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* = Presenting author

P035 Comparative structural, functional, nonclinical, and phase 1 similarity assessments of PF-06438179, a potential biosimilar to infliximab, and marketed reference products

J.E. McClellan*1, C. Udata2, D. Yin2, S. Salts3, T.R. Johnson4, M. Derzi5, M. Bolt5, H.D. Conlon6, C.F. Kirchhoff7, L.G. Lorello8, J. McNally9, M.I. Rehman10

1Pfizer Inc., Biosimilars Research and Development Unit, New York, NY, United States, 2Pfizer Inc., Clinical Pharmacology, San Diego, CA , United States, 3Pfizer Inc., Clinician, San Diego, CA , United States, 4Pfizer Inc., Pharmacokinetics, Dynamics and Metabolism, San Diego, CA , United States, 5Pfizer Inc., Drug Safety Research & Development, Andover, MA , United States, 6Pfizer Inc., Analytical Research & Development, Andover, MA , United States, 7Pfizer Inc., Global Technology Services Biomanufacturing Sciences, Chesterfield, MO, United States, 8Pfizer Inc., Pharmacokinetics, Dynamics and Metabolism, Groton, CT, United States, 9Pfizer Inc., Pharmacokinetics, Dynamics and Metabolism, Andover, MA , United States, 10Pfizer Inc., Biosimilars Research, Cambridge, MA, United States

Background

PF-06438179 is being developed as a potential biosimilar to Remicade® (infliximab), which is a chimeric mouse/human monoclonal antibody that binds to the tumour necrosis factor (TNF) protein, in a stepwise approach following globally accepted regulatory guidelines. The similarity of PF-06438179 to infliximab reference products sourced from the United States (infliximab-US) and from the European Union (infliximab-EU) was assessed in structural, functional, in vivo nonclinical pharmacokinetic (PK)/tolerability and clinical PK studies.

Methods

Structural similarity was assessed using chromatographic peptide mapping. Functional similarity was assessed in vitro using an inhibition of soluble TNF-induced cell apoptosis assay. PK, tolerability and anti-drug antibody (ADA) response were evaluated in rats administered a single IV dose (0, 10 or 50 mg/kg) of PF-06438179 or infliximab-EU. In a phase 1 study (NCT01844804), 146 healthy volunteers received a single 10 mg/kg IV dose of PF-06438179 (n=49), infliximab-US (n=48), or infliximab-EU (n=49). All subjects provided informed consent. PK was evaluated over 8 weeks; safety and ADA were assessed up to 12 weeks. PK similarity in humans was considered to be demonstrated if the 90% confidence interval (CI) of the test-to-reference ratio of maximum concentration (Cmax) and area under the concentration time curve (AUC) were within the 80.00%-125.00% bioequivalence (BE) acceptance window.

Results

Peptide mapping showed superimposable chromatographic profiles of PF-06438179, infliximab-US and infliximab-EU, demonstrating structural similarity. The dose-response curves of inhibition of cell apoptosis induced by all three study drugs were also superimposable, demonstrating functional similarity. In rats, PF-06438179 and infliximab-EU were well-tolerated. Systemic exposures (assessed by Cmax and AUC) in dosed animals appeared similar, with mean exposure ratios of PF-06438179 relative to infliximab-EU ranging from 0.88 to 1.16. None of the rats developed detectable levels of ADA. In healthy volunteers, the three study drugs exhibited a similar PK profile, and the 90% CI for the ratios of Cmax and AUC were within the BE acceptance window of 80.00%-125.00% for each, individual three-way comparison. Overall safety and ADA profiles were comparable among the treatment groups.

Conclusion

Comparative studies demonstrated structural, functional, and nonclinical and clinical PK profiles of PF-06438179 to be similar to infliximab-US and/or infliximab-EU. A global, comparative clinical study is ongoing to assess efficacy and safety of PF-06438179 and infliximab-EU in combination with methotrexate in subjects with active rheumatoid arthritis.