Biosimilars in Inflammatory Bowel Disease: Facts and Fears of Extrapolation

Shomron Ben-Horin; Niels Vande Casteele; Stefan Schreiber; Peter Laszlo Lakatos

| Disclosures

Clin Gastroenterol Hepatol. 2016;14(12):1685-1696. 

 

Abstract and Introduction

Abstract

Biologic drugs such as infliximab and other anti–tumor necrosis factor monoclonal antibodies have transformed the treatment of immune-mediated inflammatory conditions such as Crohn's disease and ulcerative colitis (collectively known as inflammatory bowel disease [IBD]). However, the complex manufacturing processes involved in producing these drugs mean their use in clinical practice is expensive. Recent or impending expiration of patents for several biologics has led to development of biosimilar versions of these drugs, with the aim of providing substantial cost savings and increased accessibility to treatment. Biosimilars undergo an expedited regulatory process. This involves proving structural, functional, and biological biosimilarity to the reference product (RP). It is also expected that clinical equivalency/comparability will be demonstrated in a clinical trial in one (or more) sensitive population. Once these requirements are fulfilled, extrapolation of biosimilar approval to other indications for which the RP is approved is permitted without the need for further clinical trials, as long as this is scientifically justifiable. However, such justification requires that the mechanism(s) of action of the RP in question should be similar across indications and also comparable between the RP and the biosimilar in the clinically tested population(s). Likewise, the pharmacokinetics, immunogenicity, and safety of the RP should be similar across indications and comparable between the RP and biosimilar in the clinically tested population(s). To date, most anti–tumor necrosis factor biosimilars have been tested in trials recruiting patients with rheumatoid arthritis. Concerns have been raised regarding extrapolation of clinical data obtained in rheumatologic populations to IBD indications. In this review, we discuss the issues surrounding indication extrapolation, with a focus on extrapolation to IBD.

Introduction

Crohn's disease (CD) and ulcerative colitis (UC), collectively known as inflammatory bowel disease (IBD), are chronic, relapsing immune-mediated inflammatory diseases of the gastrointestinal tract. The advent of biologic drugs, starting with the anti–tumor necrosis factor (TNF) monoclonal antibodies, has significantly improved outcomes for patients with IBD.

The relatively high cost of anti-TNF agents and their looming or actual patent expiration have triggered the development of highly similar versions of these drugs that are known as biosimilars. Compared with originator biologics, biosimilars follow an expedited process for regulatory approval. Most notably and provided that certain requirements are met, virtually all regulatory agencies allow, in principle, for extrapolation of indications. Extrapolation means that once biosimilarity has been established in 1 or more indications, a biosimilar may be approved for additional or all other indications for which the originator, or reference product (RP), has been approved without the need for clinical trials in the latter indications.[1,2] Nonetheless, there has been much debate on the validity of extrapolation of clinical data for biosimilars.[3–6] In this review, we consider the fears and facts regarding extrapolation of biosimilar data to IBD, starting with a brief introduction to some important biosimilar concepts.

 
1 of 6
 
 
Latest in Gastroenterology
Table 1.  Biosimilars Approved or Under Development for Possible Use in IBD a
RP Biosimilar name Company Current development stage Approval status
Infliximab CT-P13 (Remsima®; Inflectra®) CELLTRION Phase III completed in RA and AS Approved in Europe, USA, and elsewhere
SB2 (Flixabi®) Samsung Bioepis Phase III completed in RA Approved in Europe and Korea; under review by FDA
BOW015 (Infimab™) Epirus Biopharmaceuticals/Sun Pharma/Ranbaxy Laboratories Phase III trial in RA currently recruiting Approved in India only
NI-07121 Nichi-Iko Pharmaceutical Phase III completed in RA Not approved or under review
PF-06438179 Pfizer/Sandoz Phase III ongoing in RA Not approved or under review
Adalimumab ABP 501 Amgen Phase III completed in RA and PsO Approved in USA; under review by EMA
Exemptia Zydus Cadila Phase III completed in RA Approved in India only
SB5 Samsung Bioepis Phase III completed in RA Under review by EMA
MSB1102281 Merck KGaA Phase III ongoing in PsO Not approved or under review
GP2017 Sandoz Phase III ongoing in PsO Not approved or under review
BI695501 Boehringer Ingelheim Phase III ongoing in RA Not approved or under review
FKB32782 Fujifilm Kyowa Kirin Biologics Phase III ongoing in RA Not approved or under review
PF-06410293 Pfizer Phase III ongoing in RA Not approved or under review
CHS-1420 Coherus Biosciences Phase III ongoing in PsO Not approved or under review
M923 Momenta Pharmaceuticals/Baxalta Phase III ongoing in PsO Not approved or under review
LBAL83 LG Life Sciences/Mochida Pharmaceutical Phase I completed in healthy volunteers Not approved or under review
ONS-3010 Oncobiologics/Viropro Phase I completed in healthy volunteers Not approved or under review
BOW050 Epirus Biopharmaceuticals Preclinical Not approved or under review
Golimumab BOW100 Epirus Biopharmaceuticals Preclinical Not approved or under review
Certolizumab pegol PF688 Pfenex Preclinical Not approved or under review
Xcimzane Xbrane Preclinical Not approved or under review

PsO, plaque psoriasis.
aInformation was obtained from company websites unless otherwise stated.

Table 2.  Available Published Evidence on Comparable Functional/Biological Activity of CT-P13 and ABP 501 and Their Respective RPs
Functional/biological activity CT-P13 vs infliximab RP34 ABP 501 vs adalimumab RP33
Binding to TNF
  • Comparable binding to hTNF as determined by ELISA

  • Comparable binding to monomeric and trimeric hTNF as determined by surface plasmon resonance

  • Comparable binding to tmTNF as determined by a cell-based ELISA

  • Comparable binding affinity to sTNF as determined by surface plasmon resonance

  • Comparable binding to tmTNF as determined by competitive imaging cytometry-based assay

Neutralization
  • Comparable and dose-dependent neutralization in a cell-based assay by using a TNF-sensitive cell line

  • Comparable and dose-dependent suppression of cytokine secretion by blocking sTNF in an IBD model (epithelial cells)

  • Comparable and dose-dependent suppression of apoptosis by blocking sTNF in an IBD model (epithelial cells)

  • Comparable blocking of TNF-induced caspase activation

  • Comparable blocking of TNF-induced interleukin-8 secretion

  • Comparable blocking of TNF-induced cytotoxicity

Binding to Fcγ receptors
  • Comparable relative binding affinities to FcγRI, FcγRIIa, FcγRIIb, and FcRn

  • Reduced relative binding affinities to FcγRIIIa and FcγRIIIb for CT-P13

  • Reduced relative binding affinities to NK cells of healthy donors and CD patients for CT-P13 (difference was genotype-specific [V/V and V/F] and disappeared in presence of diluted CD patient serum)

  • Comparable binding affinities to neutrophils from healthy donors or CD patients

  • Comparable binding to FcRn as determined in a competitive cell-based assay

  • Comparable binding to FcγRIIIa (158V) as determined by AlphaLISA™

Reverse signaling
  • Comparable induction of apoptosis by reverse signaling through tmTNF by using a cell-based assay (PBMC from healthy donors and CD patients)

  • Comparable blockade of proinflammatory cytokine production by reverse signaling by using a cell-based assay (PBMC from healthy donors and CD patients)

  • Not reported

Cytotoxicity
  • Comparable C1q binding and CDC activity as determined by ELISA and other assays

  • Comparable ADCC activity by using tmTNF-expressing Jurkat cells as target cells and PBMC or NK cells from healthy donors as effector cells

  • Comparable ADCC activity by using tmTNF-expressing Jurkat cells as target cells and PBMC from CD patients as effector cells

  • Reduced ADCC activity for CT-P13 by using tmTNF-expressing Jurkat cells as target cells and NK from CD patients as effector cells (genotype-specific)

  • Comparable ADCC activity by using tmTNF-expressing Jurkat cells as target cells and whole blood from healthy donors or CD patients as effector cells

  • Comparable ADCC activity by using LPS-stimulated monocytes from healthy donors or CD patients as target cells and PBMC as effector cells

  • Comparable dose-response profile for CDC by using cells expressing tmTNF

  • Comparable dose-response profile for ADCC by using cells expressing tmTNF

  • Comparable dose-response profile for ADCC by using NK92-M1 cells expressing FcγRIIIa (158V)

NOTE. Data on other biosimilars in development were not in the public domain at the time that this article was developed.
CDC, complement-dependent cytotoxicity; ELISA, enzyme-linked immunosorbent assay; hTNF, human TNF; LPS, lipopolysaccharide; NK, natural killer; PBMC, peripheral blood mononuclear cells.

Table 3.  Summary of Real-world Efficacy and Safety of CT-P13 in IBDs
Study Follow-up IBD N TNF-naïve (n) Efficacy Safety
Clinical response (% of patients; [n/N]) Remission rate (% of patients; [n/N]) Adverse event (% of patients; [n/N]) IRR (% of patients; [n/N])
Farkas et al68 8 wk CD 18 16 37.5a (6/16) 50.0a (8/16) NR NR
UC 21 19 20.0a (3/15) 66.7a (10/15) NR NR
Gecse et al69 14 wk CD 126 93 81.4 (79/97) 53.6 (52/97) 17.1b (36/210) 6.6b (14/210)
UC 84 68 77.6 (45/58) 58.6 (34/58)
Jahnsen et al70 14 wk CD 46 33 NR 79.0 (34/43) NR 2.2 (1/46)
UC 32 27 NR 56.0 (18/32) NR 3.1 (1/32)
Jung et al71 54 wk CD 59 32 87.5c (7/8) 75.0c (6/8) 0.0 (0/59) 0.0
UC 51 42 100.0c (12/12) 50.0c (6/12) 11.8 (6/51) NR
Kang et al72 8 wk CD 8 3 66.7c (2/3) 66.7c (2/3) 0.0 NR
UC 9 5 100.0c (5/5) 100.0c (5/5) 0.0 NR
Keil et al73 14 wk CD 30 30 100.0 (30/30) 50.0 (15/30) NR 1.9 (1/52)
UC 22 22 95.5 (21/22) 40.9 (9/22)
Park et al74 30 wk CDd 95 51 77.8c (35/45) 57.8c (26/45) 17.9 (17/95) 2.1 (2/95)
UC 78 62 72.2c (39/54) 37.0c (20/54) 26.9 (21/78) 1.3 (1/78)
Sieczkowska et al75 8 mo (mean) pCD 32e 26 NR 87.5 (28/32) NR 3.1 (1/32)
5 mo (mean) pUC 7e 6 NR 57.1 (4/7) NR 28.6 (2/7)

NOTE. Data are from studies published in full form and listed on PubMed.
IRR, infusion-related reaction; NR, not reported; p, pediatric.
aOf patients who completed induction treatment.
bAt week 30.
cIn TNF-naïve patients only.
dIncluding fistulizing active CD (n = 12).
ePatients had switched from infliximab to CT-P13.

References

  1. European Medicines Agency. Guideline on similar biological medicinal products. October 23, 2014. CHMP/437/04 Rev 1. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/10/WC500176768.pdf. Accessed February 28, 2016.

  2. U. S. Food and Drug Administration. Scientific considerations in demonstrating biosimilarity to a reference product: guidance for industry. April 2015. Available at: http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. Accessed February 28, 2016.

  3. Annese V, Vecchi M. Use of biosimilars in inflammatory bowel disease: statements of the Italian Group for Inflammatory Bowel Disease. Dig Liver Dis 2014;46:963–968.

  4. Devlin SM, Bressler B, Bernstein CN, et al. Overview of subsequent entry biologics for the management of inflammatory bowel disease and Canadian Association of Gastroenterology position statement on subsequent entry biologics. Can J Gastroenterol 2013;27:567–571.

  5. Feagan BG, Choquette D, Ghosh S, et al. The challenge of indication extrapolation for infliximab biosimilars. Biologicals 2014;42:177–183.

  6. Danese S, Fiorino G, Michetti P. Viewpoint: knowledge and viewpoints on biosimilar monoclonal antibodies among members of the European Crohn's and Colitis Organization. J Crohns Colitis 2014;8:1548–1550.

  7. World Health Organization. Expert Committee on Biological Standardization: guidelines on evaluation of similar biotherapeutic products. 2009. Available at: http://www.who.int/biologicals/areas/biological_therapeutics/BIOTHERAPEUTICS_FOR_WEB_22APRIL2010.pdf. Accessed February 28, 2016.

  8. Al-Sabbagh A, Olech E, McClellan JE, et al. Development of biosimilars. Semin Arthritis Rheum 2016;45(Suppl 5):S11–S18.

  9. U. S. Food and Drug Administration. Demonstration of comparability of human biological products, including therapeutic biotechnology-derived products. Available at: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm122879.htm. Accessed April 4, 2016.

  10. International Conference on Harmonisation. Q5E Comparability of biotechnological/biological products subject to changes in their manufacturing process. Available at: http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q5E/Step4/Q5E_Guideline.pdf. Accessed April 4, 2016.

  11. INFLECTRA prescribing information. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125544s000lbl.pdf. Accessed April 11, 2016.

  12. Park W, Hrycaj P, Jeka S, et al. A randomised, double-blind, multicentre, parallel-group, prospective study comparing the pharmacokinetics, safety, and efficacy of CT-P13 and innovator infliximab in patients with ankylosing spondylitis: the PLANETAS study. Ann Rheum Dis 2013;72:1605–1612.

  13. Park W, Yoo DH, Jaworski J, et al. Comparable long-termefficacy, as assessed by patient-reported outcomes, safety and pharmacokinetics, of CT-P13 and reference infliximab in patients with ankylosing spondylitis: 54-week results from the randomized, parallel-group PLANETAS study. Arthritis Res Ther 2016;18:25.

  14. Yoo DH, Hrycaj P, Miranda P, et al. A randomised, double-blind, parallel-group study to demonstrate equivalence in efficacy and safety of CT-P13 compared with innovator infliximab when coadministered with methotrexate in patients with active rheumatoid arthritis: the PLANETRA study. Ann Rheum Dis 2013;72:1613–1620.

  15. Yoo DH, Racewicz A, Brzezicki J, et al. A phase III randomized study to evaluate the efficacy and safety of CT-P13 compared with reference infliximab in patients with active rheumatoid arthritis: 54-week results from the PLANETRA study. Arthritis Res Ther 2016;18:82.

  16. Park W, Yoo DH, Miranda P, et al. Efficacy and safety of switching from reference infliximab to CT-P13 compared to maintenance of CT-P13 in ankylosing spondylitis: 102-week data from the PLANETAS extension study. Ann Rheum Dis 2016; http://dx.doi.org/10.1136/annrheumdis-2015-208783.

  17. Yoo DH, Prodanovic N, Jaworski, J, et al. Efficacy and safety of CT-P13 (biosimilar infliximab) in patients with rheumatoid arthritis: comparison between switching from reference infliximab to CT-P13 and continuing CT-P13 in the PLANETRA extension study. Ann Rheum Dis 2016; http://dx.doi.org/10.1136/annrheumdis-2015-208786.

  18. Health Canada. Regulatory decision summary for REMSIMA (Control number 184568). August 5, 2016. Available at: http://www.hc-sc.gc.ca/dhp-mps/prodpharma/rds-sdr/drug-med/rdssdr-remsima-184568-eng.php. Accessed October 7, 2016.

  19. Choe JY, Prodanovic N, Niebrzydowski J, et al. A randomised, double-blind, phase III study comparing SB2, an infliximab biosimilar, to the infliximab reference product Remicade in patients with moderate to severe rheumatoid arthritis despite methotrexate therapy. Ann Rheum Dis 2015; http://dx.doi.org/10.1136/annrheumdis-2015-207764.

  20. Kay J, Wyand M, Chandrashekara S, et al. BOW015, a biosimilar infliximab, in patients with active rheumatoid arthritis on stable methotrexate doses: 54-week results of a randomized, double-blind, active comparator study. Arthritis Rheumatol 2014;66:3538 (L20).

  21. Nichi-Iko Pharmaceuticals. Phase III testing for NI-071 results (preliminary report). June 22, 2015. Available at: http://www.nichiiko.co.jp/finance/gif/4541_20150622_01.pdf. Accessed February 28, 2016.

  22. Biogen press release. FLIXABI®, Biogen's infliximab biosimilar referencing Remicade®, approved in the European Union. May 30, 2016. Available at: http://media.biogen.com/press-release/biosimilars/flixabi-biogens-infliximab-biosimilar-referencingremicade-approved-europe. Accessed October 7, 2016.

  23. Kaur P, Chow V, Zhang N, et al. A randomized, single-blind, single-dose, three-arm, parallel group study in healthy subjects to demonstrate pharmacokinetic equivalence of ABP-501 and adalimumab: results of comparison with adalimumab (EU). Ann Rheum Dis 2014;73:479 [FRI0264].

  24. Amgen press release. Amgen announces positive top-line results from phase 3 study evaluating the efficacy and safety of biosimilar candidate ABP 501 compared with adalimumab in patients with moderate-to-severe plaque psoriasis. October 8, 2014. Available at: http://investors.amgen.com/phoenix.zhtml?c=61656&p=irol-newsArticle&ID=1975377. Accessed February 28, 2016.

  25. Cohen SB, Genovese MC, Choy EH, et al. Randomized, doubleblind, phase 3 study of efficacy and safety of ABP 501 compared with adalimumab in subjects with moderate to severe rheumatoid arthritis. Arthritis Rheum 2015;67(Suppl 10):A2054.

  26. European Medicines Agency. Remsima assessment report. June 27, 2013. EMA/CHMP/589317/2013. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002576/WC500151486.pdf. Accessed February 28, 2016.

  27. Blandizzi C, Gionchetti P, Armuzzi A, et al. The role of tumour necrosis factor in the pathogenesis of immune-mediated diseases. Int J Immunopathol Pharmacol 2014;27:1–10.

  28. Sedger LM, McDermott MF. TNF and TNF-receptors: from mediators of cell death and inflammation to therapeutic giants—past, present and future. Cytokine Growth Factor Rev 2014;25:453–472.

  29. Van den Brande JMH, Koehler TC, Zelinkova Z, et al. Prediction of antitumour necrosis factor clinical efficacy by real-time visualization of apoptosis in patients with Crohn's disease. Gut 2007;56:509–517.

  30. Shen C, Assche GV, Colpaert S, et al. Adalimumab induces apoptosis of human monocytes: a comparative study with infliximab and etanercept. Aliment Pharmacol Ther 2005;21:251–258.

  31. Van den Brande JM, Braat H, van den Brink GR, et al. Infliximab but not etanercept induces apoptosis in lamina propria Tlymphocytes from patients with Crohn's disease. Gastroenterology 2003;124:1774–1785.

  32. European Medicines Agency. Benepali assessment report. November 19, 2015. EMA/CHMP/819219/2015. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/004007/WC500200380.pdf. Accessed April 4, 2016.

  33. Born T, Velayudhan J, Chen Y, et al. Demonstration of functional similarity comparing adalimumab to biosimilar candidate ABP 501. Arthritis Rheum 2014;10(Suppl):S661 [A1503].

  34. U. S. Food and Drug Administration. FDA briefing document. Arthritis Advisory Committee Meeting. BLA 125544. February 9, 2016. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM484859.pdf. Accessed February 28, 2016.

  35. Vos AC, Wildenberg ME, Duijvestein M, et al. Anti–tumor necrosis factor-a antibodies induce regulatory macrophages in an Fc region-dependent manner. Gastroenterology 2011; 140:221–230 e3.

  36. Vos AC, Wildenberg ME, Arijs I, et al. Regulatory macrophages induced by infliximab are involved in healing in vivo and in vitro. Inflamm Bowel Dis 2012;18:401–408.

  37. Hebuterne X, Lemann M, Bouhnik Y, et al. Endoscopic improvement of mucosal lesions in patients with moderate to severe ileocolonic Crohn's disease following treatment with certolizumab pegol. Gut 2013;62:201–208.

  38. McRae BL, Levin AD, Wildenberg ME, et al. Fc receptor-mediated effector function contributes to the therapeutic response of anti-TNF monoclonal antibodies in a mouse model of inflammatory bowel disease. J Crohns Colitis 2016;10:69–76.

  39. Long EO, Kim HS, Liu D, et al. Controlling NK cell responses: integration of signals for activation and inhibition. Annu Rev Immunol 2013;31:227–258.

  40. Louis E, El Ghoul Z, Vermeire S, et al. Association between polymorphism in IgG Fc receptor IIIa coding gene and biological response to infliximab in Crohn's disease. Aliment Pharmacol Ther 2004;19:511–519.

  41. Moroi R, Endo K, Kinouchi Y, et al. FCGR3A-158 polymorphism influences the biological response to infliximab in Crohn's disease through affecting the ADCC activity. Immunogenetics 2013;65:265–271.

  42. Louis EJ, Watier HE, Schreiber S, et al. Polymorphism in IgG Fc receptor gene FCGR3A and response to infliximab in Crohn's disease: a subanalysis of the ACCENT I study. Pharmacogenet Genomics 2006;16:911–914.

  43. Ternant D, Berkane Z, Picon L, et al. Assessment of the influence of inflammation and FCGR3A genotype on infliximab pharmacokinetics and time to relapse in patients with Crohn's disease. Clin Pharmacokinet 2015;54:551–562.

  44. Baumgart DC, Lowder JN, Targan SR, et al. Transient cytokine-induced liver injury following administration of the humanized anti-CD3 antibody visilizumab (HuM291) in Crohn's disease. Am J Gastroenterol 2009;104:868–876.

  45. Brennan FR, Morton LD, Spindeldreher S, et al. Safety and immunotoxicity assessment of immunomodulatory monoclonal antibodies. MAbs 2010;2:233–255.

  46. Winkler U, Jensen M, Manzke O, et al. Cytokine-release syndrome in patients with B-cell chronic lymphocytic leukemia and high lymphocyte counts after treatment with an anti-CD20 monoclonal antibody (Rituximab, IDEC-C2B8). Blood 1999;94:2217–2224.

  47. Reinisch W, Louis E, Danese S. The scientific and regulatory rationale for indication extrapolation: a case study based on the infliximab biosimilar CT-P13. Expert Rev Gastroenterol Hepatol 2015;9(Suppl 1):17–26.

  48. Takeuchi T, Yamanaka H, Tanaka Y, et al. Evaluation of the pharmacokinetic equivalence and 54-week efficacy and safety of CT-P13 and innovator infliximab in Japanese patients with rheumatoid arthritis. Mod Rheumatol 2015;25:817–824.

  49. Park W, Lee SJ, Yun J, et al. Comparison of the pharmacokinetics and safety of three formulations of infliximab (CT-P13, EU-approved reference infliximab and the US-licensed reference infliximab) in healthy subjects: a randomized, double-blind, three-arm, parallel-group, single-dose, Phase I study. Expert Rev Clin Immunol 2015;11(Suppl 1):S25–S31.

  50. Lambert J, Wyand M, Lassen C, et al. Pharmacokinetic results from a phase 1, single-centre, double-blind, randomised, single-dose, parallel group study comparing 5 mg/kg IV infusion of BOW015 and reference infliximab in healthy male volunteers. Ann Rheum Dis 2015;74(Suppl 2):462 (FRI0116).

  51. Wynne C, Petkova M, Rombout F, et al. BI 695501, a proposed biosimilar for adalimumab, shows bioequivalence to adalimumab reference products in a randomized, double-blind phase I trial in healthy subjects. Arthritis Rheumatol 2015;67(Suppl 10):A2727.

  52. Fasanmade AA, Adedokun OJ, Blank M, et al. Pharmacokinetic properties of infliximab in children and adults with Crohn's disease: a retrospective analysis of data from 2 phase III clinical trials. Clin Ther 2011;33:946–964.

  53. Fasanmade AA, Adedokun OJ, Ford J, et al. Population pharmacokinetic analysis of infliximab in patients with ulcerative colitis. Eur J Clin Pharmacol 2009;65:1211–1228.

  54. Xu Z, Seitz K, Fasanmade A, et al. Population pharmacokinetics of infliximab in patients with ankylosing spondylitis. J Clin Pharmacol 2008;48:681–695.

  55. Brandse JF, van den Brink GR, Wildenberg ME, et al. Loss of infliximab into feces is associated with lack of response to therapy in patients with severe ulcerative colitis. Gastroenterology 2015;149:350–355 e2.

  56. Vande Casteele N, Gils A. Pharmacokinetics of anti-TNF monoclonal antibodies in inflammatory bowel disease: adding value to current practice. J Clin Pharmacol 2015;55(Suppl 3):S39–S50.

  57. Yarur AJ, Jain A, Sussman DA, et al. The association of tissue anti-TNF drug levels with serological and endoscopic disease activity in inflammatory bowel disease: the ATLAS study. Gut 2015;65:249–255.

  58. Lee H. Is extrapolation of the safety and efficacy data in one indication to another appropriate for biosimilars? AAPS J 2014;16:22–26.

  59. Ben-Horin S, Heap GA, Ahmad T, et al. The immunogenicity of biosimilar infliximab: can we extrapolate the data across indications? Expert Rev Gastroenterol Hepatol 2015;9(Suppl 1):27–34.

  60. Feagan BG, McDonald JW, Panaccione R, et al. Methotrexate in combination with infliximab is no more effective than infliximab alone in patients with Crohn's disease. Gastroenterology 2014;146:681–688 e1.

  61. St Clair EW, Wagner CL, Fasanmade AA, et al. The relationship of serum infliximab concentrations to clinical improvement in rheumatoid arthritis: results from ATTRACT, a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2002;46:1451–1459.

  62. Ben-Horin S, Yavzori M, Benhar I, et al. Cross-immunogenicity: antibodies to infliximab in Remicade-treated patients with IBD similarly recognise the biosimilar Remsima. Gut 2015;65:1132–1138.

  63. Present DH, Rutgeerts P, Targan S, et al. Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med 1999;340:1398–1405.

  64. Hyder SA, Travis SP, Jewell DP, et al. Fistulating anal Crohn's disease: results of combined surgical and infliximab treatment. Dis Colon Rectum 2006;49:1837–1841.

  65. Van Assche G, Lewis JD, Lichtenstein GR, et al. The London position statement of the World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn's and Colitis Organisation: safety. Am J Gastroenterol 2011;106:1594–1602.

  66. Lichtenstein GR, Olson A, Travers S, et al. Factors associated with the development of intestinal strictures or obstructions in patients with Crohn's disease. Am J Gastroenterol 2006;101:1030–1038.

  67. Pallotta N, Barberani F, Hassan NA, et al. Effect of infliximab on small bowel stenoses in patients with Crohn's disease. World J Gastroenterol 2008;14:1885–1890.

  68. Farkas K, Rutka M, Balint A, et al. Efficacy of the new infliximab biosimilar CT-P13 induction therapy in Crohn's disease and ulcerative colitis: experiences from a single center. Expert Opin Biol Ther 2015;15:1257–1262.

  69. Gecse KB, Lovasz BD, Farkas K, et al. Efficacy and safety of the biosimilar infliximab CT-P13 treatment in inflammatory bowel diseases: a prospective, multicentre, nationwide cohort. J Crohns Colitis 2015;10:133–140.

  70. Jahnsen J, Detlie TE, Vatn S, et al. Biosimilar infliximab (CT-P13) in the treatment of inflammatory bowel disease: a Norwegian observational study. Expert Rev Gastroenterol Hepatol 2015;9(Suppl 1):45–52.

  71. Jung YS, Park DI, Kim YH, et al. Efficacy and safety of CT-P13, a biosimilar of infliximab, in patients with inflammatory bowel disease: a retrospective multicenter study. J Gastroenterol Hepatol 2015;30:1705–1712.

  72. Kang YS, Moon HH, Lee SE, et al. Clinical experience of the use of CT-P13, a biosimilar to infliximab in patients with inflammatory bowel disease: a case series. Dig Dis Sci 2015;60:951–956.

  73. Keil R, Wasserbaeur M, Zádorvá Z, et al. Clinical monitoring: infliximab biosimilar CT-P13 in the treatment of Crohn's disease and ulcerative colitis. Scand J Gastroenterol 2016;51:1062–1068.

  74. Park SH, Kim YH, Lee JH, et al. Post-marketing study of biosimilar infliximab (CT-P13) to evaluate its safety and efficacy in Korea. Expert Rev Gastroenterol Hepatol 2015;9(Suppl 1):35–44.

  75. Sieczkowska J, Jarzebicka D, Banaszkiewicz A, et al. Switching between infliximab originator and biosimilar in pediatric patients with inflammatory bowel disease: preliminary observations. J Crohns Colitis 2016;10:127–132.

  76. Murphy C, Sugrue K, Mohamad J, et al. Biosimilar but not the same. J Crohns Colitis 2015;9(Suppl 1):S331–S332 (P505).

  77. U. S. Food and Drug Administration. Information on biosimilars. Available at: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/default.htm. Accessed March 25, 2016.

  78. Vande Casteele N, Gils A. Preemptive dose optimization using therapeutic drug monitoring for biologic therapy of Crohn's disease: avoiding failure while lowering costs? Dig Dis Sci 2015;60:2571–2573.

  79. ClinicalTrials.gov. Demonstrate noninferiority in efficacy and to assess safety of CT-P13 in patients with active Crohn's disease. Available at: https://clinicaltrials.gov/ct2/show/NCT02096861. Accessed February 28, 2016.

  80. ClinicalTrials.gov. The NOR-SWITCH Study. Available at: https://clinicaltrials.gov/ct2/show/NCT02148640. Accessed February 28, 2016.

  81. Generics and Biosimilars Initiative. Merck Group starts phase III trial for adalimumab biosimilar. March 18, 2016. Available at: http://www.gabionline.net/Biosimilars/News/Merck-Group-starts-phase-III-trial-for-adalimumab-biosimilar. Accessed April 5, 2016.

  82. ClinicalTrials.gov. A study to compare FKB327 efficacy and safety with Humira® in rheumatoid arthritis patients (ARABESC). Available at: https://clinicaltrials.gov/ct2/show/NCT02260791. Accessed April 5, 2016.

  83. ClinicalTrials.gov. Pharmacokinetics and safety study of LBAL in healthy subjects. Available at: https://clinicaltrials.gov/ct2/show/NCT02206867. Accessed April 5, 2016.

Authors and Disclosures

Shomron Ben-Horin*, Niels Vande Casteele‡,§, Stefan Schreiber|| and Peter Laszlo Lakatos

*Gastroenterology Department, Sheba Medical Center and Sackler School of Medicine, Tel-Aviv University, Tel Hashomer, Israel; Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium; §Division of Gastroenterology, University of California San Diego, La Jolla, California; ||Klinik für Innere Medizin I, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Germany; and First Department of Internal Medicine, Semmelweis University, Budapest, Hungary

Address requests for reprints to
Shomron Ben-Horin, MD, Gastroenterology Department, Sheba Medical Center, Tel Hashomer, Ramat-Gan 52621, Israel. e-mail: shomron.benhorin@gmail.com; fax: +972-3-5303160.

Conflicts of interest
The authors disclose the following: Shomron Ben-Horin has received consultancy and/or advisory board fees from Schering-Plough, AbbVie, CELLTRION, Janssen, and Takeda and has received research support from CELLTRION and AbbVie. Niels Vande Casteele is a Postdoctoral Fellow of the Research Foundation - Flanders (FWO), Belgium (grant number 1260714N) and has received consultancy fees from MSD, Janssen Biologics BV, UCB, Pfizer, and Takeda and lecture fees from AbbVie. Stefan Schreiber has served on advisory boards for AbbVie, Biogen, CELLTRION, Hospira, Merck, Mundipharma, Takeda, and UCB and has given paid lectures for AbbVie, Hospira, Merck, Mundipharma, and Takeda. Peter Laszlo Lakatos has served as a speaker and/or advisory board member for AbbVie, CELLTRION, EGIS, Falk Pharma GmbH, Ferring, Genentech, Kyowa Hakko Kirin Pharma, Mitsubishi Tanabe Pharma Corporation, MSD, Otsuka, Pharmacosmos, Pfizer, Roche, and Takeda and has received unrestricted research grants from AbbVie, MSD, and Pfizer/Hospira.

Funding
Medical writing assistance was provided by Alice Wareham, PhD at Aspire Scientific Limited (Bollington, United Kingdom) and was funded by CELLTRION Healthcare Co, Ltd (Incheon, Republic of Korea).

processing....