A randomized phase l pharmacokinetic study comparing SB4 and etanercept reference product (Enbrel®) in healthy subjects

Yoon Jung Lee, Donghoon Shin, Youngdoe Kim, Jungwon Kang, Anke Gauliard, Rainard Fuhr, Yoon Jung Lee, Donghoon Shin, Youngdoe Kim, Jungwon Kang, Anke Gauliard, Rainard Fuhr

Abstract

Aims: SB4 has been developed as a biosimilar of etanercept. The primary objective of the present study was to demonstrate the pharmacokinetic (PK) equivalence between SB4 and European Union -sourced etanercept (EU-ETN), SB4 and United States-sourced etanercept (US-ETN), and EU-ETN and US-ETN. The safety and immunogenicity were also compared between the treatments.

Methods: This was a single-blind, three-part, crossover study in 138 healthy male subjects. In each part, 46 subjects were randomized at a 1:1 ratio to receive a single 50 mg subcutaneous dose of the treatments (part A: SB4 or EU-ETN; part B: SB4 or US-ETN; and part C: EU-ETN or US-ETN) in period 1, followed by the crossover treatment in period 2 according to their assigned sequences. PK equivalence between the treatments was determined using the standard equivalence margin of 80-125%.

Results: The geometric least squares means ratios of AUCinf , AUClast and Cmax were 99.04%, 98.62% and 103.71% (part A: SB4 vs. EU-ETN); 101.09%, 100.96% and 104.36% (part B: SB4 vs. US-ETN); and 100.51%, 101.27% and 103.29% (part C: EU-ETN vs. US-ETN), respectively, and the corresponding 90% confidence intervals were completely contained within the limits of 80-125 %. The incidence of treatment-emergent adverse events was comparable, and the incidence of the antidrug antibodies was lower in SB4 compared with the reference products.

Conclusions: The present study demonstrated PK equivalence between SB4 and EU-ETN, SB4 and US-ETN, and EU-ETN and US-ETN in healthy male subjects. SB4 was well tolerated, with a lower immunogenicity profile and similar safety profile compared with those of the reference products.

Keywords: SB4; biosimilar; etanercept; immunogenicity; pharmacokinetics; safety.

© 2016 Samsung Bioepis Co., Ltd. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Figures

Figure 1
Figure 1
Three‐part, two‐period, two‐sequence, single‐dose, crossover study design. In each of parts A, B and C, 46 healthy male subjects were randomized 1:1 to receive a single 50 mg subcutaneous dose of the treatments [part A: SB4 or EU‐ETN; part B: SB4 or US‐ETN; part C: EU‐ETN or US‐ETN) in period 1, followed by the crossover treatment in period 2, according to their assigned sequences. The study treatments were separated by a 28‐day washout period. PK, pharmacokinetic
Figure 2
Figure 2
Summary of subject disposition. All enrolled subjects were included in the safety analysis. Among them, subjects who completed both period 1 and period 2 were included in the PK analysis. ALT, alanine transaminase
Figure 3
Figure 3
Mean (SD) serum concentration of etanercept after single 50 mg subcutaneous dose of (A) SB4 or EU‐ETN in part A; (B) SB4 or US‐ETN in part B; and (C) EU‐ETN vs. US‐ETN in part C. SD, standard deviation

References

    1. Mohler KM, Torrance DS, Smith CA, Goodwin RG, Stremler KE, Fung VP, Madani H, Widmer MB. Soluble tumor necrosis factor (TNF) receptors are effective therapeutic agents in lethal endotoxemia and function simultaneously as both TNF carriers and TNF antagonists. J Immunol 1993; 151: 1548–61.
    1. Moreland LW, Baumgartner SW, Schiff MH, Tindall EA, Fleischmann RM, Weaver AL, Ettlinger RE, Cohen S, Koopman WJ, Mohler K, Widmer MB, Blosch CM. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)‐Fc fusion protein. N Engl J Med 1997; 337: 141–7.
    1. Moreland LW, Schiff MH, Baumgartner SW, Tindall EA, Fleischmann RM, Bulpitt KJ, Weaver AL, Keystone EC, Furst DE, Mease PJ, Ruderman EM, Horwitz DA, Arkfeld DG, Garrison L, Burge DJ, Blosch CM, Lange ML, McDonnell ND, Weinblatt ME. Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial. Ann Intern Med 1999; 130: 478–86.
    1. Weinblatt ME, Kremer JM, Bankhurst AD, Bulpitt KJ, Fleischmann RM, Fox RI, Jackson CG, Lange M, Burge DJ. A trial of etanercept, a recombinant tumor necrosis factor receptor: Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 1999; 340: 253–9.
    1. Mease PJ, Goffe BS, Metz J, VanderStoep A, Finck B, Burge DJ. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial. Lancet 2000; 356: 385–90.
    1. Korth‐Bradley JM, Rubin AS, Hanna RK, Simcoe DK, Lebsack ME. The pharmacokinetics of etanercept in healthy volunteers. Ann Pharmacother 2000; 34: 161–4.
    1. Nestorov I, Zitnik R, DeVries T, Nakanishi AM, Wang A, Banfield C. Pharmacokinetics of subcutaneously administered etanercept in subjects with psoriasis. Br J Clin Pharmacol 2006; 62: 435–45.
    1. ENBREL®[etanercept] . Summary of product characteristics, 2014.
    1. Committee for Medicinal Products for Human Use (CHMP) . Guideline on similar biological medicinal products containing monoclonal antibodies – non clinical and clinical issues. European Medicines Agency, 2012.
    1. Committee for Medicinal Products for Human Use (CHMP) . Guideline on similar biological medicinal product. European Medicines Agency, 2005.
    1. Food and Drug Administration Center for Drug Evaluation and Research . Guidance for industry: scientific considerations in demonstrating biosimilarity to a reference product. U.S. Department of Health and Human Services, 2015.
    1. Committee for Medicinal Products for Human Use (CHMP). Benepali: Assessment report. 2015. Available at
    1. Sullivan JT, Ni L, Sheelo C, Salfi M, Peloso PM. Bioequivalence of liquid and reconstituted lyophilized etanercept subcutaneous injections. J Clin Pharmacol 2006; 46: 654–61.
    1. Committee for Medicinal Products for Human Use (CHMP) . Guideline on the investigation of bioequivalence. European Medicines Agency, 2010.
    1. Food and Drug Administration Center for Drug Evaluation and Research . Guidance for industry: statistical approaches to establishing bioequivalence. US Department of Health and Human Services, 2001.
    1. Food and Drug Administration Center for Drug Evaluation and Research . Guidance for industry: bioavailability and bioequivalence studies submitted in NDAs or INDs – general considerations. US Department of Health and Human Service, 2014.
    1. William EJ. Experimental designs balanced for the estimation of residual effects of treatments. Aust J Chem 1949; 2: 149–68.
    1. Marzo A. Open questions on bioequivalence: some problems and some solutions. Pharmacol Res 1999; 40: 357–68.
    1. Zhou H. Clinical pharmacokinetics of etanercept: a fully humanized soluble recombinant tumor necrosis factor receptor fusion protein. J Clin Pharmacol 2005; 45: 490–7.
    1. Kawai S, Sekino H, Yamashita N, Tsuchiwata S, Liu H, Korth‐Bradley JM. The comparability of etanercept pharmacokinetics in healthy Japanese and American subjects. J Clin Pharmacol 2006; 46: 418–23.
    1. Keystone EC, Schiff MH, Kremer JM, Kafka S, Lovy M, DeVries T, Burge DJ. Once‐weekly administration of 50 mg etanercept in patients with active rheumatoid arthritis: results of a multicenter, randomized, double‐blind, placebo‐controlled trial. Arthritis Rheum 2004; 50: 353–63.
    1. Elewski B, Leonardi C, Gottlieb AB, Strober BE, Simiens MA, Dunn M, Jahreis A. Comparison of clinical and pharmacokinetic profiles of etanercept 25 mg twice weekly and 50 mg once weekly in patients with psoriasis. Br J Dermatol 2007; 156: 138–42.
    1. Gu N, Yi S, Kim TE, Shin SG, Jang IJ, Yu KS. Comparative pharmacokinetics and tolerability of branded etanercept (25 mg) and its biosimilar (25 mg): a randomized, open‐label, single‐dose, two‐sequence, crossover study in healthy Korean male volunteers. Clin Ther 2011; 33: 2029–37.
    1. Yi S, Kim SE, Park MK, Yoon SH, Cho JY, Lim KS, Shin SG, Jang IJ, Yu KS. Comparative pharmacokinetics of HD203, a biosimilar of etanercept, with marketed etanercept (Enbrel®): a double‐blind, single‐dose, crossover study in healthy volunteers. BioDrugs 2012; 26: 177–84.
    1. Ring A, Morris TB, Hohl K, Schall R. Indirect bioequivalence assessment using network meta‐analyses. Eur J Clin Pharmacol 2014; 70: 947–55.
    1. Emery P, Vencovský J, Sylwestrzak A, Leszczyński P, Porawska W, Baranauskaite A, Tseluyko V, Zhdan VM, Stasiuk B, Milasiene R, Rodriguez AAB, Cheong SY, Ghil J. A phase III randomised, double‐blind, parallel‐group study comparing SB4 with etanercept reference product in patients with active rheumatoid arthritis despite methotrexate therapy. Ann Rheum Dis 2015; (epub ahead of print).
    1. Singh SK. Impact of product‐related factors on immunogenicity of biotherapeutics. J Pharm Sci 2011; 100: 354–87.
    1. Hermeling S, Crommelin DJ, Schellekens H, Jiskoot W. Structure–immunogenicity relationships of therapeutic proteins. Pharm Res 2004; 21: 897–903.
    1. Rosenberg AS. Effects of protein aggregates: an immunologic perspective. AAPS J 2006; 8: E501–7.
    1. Noguchi A, Mukuria CJ, Suzuki E, Naiki M. Immunogenicity of N‐glycolylneuraminic acid‐containing carbohydrate chains of recombinant human erythropoietin expressed in Chinese hamster ovary cells. J Biochem 1995; 117: 59–62.
    1. Sheeley DM, Merrill BM, Taylor LC. Characterization of monoclonal antibody glycosylation: comparison of expression systems and identification of terminal alpha‐linked galactose. Anal Biochem 1997; 247: 102–10.
    1. Qian J, Liu T, Yang L, Daus A, Crowley R, Zhou Q. Structural characterization of N‐linked oligosaccharides on monoclonal antibody cetuximab by the combination of orthogonal matrix‐assisted laser desorption/ionization hybrid quadrupole–quadrupole time‐of‐flight tandem mass spectrometry and sequential enzymatic digestion. Anal Biochem 2007; 364: 8–18.
    1. Flynn GC, Chen X, Liu YD, Shah B, Zhang Z. Naturally occurring glycan forms of human immunoglobulins G1 and G2. Mol Immunol 2010; 47: 2074–82.

Source: PubMed

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