Biosimilars in Inflammatory Bowel Disease: Facts and Fears of Extrapolation
Authors: Shomron Ben-Horin, Niels Vande Casteele, Stefan Schreiber, Peter Laszlo Lakatos
Journal: Clinical Gastroenterology and Hepatology (2016)

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. 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. 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.1European 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.Google Scholar, 2U. 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.Google Scholar Nonetheless, there has been much debate on the validity of extrapolation of clinical data for biosimilars.3Annese V. Vecchi M. Use of biosimilars in inflammatory bowel disease: statements of the Italian Group for Inflammatory Bowel Disease.Dig Liver Dis. 2014; 46: 963-968Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, 4Devlin S.M. Bressler B. Bernstein C.N. 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: 567-571Crossref PubMed Scopus (28) Google Scholar, 5Feagan B.G. Choquette D. Ghosh S. et al.The challenge of indication extrapolation for infliximab biosimilars.Biologicals. 2014; 42: 177-183Crossref PubMed Scopus (125) Google Scholar, 6Danese 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: 1548-1550Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar 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. The World Health Organization defines a biosimilar as a "biotherapeutic product which is similar in terms of quality, safety and efficacy to an already licensed reference biotherapeutic product".7World 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.Google Scholar The primary amino acid sequences of a biosimilar and its RP are the same, although often subtle variations in their complex manufacturing processes mean the 2 products are not identical in every way. In fact, the inherent variability of the living bacteria-based systems used to make all biologic drugs means no 2 batches of a single biologic (either an RP or biosimilar) will ever be exactly alike.8Al-Sabbagh A. Olech E. McClellan J.E. et al.Development of biosimilars.Semin Arthritis Rheum. 2016; 45: S11-S18Crossref Scopus (35) Google Scholar For RPs, batch-to-batch microheterogeneity, or changes due to alterations in manufacturing processes, are acceptable if the product falls within defined tolerance boundaries.9U. 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.Google Scholar, 10International 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.Google Scholar This principle is similarly applied to the development of biosimilars; minor differences in clinically inactive components between the biosimilar and RP are considered acceptable as long as there are no clinically meaningful differences between the drugs in terms of safety, purity, and potency.2U. 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.Google Scholar Comprehensive comparability testing is required to prove biosimilarity and to show that any differences found are not clinically meaningful. Such testing begins with a detailed analytical comparison of a biosimilar and its RP in terms of structure and functional/biological activity, complemented with nonclinical in vivo studies. However, the expedited process for biosimilar development requires fewer clinical data than were needed for its RP. According to guidance provided by the U. S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), the clinical efficacy and side effects of a biosimilar are anticipated to be studied in one of the RP-approved indications.1European 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.Google Scholar, 2U. 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.Google Scholar Four anti-TNF drugs (infliximab, adalimumab, certolizumab pegol, and golimumab) and 2 anti-integrin antibodies (natalizumab and vedolizumab) are presently approved in IBD indications in the United States. Expiration of patents protecting some anti-TNF drugs has heralded development of several biosimilars by different companies (Table 1).Table 1Biosimilars Approved or Under Development for Possible Use in IBDaInformation was obtained from company websites unless otherwise stated.RPBiosimilar nameCompanyCurrent development stageApproval statusInfliximabCT-P13 (Remsima®; Inflectra®)CELLTRIONPhase III completed in RA and ASApproved in Europe, USA, and elsewhereSB2 (Flixabi®)Samsung BioepisPhase III completed in RAApproved in Europe and Korea; under review by FDABOW015 (Infimab™)Epirus Biopharmaceuticals/Sun Pharma/Ranbaxy LaboratoriesPhase III trial in RA currently recruitingApproved in India onlyNI-07121Nichi-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.Google ScholarNichi-Iko PharmaceuticalPhase III completed in RANot approved or under reviewPF-06438179Pfizer/SandozPhase III ongoing in RANot approved or under reviewAdalimumabABP 501AmgenPhase III completed in RA and PsOApproved in USA; under review by EMAExemptiaZydus CadilaPhase III completed in RAApproved in India onlySB5Samsung BioepisPhase III completed in RAUnder review by EMAMSB1102281Generics 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.Google ScholarMerck KGaAPhase III ongoing in PsONot approved or under reviewGP2017SandozPhase III ongoing in PsONot approved or under reviewBI695501Boehringer IngelheimPhase III ongoing in RANot approved or under reviewFKB32782ClinicalTrials.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.Google ScholarFujifilm Kyowa Kirin BiologicsPhase III ongoing in RANot approved or under reviewPF-06410293PfizerPhase III ongoing in RANot approved or under reviewCHS-1420Coherus BiosciencesPhase III ongoing in PsONot approved or under reviewM923Momenta Pharmaceuticals/BaxaltaPhase III ongoing in PsONot approved or under reviewLBAL83ClinicalTrials.gov. Pharmacokinetics and safety study of LBAL in healthy subjects. Available at: https://clinicaltrials.gov/ct2/show/NCT02206867. Accessed April 5, 2016.Google ScholarLG Life Sciences/Mochida PharmaceuticalPhase I completed in healthy volunteersNot approved or under reviewONS-3010Oncobiologics/ViroproPhase I completed in healthy volunteersNot approved or under reviewBOW050Epirus BiopharmaceuticalsPreclinicalNot approved or under reviewGolimumabBOW100Epirus BiopharmaceuticalsPreclinicalNot approved or under reviewCertolizumab pegolPF688PfenexPreclinicalNot approved or under reviewXcimzaneXbranePreclinicalNot approved or under reviewPsO, plaque psoriasis.a Information was obtained from company websites unless otherwise stated. Open table in a new tab PsO, plaque psoriasis. The infliximab biosimilar CT-P13 (developed by CELLTRION, Inc, Incheon, South Korea and marketed under the trade name Remsima or Inflectra) was the first biosimilar licensed for use in IBD in Europe, receiving approval from the EMA in September 2013. In April 2016, CT-P13 was also approved in IBD by the U. S. FDA with the generic name infliximab-dyyb.11INFLECTRA prescribing information. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125544s000lbl.pdf. Accessed April 11, 2016.Google Scholar This approval meant that CT-P13 became the first biosimilar monoclonal antibody to be licensed in the United States. Regulatory approval of CT-P13 was based on comprehensive structural, functional, biological, and other nonclinical comparisons with the infliximab RP. These analyses were supported by 2 randomized controlled trials (RCTs) that demonstrated pharmacokinetic (PK) and efficacy equivalence, as well as comparability of safety and immunogenicity, of CT-P13 and infliximab RP in patients with active rheumatoid arthritis (RA) or ankylosing spondylitis (AS).12Park 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: 1605-1612Crossref PubMed Scopus (505) Google Scholar, 13Park W. Yoo D.H. Jaworski J. et al.Comparable long-term efficacy, 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: 25Crossref Scopus (111) Google Scholar, 14Yoo D.H. 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: 1613-1620Crossref PubMed Scopus (537) Google Scholar, 15Yoo D.H. 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: 82Crossref Scopus (141) Google Scholar Extension studies of these RCTs also demonstrated that treatment efficacy, safety, and immunogenicity were unaffected when patients were switched from RP to CT-P13 at week 54 of treatment and followed up to week 102.16Park 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.Google Scholar, 17Yoo 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.Google Scholar On the basis of all available data, CT-P13 was approved in RA and AS plus extrapolated indications including CD and UC in regions/countries including Europe, Japan, Australia, the United States, and, most recently, Canada.11INFLECTRA prescribing information. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125544s000lbl.pdf. Accessed April 11, 2016.Google Scholar, 18Health 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/rds-sdr-remsima-184568-eng.php. Accessed October 7, 2016.Google Scholar Other infliximab biosimilars, namely SB2, BOW015, NI-071, and PF-06438179 (Table 1), have generally followed similar developmental routes involving comprehensive bioanalytical comparisons with the RP, and some have completed phase III clinical trials.19Choe J.Y. 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)Google Scholar, 20Kay 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))Google Scholar, 21Nichi-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.Google Scholar SB2 (developed by Samsung Bioepis, Incheon, South Korea) is the only other infliximab biosimilar to be approved in Europe.22Biogen 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-referencing-remicade-approved-europe. Accessed October 7, 2016.Google Scholar None are yet approved in the United States. Patents protecting adalimumab are due to expire in 2016 and 2018 in the United States and Europe, respectively. As a result, biosimilars for adalimumab are potentially nearing launch (Table 1). The first of these may be ABP 501 (Amgen, Thousand Oaks, CA), which has recently been approved by the US FDA, and is under review by the EMA. Findings supporting the approval of ABP 501 include PK equivalence versus adalimumab RP in a phase I study in healthy subjects23Kaur 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])Crossref Google Scholar and equivalent efficacy and comparable safety and immunogenicity in RCTs in RA and psoriasis.24Amgen 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.Google Scholar, 25Cohen S.B. Genovese M.C. Choy E.H. et al.Randomized, double-blind, 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: A2054Google Scholar However, the United States Patent and Trademark Office has approved several patents that protect post-launch innovations regarding the RP, including formulation and dosing schemes. Potentially these new patents could effectively extend the life of the whole adalimumab patent for another decade or later. Thus, patent litigation will likely become an important factor influencing market entry for adalimumab biosimilars. Regarding other anti-TNF RPs, golimumab and certolizumab patents will expire around the end of this decade, and biosimilars of these drugs are also in development (Table 1). For the majority of biosimilars tested in clinical trials, efficacy versus each RP has been assessed in patients with RA (Table 1). This choice was made and deemed appropriate by regulatory agencies because clinical experience with these drugs is greatest in RA, and because RA is considered a sufficiently sensitive model for establishing the equivalence of efficacy between an anti-TNF biosimilar and its RP.26European 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.Google Scholar Although most anti-TNF biosimilar developers chose RA as the population for efficacy testing, some have also performed an additional RCT in AS (as for CT-P13) or in psoriasis (as for ABP 501) (Table 1). The guiding principle underpinning the development of biosimilars is the hope of healthcare providers and patients alike that these agents will reduce the financial costs of biologic therapy, thereby increasing access to these drugs and facilitating intensified treatment regimens when clinically required. For these benefits to be realized, extrapolation is necessary. This is because this process reduces the number of clinical trials required for biosimilar approval and thereby lowers development costs. Nonetheless, extrapolation has also created concerns regarding whether bioanalytical similarity coupled with proven clinical safety and efficacy in 1 or 2 indications can ensure safety and efficacy in other indications. However, although many unknowns exist during development of an RP biologic, biosimilars enjoy the conceptual advantage of having a known comparator drug with well-defined structure, biological function, and clinical safety and efficacy. On the other hand, each "current" batch of an RP enjoys the putative advantage of having been compared with the original batches used in RP clinical trials. Original batches of an RP are not usually available to the biosimilar manufacturers, raising the possibility of further "manufacturing drift" during the biosimilars' development. For extrapolation to be considered valid by the FDA, the mechanism of action, PK (including biodistribution), immunogenicity, and safety of an RP all need to be similar in the extrapolated indication(s) and the clinically tested indication(s).2U. 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.Google Scholar If one of these attributes is unique for an extrapolated indication, additional evidence is required to show why the biosimilar can be anticipated to behave similarly in that indication despite not being tested clinically. Furthermore, if minor differences in structure or function exist between the biosimilar and RP and have negligible impact in clinical trials in the tested indication, it should be shown why these differences would also have negligible clinical meaning in the extrapolated indication. The validity of using extrapolation from clinical trials in rheumatologic diseases to approve a biosimilar in IBD can be tested by considering the following questions:•Are the mechanisms of action, PK, pharmacodynamics, immunogenicity, and safety of the RP similar between IBD and the clinically tested population, and are they comparable between the RP and biosimilar in that population?•After approval, does the evidence from post-marketing surveillance programs and other "real-life" data in IBD provide any reasons for concern? In the following sections, we consider these questions by referring to information on biosimilars approved or in development for IBD. All indications for infliximab and other anti-TNF drugs are immune-mediated inflammatory diseases that share common underlying pathophysiological processes, with the proinflammatory cytokine TNF playing an especially pivotal role.27Blandizzi 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: 1-10Crossref PubMed Scopus (66) Google Scholar TNF can be expressed on the cell surface as transmembrane TNF (tmTNF) or cleaved and released as soluble TNF (sTNF). Binding of TNF to its receptor triggers numerous intracellular forward-signaling pathways, including induction of apoptosis in some cell lineages (eg, intestinal epithelial cells) or cellular activation and secretion of other proinflammatory cytokines in others (eg, effector T cells).27Blandizzi 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: 1-10Crossref PubMed Scopus (66) Google Scholar Anti-TNF monoclonal antibodies have large complex structures comprising Fc and Fab regions, each mediating different immune functions via diverse mechanisms of actions. The binding and neutralization of TNF (both sTNF and tmTNF) is a mechanism common to all anti-TNF monoclonal antibodies (Figure 1). However, there are other possible mechanisms of action of these drugs that are also potentially instrumental in IBD. The binding of an anti-TNF antibody to tmTNF can trigger signaling pathways within the tmTNF-expressing cell. This process is referred to as reverse signaling, and its downstream effects include induction of apoptosis and suppression of proinflammatory cytokine expression, both of which are believed to be important mechanisms of action for anti-TNF agents in IBD.28Sedger L.M. McDermott M.F. TNF and TNF-receptors: from mediators of cell death and inflammation to therapeutic giants—past, present and future.Cytokine Growth Factor Rev. 2014; 25: 453-472Crossref PubMed Scopus (532) Google Scholar, 29Van den Brande J.M.H. Koehler T.C. Zelinkova Z. et al.Prediction of antitumour necrosis factor clinical efficacy by real-time visualisation of apoptosis in patients with Crohn's disease.Gut. 2007; 56: 509-517Crossref PubMed Scopus (154) Google Scholar This contention is supported by the fact that reverse signaling is induced by TNF inhibitors that are clinically effective in IBD, including infliximab and adalimumab, but not by etanercept (which primarily blocks sTNF and is ineffective in IBD).30Shen C. Assche G.V. Colpaert S. et al.Adalimumab induces apoptosis of human monocytes: a comparative study with infliximab and etanercept.Aliment Pharmacol Ther. 2005; 21: 251-258Crossref PubMed Scopus (219) Google Scholar, 31Van den Brande J.M. Braat H. van den Brink G.R. et al.Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn's disease.Gastroenterology. 2003; 124: 1774-1785Abstract Full Text Full Text PDF PubMed Scopus (676) Google Scholar As such, although the etanercept biosimilar SB4 was recently approved by the EMA, this drug (like its RP) is not licensed in IBD.32European 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.Google Scholar Both blockade of proinflammatory cytokines and induction of apoptosis via reverse signaling were shown to be highly comparable for CT-P13 and for ABP 501 versus their respective infliximab and adalimumab RPs (Table 2),26European 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.Google Scholar, 33Born T. Velayudhan J. Chen Y. et al.Demonstration of functional similarity comparing adalimumab to biosimilar candidate ABP 501.Arthritis Rheum. 2014; 10 (S661 [A1503])Google Scholar, 34U. 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.Google Scholar serving as part of the scientific justification for their extrapolation to IBD. Functional data on other anti-TN