were collected for anti-drug antibody (ADA) testing throughout the study.

Results: Pharmacokinetic parameters were similar across groups. The respective geometric least-squares mean ratios (GLSMR) of AUC0-inf, AUClast and Cmax were: 95.7%, 96.0% and 101.8% for HLX04 versus bevacizumab-US; 94.3%, 94.6% and 100.5% for HLX04 versus bevacizumab-EU; and 90.0%, 90.4% and 98.2% for HLX04 versus bevacizumab-CN. For all test-to-reference comparisons, two-sided 90% confidence intervals of GLSMR for AUC0-inf, AUClast and Cmax fell in the pre-specified bioequivalence range (80-125%). There were no notable differences in the frequency, nature and/or grade of TEAEs. No deaths were reported and no ADAs were detected during the study.

Conclusion: HLX04 had similar safety and pharmacokinetic profiles to reference bevacizumab in healthy Chinese males, supporting the confirmatory Phase 3 study investigating the efficacy and safety equivalence between HLX04 and bevacizumab in patients with metastatic colorectal cancer (NCT03511963).

Clinical trial registration: The study was registered with Clinicaltrials.gov, NCT03483649.

Keywords: Bevacizumab; Bioequivalence; Biosimilar; Pharmacokinetics.

Conflict of interest statement

Xiaodi Zhang and Katherine Chai are employees of Shanghai Henlius Biotech, Inc. All other authors declare no competing interests.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Study design
Fig. 2
Fig. 2
Participants disposition. BV bevacizumab, CN China, EU European Union, US United States. *Due to abdominal pain and diarrhea (HLX04, n = 1), or abnormal blood pressure (bevacizumab-US, n = 1; bevacizumab-CN, n = 5)
Fig. 3
Fig. 3
Mean (SD) serum HLX04, bevacizumab-US, bevacizumab-EU and bevacizumab-CN concentration over time: linear (a) and semi-logarithmic (b) scales (pharmacokinetic analysis population). CN China, EU European Union, SD standard deviation, US United States

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