An FDA perspective on the assessment of proposed biosimilar therapeutic proteins in rheumatology

Abstract

Biologic products have revolutionized the management of many rheumatic diseases, but access to these products might be limited by their relatively high costs. The US Biologics Price Competition and Innovation Act of 2009, which is contained within the Patient Protection and Affordable Care Act, established an abbreviated pathway for licensure by the FDA of biologic products that are demonstrated to be biosimilar to or interchangeable with FDA-licensed biologic products, termed reference products. This law allows for the approval of biosimilar biologic products, which are expected to increase access to treatment for patients, and ensuring the implementation of this Act is a high priority for the FDA. In this Perspectives article we describe the considerations for approval of proposed biosimilar products, including those to treat rheumatological conditions, by describing the FDA's rigorous approach to assessment of biosimilarity.

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Figure 1: Overview of biosimilar product development.
Figure 2: Features of antibody structure important for biosimilar cytotoxic effects.

References

  1. 1

    US Food and Drug Administration. Guidance for industry — scientific considerations in demonstrating biosimilarity to a reference product. FDA http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf (2015).

  2. 2

    US Food and Drug Administration. Guidance for industry — quality considerations in demonstrating biosimilarity to a reference protein product. FDA http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291134.pdf (2015).

  3. 3

    Woodcock, J. et al. The FDA's assessment of follow-on protein products: a historical perspective. Nat. Rev. Drug Discov. 6, 437–442 (2007).

    Article  Google Scholar 

  4. 4

    FDA Center for Drug Evaluation and Research. List of licensed biological products with (1) reference product exclusivity and (2) biosimilarity or interchangeability evaluations to date. FDA http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/UCM439049.pdf (2016).

  5. 5

    US Food and Drug Administration. Guidance for industry: clinical pharmacology data to support a demonstration of biosimilarity to a reference product. DRAFT GUIDANCE. FDA http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM397017.pdf (2014).

  6. 6

    Jefferis, R. Isotype and glycoform selection for antibody therapeutics. Arch. Biochem. Biophys. 526, 159–166 (2012).

    CAS  Article  Google Scholar 

  7. 7

    Jefferis, R. Recombinant antibody therapeutics: the impact of glycosylation on mechanisms of action. Trends Pharmacol. Sci. 30, 356–362 (2009).

    CAS  Article  Google Scholar 

  8. 8

    Hodoniczky, J., Zheng, Y. Z. & James, D. C. Control of recombinant monoclonal antibody effector functions by Fc N-glycan remodeling in vitro. Biotechnol. Prog. 21, 1644–1652 (2005).

    CAS  Article  Google Scholar 

  9. 9

    Boyd, P. N., Lines, A. C. & Patel, A. K. The effect of the removal of sialic acid, galactose and total carbohydrate on the functional activity of Campath-1H. Mol. Immunol. 32, 1311–1318 (1995).

    CAS  Article  Google Scholar 

  10. 10

    Shinkawa, T. et al. The absence of fucose but not the presence of galactose or bisecting N-acetylglucosamine of human IgG1 complex-type oligosaccharides shows the critical role of enhancing antibody-dependent cellular cytotoxicity. J. Biol. Chem. 278, 3466–3473 (2003).

    CAS  Article  Google Scholar 

  11. 11

    Shields, R. L. et al. Lack of fucose on human IgG1 N-linked oligosaccharide improves binding to human Fcgamma RIII and antibody-dependent cellular toxicity. J. Biol. Chem. 277, 26733–26740 (2002).

    CAS  Article  Google Scholar 

  12. 12

    Ferrara, C. et al. Unique carbohydrate-carbohydrate interactions are required for high affinity binding between FcgammaRIII and antibodies lacking core fucose. Proc. Natl Acad. Sci. USA 108, 12669–12674 (2011).

    CAS  Article  Google Scholar 

  13. 13

    Peipp, M. et al. Antibody fucosylation differentially impacts cytotoxicity mediated by NK and PMN effector cells. Blood 112, 2390–2399 (2008).

    CAS  Article  Google Scholar 

  14. 14

    Ferrara, C., Stuart, F., Sondermann, P., Brunker, P. & Umana, P. The carbohydrate at FcgammaRIIIa Asn-162. An element required for high affinity binding to non-fucosylated IgG glycoforms. J. Biol. Chem. 281, 5032–5036 (2006).

    CAS  Article  Google Scholar 

  15. 15

    Smith, K. G. & Clatworthy, M. R. FcgammaRIIB in autoimmunity and infection: evolutionary and therapeutic implications. Nat. Rev. Immunol. 10, 328–343 (2010).

    CAS  Article  Google Scholar 

  16. 16

    Herter, S. et al. Glycoengineering of therapeutic antibodies enhances monocyte/macrophage-mediated phagocytosis and cytotoxicity. J. Immunol. 192, 2252–2260 (2014).

    CAS  Article  Google Scholar 

  17. 17

    Lin, C. W. et al. A common glycan structure on immunoglobulin G for enhancement of effector functions. Proc. Natl Acad. Sci. USA 112, 10611–10616 (2015).

    CAS  Article  Google Scholar 

  18. 18

    Thomann, M., Reckermann, K., Reusch, D., Prasser, J. & Tejada, M. L. Fc-galactosylation modulates antibody-dependent cellular cytotoxicity of therapeutic antibodies. Mol. Immunol. 73, 69–75 (2016).

    CAS  Article  Google Scholar 

  19. 19

    Pace, D. et al. Characterizing the effect of multiple Fc glycan attributes on the effector functions and FcgammaRIIIa receptor binding activity of an IgG1 antibody. Biotechnol. Prog. 32, 1181–1192 (2016).

    CAS  Article  Google Scholar 

  20. 20

    Putnam, W. S., Prabhu, S., Zheng, Y., Subramanyam, M. & Wang, Y. M. Pharmacokinetic, pharmacodynamic and immunogenicity comparability assessment strategies for monoclonal antibodies. Trends Biotechnol. 28, 509–516 (2010).

    CAS  Article  Google Scholar 

  21. 21

    Wright, A. & Morrison, S. L. Effect of C2-associated carbohydrate structure on Ig effector function: studies with chimeric mouse-human IgG1 antibodies in glycosylation mutants of Chinese hamster ovary cells. J. Immunol. 160, 3393–3402 (1998).

    CAS  PubMed  Google Scholar 

  22. 22

    Yu, M. et al. Production, characterization, and pharmacokinetic properties of antibodies with N-linked mannose-5 glycans. MAbs 4, 475–487 (2012).

    Article  Google Scholar 

  23. 23

    Keck, R. et al. Characterization of a complex glycoprotein whose variable metabolic clearance in humans is dependent on terminal N-acetylglucosamine content. Biologicals 36, 49–60 (2008).

    CAS  Article  Google Scholar 

  24. 24

    Jones, A. J. et al. Selective clearance of glycoforms of a complex glycoprotein pharmaceutical caused by terminal N-acetylglucosamine is similar in humans and cynomolgus monkeys. Glycobiology 17, 529–540 (2007).

    CAS  Article  Google Scholar 

  25. 25

    Raju, T. S. & Jordan, R. E. Galactosylation variations in marketed therapeutic antibodies. MAbs 4, 385–391 (2012).

    Article  Google Scholar 

  26. 26

    Raju, T. S., Briggs, J. B., Borge, S. M. & Jones, A. J. Species-specific variation in glycosylation of IgG: evidence for the species-specific sialylation and branch-specific galactosylation and importance for engineering recombinant glycoprotein therapeutics. Glycobiology 10, 477–486 (2000).

    CAS  Article  Google Scholar 

  27. 27

    Gomord, V. et al. Plant-specific glycosylation patterns in the context of therapeutic protein production. Plant Biotechnol. J. 8, 564–587 (2010).

    CAS  Article  Google Scholar 

  28. 28

    US Food and Drug Administration. 2015 Meeting Materials, Oncologic Drugs Advisory Committee. FDA http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/ucm426351.htm (2015).

  29. 29

    US Food and Drug Administration. Drugs@FDA Zarxio. FDA http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/125553Orig1s000TOC.cfm (2015).

  30. 30

    Felson, D. T. et al. American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum. 38, 727–735 (1995).

    CAS  Article  Google Scholar 

  31. 31

    Demin, I., Hamren, B., Luttringer, O., Pillai, G. & Jung, T. Longitudinal model-based meta-analysis in rheumatoid arthritis: an application toward model-based drug development. Clin. Pharmacol. Ther. 92, 352–359 (2012).

    CAS  Article  Google Scholar 

  32. 32

    US Food and Drug Administration. Guidance for industry — biosimilars: questions and answers regarding implementation of the Biologics Price Competition and Innovation Act of 2009. FDA http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM273001.pdf (2015).

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Acknowledgements

The authors thank S. Yim, B. Chowdhury, S. Kozlowski, K. Clouse, S. Lim, J. Weiner, L. Zhang, D. Abernethy and L. Christl for critical review of the manuscript. This article reflects the views of the authors and should not be construed to represent FDA's views or policies.

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Both authors researched data for article and made substantial contributions to discussions of the content, writing and review/editing of manuscript before submission.

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Correspondence to Nikolay P. Nikolov.

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Nikolov, N., Shapiro, M. An FDA perspective on the assessment of proposed biosimilar therapeutic proteins in rheumatology. Nat Rev Rheumatol 13, 123–128 (2017). https://doi.org/10.1038/nrrheum.2016.204

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