A Global Phase I Clinical Study Comparing the Safety and Pharmacokinetics of Proposed Biosimilar BAT1706 and Bevacizumab (Avastin®) in Healthy Male Subjects

Abstract

Objective

BAT1706 is a proposed biosimilar of bevacizumab (BEV). The objective of this phase I clinical trial was to establish pairwise similarity between BAT1706, US-sourced BEV (US-BEV), and EU-sourced BEV (EU-BEV) after a single intravenous (IV) infusion in healthy male subjects.

Methods

This phase I clinical trial was a randomized, double-blinded, three-arm study in 128 healthy adult male subjects. Every subject received a single IV infusion of 1 mg/kg of study drug and was subsequently monitored for 14 weeks. Pharmacokinetic, safety, and immunogenicity data were collected from each patient. The primary pharmacokinetic endpoint of this clinical study was area under the concentration curve from time zero to infinity (AUC0–inf). Biosimilarity of the study drugs was confirmed if the two-sided 90% confidence interval (CI) ratios of the geometric means for the three pairwise comparisons were contained within the range 80–125%. Other pharmacokinetic parameters including area under the concentration curve to time t (AUC0–t), maximum concentration of drug in plasma (Cmax), half-life (t½), and time to Cmax (tmax) were also measured.

Results

The pharmacokinetic parameters were comparable for the three drug products evaluated. The 90% CI for the AUC0–inf was 99–112% for BAT1706 versus EU-BEV, 97–110% for BAT1706 vs US-BEV and 92–104% for EU-BEV versus US-BEV comparisons, respectively, demonstrating biosimilarity. There were no significant adverse events attributable to BAT1706, as compared to EU-BEV and US-BEV. BAT1706 demonstrated a similar safety profile to EU-BEV and US-BEV. In addition, no anti-drug antibody positive result was reported for any subject included in the study.

Conclusion

In this study, BAT1706, a proposed biosimilar of BEV, was shown to be highly similar to EU-BEV and US-BEV in terms of pharmacokinetic equivalence, safety, and immunogenicity in healthy subjects after a single IV infusion.

Trial Registration

NCT03030430.

This is a preview of subscription content, log in to check access.

Fig. 1

References

  1. 1.

    Ferrara N. Role of vascular endothelial growth factor in regulation of physiological angiogenesis. Am J Physiol Cell Physiol. 2001;280:C1358–66.

    CAS  Article  Google Scholar 

  2. 2.

    Avastin® US Label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125085s323lbl.pdf.

  3. 3.

    Presta LG, Chen H, O’Connor SJ, Chisholm V, Meng YG, Krummen L, Winkler M, Ferrara N. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res. 1997;57:4593–9.

    CAS  PubMed  Google Scholar 

  4. 4.

    Fox WD, Higgins B, Maiese KM, Drobnjak M, Cordon-Cardo C, Scher HI, Agus DB. Antibody to vascular endothelial growth factor slows growth of an androgen-independent xenograft model of prostate cancer. Clin Cancer Res. 2002;8:3226–31.

    CAS  PubMed  Google Scholar 

  5. 5.

    Mabuchi S, Terai Y, Morishige K, Tanabe-Kimura A, Sasaki H, Kanemura M, Tsunetoh S, Tanaka Y, Sakata M, Burger RA, et al. Maintenance treatment with bevacizumab prolongs survival in an in vivo ovarian cancer model. Clin Cancer Res. 2008;14:7781–9.

    CAS  Article  Google Scholar 

  6. 6.

    European Medicines Agency Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. 2014. https://www.ema.europa.eu/documents/scientific-guideline/guideline-similar-biological-medicinal-products-containing-biotechnology-derived-proteins-active_en-2.pdf.

  7. 7.

    U.S. Food and Drug Administration Guidance for industry: scientific considerations in demonstrating biosimilarity to a reference product. 2015. https://www.fda.gov/downloads/drugs/guidances/ucm291128.pdf.

  8. 8.

    Avastin® EU label. https://www.ema.europa.eu/documents/product-information/avastin-epar-product-information_en.pdf.

  9. 9.

    Gerber H-P, Ferrara N. Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in combination with cytotoxic therapy in preclinical studies. Cancer Res. 2005;65:671–80.

    CAS  PubMed  Google Scholar 

  10. 10.

    Zhang H, Li Q, Zhu X, Li C, Li X, Liu C, Hu Y, Chen G, Wei H, Wang J, Shen Z, Ding Y. Tolerance, variability, and pharmacokinetics of bevacizumab biosimilars in Chinese healthy male subjects. Cancer Chemother Pharmacol. 2018;82:615–23.

    CAS  Article  Google Scholar 

  11. 11.

    U.S. Food and Drug Administration Guidance for industry: clinical pharmacology data to support a demonstration of biosimilarity to a reference product. 2016. https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm397017.pdf.

  12. 12.

    Markus R, Chow V, Pan Z, Hanes V. A phase I, randomized, single-dose study evaluating the pharmacokinetic equivalence of biosimilar ABP 215 and bevacizumab in healthy adult men. Cancer Chemother Pharmacol. 2017;80:755–63.

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Li Zhang.

Ethics declarations

Funding

Bio-Thera Solutions, Ltd., a biopharmaceutical company located in Guangzhou, China, provided the funding for this study.

Conflict of interest

Xiaoyun Wu is an employee of Bio-Thera Solutions. Chris Wynne is an employee of Christchurch Clinical Studies Trust, which is the contract research organization sponsored by Bio-Thera Solutions to conduct the clinical study. Chenchao Xu is an employee of Bio-Thera Solutions. Yiting Gan is an employee of Bio-Thera Solutions. Chaohe Wang is an employee of Bio-Thera Solutions. Bert E. Thomas is an employee of Bio-Thera Solutions. Jin-Chen Yu is an employee of Bio-Thera Solutions. Shengfeng Li is an employee of Bio-Thera Solutions. Li Zhang is an employee of Bio-Thera Solutions.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study protocol was reviewed and approved by the Independent Ethics Committee (IEC), New Zealand. This phase I clinical trial was registered at ClinicalTrials.gov (identifier NCT03030430).

Informed Consent

Informed consent was obtained from all individual participants included in the study.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wu, X., Wynne, C., Xu, C. et al. A Global Phase I Clinical Study Comparing the Safety and Pharmacokinetics of Proposed Biosimilar BAT1706 and Bevacizumab (Avastin®) in Healthy Male Subjects. BioDrugs 33, 335–342 (2019). https://doi.org/10.1007/s40259-019-00352-7

Download citation