Journal of Crohn's and Colitis (2014) 8, 431–435
Available online at www.sciencedirect.com
ScienceDirect
VIEWPOINT
Biosimilars: In support of extrapolation of indications Hans C. Ebbers ⁎ Utrecht University, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Department of Pharmaceutics, Utrecht, The Netherlands Utrecht University, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht, The Netherlands
Received 4 February 2014; accepted 11 February 2014 KEYWORDS Biosimilar; Extrapolation; Tumor necrosis factor alpha; Infliximab; Authorization; Safety
Abstract Biosimilars have the potential to lead to enormous cost savings in healthcare without reducing the level of care for patients. In Europe, biosimilars have to demonstrate comparability in an extensive biosimilarity exercise including analytical, preclinical and comparative clinical studies. By successfully completing the biosimilarity exercise, the biosimilar shows that all aspects that are considered relevant for the clinical activity of the product fall within the same range as observed for the innovator. It should be carefully considered whether the benefit of additional information from more comparative clinical studies weighs up to the additional barriers such studies create for biosimilars to enter clinical practice. © 2014 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.
1. Introduction In September 2013 a biosimilar version of Infliximab (Remicade®) received marketing authorization in the European Union. The product is developed by Celltrion as CT-P13 and sold as Remsima® by Celltrion and Inflectra® by Hospira. In Europe, in order to obtain marketing authorization as a biosimilar, a stepwise approach should be followed. Generally this means starting with a comparison of physicochemical characteristics, followed by in vitro and (possibly) in vivo data, and finally ⁎ P.O. Box 80 082, 3508 TB Utrecht, The Netherlands. Tel.: + 31 6 2029 6884; fax: +31 30 253 7839. E-mail address: [email protected].
comparative clinical studies that should be performed in the most ‘sensitive’ patient population. It should always be so that applicants provide sufficient data to support that a product is comparable to the reference product in all indications.1 Much debate has centered on which data is required to grant an approval for all indications of the reference product.2 European guidance states that — if adequately justified — biosimilars may receive all authorized indications of the reference product, even though comparative clinical data is only provided for a subset of authorized indications, so-called ‘extrapolation of indications’. In Europe, all indications belonging to Remicade® were granted to the biosimilar product based on comparative clinical studies in rheumatoid arthritis and ankylosing spondylitis only.3 Various learned societies have taken the position that extrapolation of
http://dx.doi.org/10.1016/j.crohns.2014.02.007 1873-9946/© 2014 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.
432 indications should never be allowed and that clinical data should be required for all indications.4–7 Others have generally supported extrapolation and advocated for careful postauthorization monitoring of the biosimilar.8 Here some considerations are presented to support the extrapolation of data to allow marketing authorization based on a tailored clinical development program.
2. Preclinical According to European guidance, products that do not have the identical primary structure as their reference product cannot follow the biosimilar pathway. The activity of tumor necrosis factor-α inhibitors (TNFIs) can be assessed in various assays, although the exact contribution of the various functions to the clinical efficacy and safety is not fully elucidated. TNFα binding affinity is determined by the complementarity determining region of the antibody and the TNFα receptor-domain, in the case of etanercept. Effector functions are mainly mediated by the Fc-portions, whereas certolizumab lacks effector functions. For infliximab, glycosylation is limited to the Fc region and has been shown to influence Fc-mediated effector functions, including antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). For CT-P13 physicochemical characterization demonstrated that the product is highly similar to Remicade® (Table 1). The TNFα binding properties of CT-P13 were indistinguishable from Remicade® and consistent throughout various batches.9 A small difference in the amount of afucosylation was observed for CT-P13 that translated to a slightly lower binding affinity towards FcγRIIIa receptor. However, this did not lead to differences in CDC or ADCC assays and was not considered to be clinically relevant by the EMA. All effector functions of CT-P13 fell within the range observed for Remicade®.3,10 CT-P13 demonstrated comparable dose-dependent suppression of cytokine secretion in various human cell lines including intestinal epithelial cells to support activity in inflammatory bowel disease. Differences in glycosylation are not known to have a relevant impact on the pharmacokinetic (PK) behavior of monoclonal antibodies, so it is unlikely that microheterogeneiety will affect PK behavior of the biosimilar.11 Indeed, the PK properties of CT-P13 were comparable to Remicade® both in rodent in vivo models and in patients.9
3. Clinical comparability If analytical and non-clinical studies demonstrate that a product is sufficiently similar to the reference product, comparative clinical studies are required to establish comparable safety and efficacy.12 These studies are not intended to demonstrate efficacy per se, but to confirm that the similarity observed in analytical, preclinical and PK studies translate into comparable clinical results. For CT-P13, rheumatoid arthritis patients were chosen (Table 1). Although RA patients are the largest patient population receiving TNFIs, from a regulatory standpoint this is somewhat surprising as RA patients usually receive concomitant methotrexate therapy. Immunosuppressants such as methotrexate and azathioprine are known to reduce the incidence of anti-drug antibodies (ADAs) although
H.C. Ebbers Table 1 CT-P13.
Attributes of the comparability exercise of
Analytical
Primary structure, higher order structures, glycosylation, content, purity, charge variants
Binding studies Fab related
TNFα (monomeric, trimeric and transmembrane), TNF-β, different species TNFα, tissue cross reactivity Fc receptor related FcγRI, FcγRIIa, FcγRIIb, FcγRIIIa, FcγRIIIb and FcRn hTNFα neutralization assay, ADCC, Biological activity a CDC, C1q binding affinity, T-cell proliferation, apoptosis, cytokine secretion, reverse signaling, FcγRIIIa and FcγRIIIb binding of NK cells and neutrophils, macrophage function Non-clinical PK Single dose IV comparison in rats Toxicity 3 repeat dose toxicity studies in rats Clinical CT-P13 1.2 PK study (n = 19) in RA patients (pilot study) receiving concomitant MTX (102 weeks) CT-P13 1.1 PK and long-term efficacy study (PLANET AS) (n = 250) in AS patients undergoing monotherapy (54 weeks) CT-P13 3.1 Long-term efficacy and safety study (PLANET RA) (n = 606) in RA patients receiving concomitant MTX (54 weeks) ADCC = antibody-dependent cellular cytotoxicity, CDC = complement dependent cytotoxicity, MTX = methotrexate, PK = pharmacokinetic. From the European public assessment report.3 a Most assays were performed in cells derived from both healthy donors and Crohn's disease patients.
the lower dose investigated in the PLANETRA study may make the assay to assess ADAs less susceptible to drug interference.13 Furthermore, the efficacy of infliximab vs. placebo in rheumatoid arthritis as determined by its preferred endpoint (ACR20 response, 50% vs. 20%) is less pronounced than for example psoriasis (PASI75, 80% vs. 3%).14,15 Nevertheless, the therapeutic efficacy was highly similar the proportion of patients achieving an ACR20 response were 60.9% and 58.6% for CT-P13 and Remicade® respectively for the intention to treat population. Also several pharmacodynamic markers related to the disease activity were measured, including erythrocyte sedimentation rate, C-reactive protein levels and rheumatoid factors, all of which showed a similar decrease for CT-P13 and Remicade®. The number of serious infections reported for CT-P13 was slightly higher than Remicade®, but the numbers were low and were considered to be a chance finding.3 The incidences of ADAs in both studies were comparable. At week 14, ADAs were detected in 25.4% of patients receiving CT-P13 and 25.8% of patients receiving Remicade®. At week 30 this was 48.4% and 48.2% for patients receiving CT-P13 and Remicade® respectively.10 In ankylosing spondylitis patients ADAs were detected in 9.1% (n = 11) and 11.0% (n = 13) of patients for CT-P13 and Remicade® at week 14 and 27.4% (n = 32) and 22.5% (n = 25) of patients for CT-P13
Biosimilars: In support of extrapolation of indications and Remicade®, respectively, at week 30.9 Despite that the patient population chosen may not have been the most sensitive, the incidence of ADA was sufficiently high in both CT-P13 and Remicade® to conclude that it is similar for the two products. The company also provided preliminary clinical data from an observational study in 23 inflammatory bowel disease patients that showed comparable efficacy to historical Remicade® data.3
4. Post authorization To obtain marketing authorization a risk management plan should be submitted for every biosimilar MAB. The following data were considered to be ‘missing information’ for CT-P13: long-term safety in not studied indications (including pediatric indications), use during lactation, lack of efficacy and hypersensitivity reactions (HSRs). The labels of biosimilars contain a black triangle to make prescribers aware that the product is subject to additional post authorization monitoring by the
433 EMA, which should encourage them to report adverse drug reactions. In addition to ‘routine pharmacovigilance’ activities, like collecting adverse event reports, the risk management plan for CT-P13 includes various long term extensions of pre-authorization studies, two additional randomized controlled trials in Japan and Russia and additional postauthorization observational studies to assess the incidence of serious infections (including tuberculosis) with a total targeted enrollment of 6200 patients (Supplementary info Table 1). The companies will also contribute to various existing European registries, like the Rheumatoid Arthritis Observation of Biologic Therapy (RABBIT) and British society for rheumatology biologics register. European regulators granted all indications, including CD and UC, based on literature data, in vitro data and preliminary observational data in a limited number of patients, stating that this evidence is convincing and sufficient to support extrapolation. It is therefore somewhat contradictory that a randomized controlled trial is included to study the efficacy and safety of CT-P13 in Crohn's disease. The question arises
Table 2 Characteristics of currently authorized tumor necrosis factor-α inhibitors. Adapted from Tracey et al.19 Infliximab
Etanercept
Adalimumab
Certolizumab-PEGol Golimumab
Class
MAB
Fc-fusion protein
MAB
Structure
Chimeric IgG1κ
TNFR2-Fc fusion protein
Human IgG1κ
Production cell line Molecular weight (kDa) Specificity Administration route EU approvals
Sp2/0 150 TNF IV RA, PsA, AS, CD, UC, Pso 3–5 mg/kg wk 0, 2, 6 Q8W
CHO 150 TNF/LT SC RA, PsA, AS, JIA, Pso
PEGylated Fab fragment PEGylated Fab fragment human IgG1 E. coli ~ 95 TNF SC RA, CD a
CHO 150 TNF SC RA, PsA, AS, CD, Pso, UC 80 mg, 40 mg 400 mg at wk 0, 2, EOW (except UC, 4 and 200 mg EOW 160 mg wk0, 80 mg wk 1, 40 mg EOW)
Sp2/0 150 TNF SC, IV a RA, PsA, AS, UC b
8–9.5 days ++
~ 3 days −c
~ 14 days +
14 days +
50 mg/month (except UC: 200 mg wk 0, 100 mg wk 2, 50 mg/4 wk ~ 12 days +
+++ +++
+++ +
+++ +++
+++ +++
+++ +++
+++ +++
+/− +/−
+++ +++
− +++
+++ +++
+++ +++
+/− +/−
+++ +++
− −
+++ +++
Dosing
Half-life (t1/2) Immunogenicity Neutralization potency Soluble TNF Trans membrane TNF neutralization Reverse signaling (apoptosis) Reverse signaling (cytokine suppression) FcγR function CDC ADCC
25 mg TIW or 50 mg QW
MAB Human IgG1κ
MAB = monoclonal antibody, PEG = poly-ethylene glycol, CHO = Chinese hamster ovary cell line, Sp2/0 = mouse myeloma cell line, TNF = tumor necrosis factor α, LT = lymphotoxin, IV = intravenous, SC = subcutaneous, RA = rheumatoid arthritis, PsA = psoriatic arthritis, AS = ankylosing spondylitis, CD = Crohn's disease, Pso = psoriasis, EOW = every other week, TIW = twice a week, QW = per week, CDC = complement dependent cytotoxicity, ADCC = antibody dependent cellular cytotoxicity, wk = week. −, not; +/−, very weak; +, weak; ++, moderate; +++, strong. a Authorized in the US only. b Has not been studied in CD. c Isolated cases of non-neutralizing antibodies against etanercept have been reported, but without loss of clinical response.
434 what would happen in the (hypothetical) case that this study does not show comparability.
5. Residual risk of immunogenicity If the potency of the product is similar both in the lab and in the clinic and the incidence of ADAs can be reliably assessed pre-authorization and is highly similar, there is no reason to assume that the long-term safety differs from the innovator product. The residual uncertainty is largely limited to a potential increase in hypersensitivity reactions (HSRs). HSRs to the product substance are contraindications in all authorized TNFIs and non-serious reactions occur commonly in all currently authorized TNFI. In Study CT-P13 3.1, 23 (8%) patients in the CT-P13 arm and 31 (10%) patients in the Remicade® arm experienced HSRs and infusion-related reactions.3 Serious HSRs such as anaphylaxis are included as safety warnings in all TNFIs with a labeled frequency of uncommon (b100 and N 1000) or rare (b 1000–N 10,000). Although it has it has been reported that murine glycosylation sequences may elicit immune responses, most serious HSRs to infliximab are the result of IgG and/or IgM antibodies against the murine part Fab portion of the antibody and thus its incidence is unlikely to differ significantly from Remicade®.16–18
6. How do biosimilars compare to currently available TNFIs? One argument against the extrapolation of clinical data for TNFIs is that, even though they all target TNFα, different products vary in their efficacy in different indications. For example, etanercept and certolizumab are not authorized for treating inflammatory bowel disease in the EU, while the full length antibodies are. This has been used as an argument supporting the need for comparative clinical data in all indications before a biosimilar can be granted marketing authorization.2 Currently authorized TNFIs have widely differing characteristics, in terms of structure, binding affinity, elimination half-life and frequency of administration, which clearly differentiates them from biosimilars19,20 (Table 2). Even so, taking only the full length MABs into account, despite considerable differences in characteristics, such as TNFα binding affinity and half-life they all show efficacy in those rheumatology, gastroenterology and dermatology indications that they have been studied in. While differences in efficacy of TNFIs may support the view that product attributes contribute differently to the efficacy in different indications, this cannot be applied to disqualifying biosimilars, which are designed to be highly similar to a product which has demonstrated efficacy in a given indication.
7. Conclusion Currently authorized TNFIs differ in many aspects that all may affect their efficacy across different indications and differentiate them from biosimilars. Biosimilars are designed to be used exactly the same way as their reference products. Before a biosimilar is authorized in the EU all aspects that are considered relevant for its biological activity are thoroughly assessed and fall within the variation observed for the originator.
H.C. Ebbers Furthermore, comparable clinical efficacy, safety and immunogenicity are established in a sensitive patient population. For such products, extrapolating the clinical safety and efficacy to all authorized indications of the reference product based on the overall evidence of comparability provided from the comparability exercise is justified. Supplementary data to this article can be found online at http://dx.doi.org/10.1016/j.crohns.2014.02.007.
Conflict of interest No competing interests to declare.
Acknowledgments and funding No funding was received for the preparation of this article. The Division of Pharmacoepidemiology & Clinical Pharmacology, has received unrestricted funding from the Netherlands Organisation for Health Research and Development (ZonMW), the Dutch Health Care Insurance Board (CVZ), the Royal Dutch Pharmacists Association (KNMP), the private–public funded Top Institute Pharma (www.tipharma.nl, which includes co-funding from universities, government, and industry), the EU Innovative Medicines Initiative (IMI), the EU 7th Framework Program (FP7), and the Dutch Ministry of Health and Industry (including GlaxoSmithKline, Pfizer, and others).
References 1. European Medicines Agency. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues EMEA/CHMP/ BMWP/42832/2005; 2006 (Available from: http://www.ema. europa.eu/docs/en_GB/document_library/Scientific_guideline/ 2009/09/WC500003920.pdf [Accessed, July 26, 2012]). 2. Lee H. Is extrapolation of the safety and efficacy data in one indication to another appropriate for biosimilars? AAPS J Oct 11 2013, http://dx.doi.org/10.1208/s12248-013-9534-y. 3. European Medicines Agency. Inflectra. European public assessment report. Available from:http://www.ema.europa.eu/ema/ index.jsp?curl=pages/medicines/human/medicines/002778/ human_med_001677.jsp&mid=WC0b01ac058001d1242013 [Accessed 6 Dec 2013]. 4. Argüelles-Arias F, Barreiro-de-Acosta M, Carballo F, Hinojosa J, Tejerina T. Joint position statement by “Sociedad Española de Patología Digestiva” (Spanish Society of Gastroenterology) and “Sociedad Española de Farmacología” (Spanish Society of Pharmacology) on biosimilar therapy for inflammatory bowel disease. Rev Esp Enferm Dig 2013;105(1):37–43. 5. American College of Rheumatology. Position statement: biosimilars. Available from:http://www.rheumatology.org/Practice/Clinical/ Position/Position_Statements/2011 [Accessed 24 Sep 2013]. 6. Espinosa Morales R, DÃaz BorjÃ3n A, Barile Fabris LA, Esquivel Valerio JA, Medrano RamÃrez G, Arce Salinas CA, et al. Biosimilar drugs in Mexico: position of the Mexican College of Rheumatology, 2012. Reumatol ClÃnica 2013;09(02) [113,116; 116]. 7. Danese S, Gomollon F. Governing Board and Operational Board of ECCO. ECCO position statement: the use of biosimilar medicines in the treatment of inflammatory bowel disease (IBD). J Crohns Colitis 2013;7(7):586–9, http://dx.doi.org/10.1016/j.crohns.2013. 03.011 [http://dx.doi.org/10.1016/j.crohns.2013.03.011].
Biosimilars: In support of extrapolation of indications 8. Kay J, Smolen JS. Biosimilars to treat inflammatory arthritis: the challenge of proving identity. Ann Rheum Dis 2013;72(10): 1589–93, http://dx.doi.org/10.1136/annrheumdis-2012-203198. 9. Park W, Hrycaj P, Jeka S, Kovalenko V, Lysenko G, Miranda P, 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 Oct 1 2013;72(10): 1605–12, http://dx.doi.org/10.1136/annrheumdis-2012-203091. 10. Yoo DH, Hrycaj P, Miranda P, Ramiterre E, Piotrowski M, Shevchuk S, 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 Oct 1 2013;72(10):1613–20, http://dx.doi.org/10.1136/annrheumdis-2012-203090 [http:// dx.doi.org/10.1136/annrheumdis-2012-203090]. 11. Goetze AM, Liu YD, Zhang Z, Shah B, Lee E, Bondarenko PV, et al. High-mannose glycans on the Fc region of therapeutic IgG antibodies increase serum clearance in humans. Glycobiology 2011;21(7):949–59, http://dx.doi.org/10.1093/glycob/cwr027 [http://dx.doi.org/10.1093/glycob/cwr027]. 12. European Medicines Agency. Guideline on similar biological medicinal products containing monoclonal antibodies—non-clinical and clinical issues. Available from:http://www.ema.europa. eu/docs/en_GB/document_library/Scientific_guideline/2012/06/ WC500128686.pdf2012 [Accessed July 16, 2012]. 13. Vermeire S, Noman M, Van Assche G, Baert F, D'Haens G, Rutgeerts P. Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn's disease. Gut 2007;56(9):1226–31, http://dx.doi.org/ 10.1136/gut.2006.099978. 14. Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M, et al. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis
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patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet Dec 4 1999;354 (9194):1932–9. Reich K, Nestle FO, Papp K, Ortonne JP, Evans R, Guzzo C, et al. Infliximab induction and maintenance therapy for moderateto-severe psoriasis: a phase III, multicentre, double-blind trial. Lancet Oct 15–21 2005;366(9494):1367–74, http://dx.doi.org/ 10.1016/S0140-6736(05)67566-6. Vultaggio A, Maggi E, Matucci A. Immediate adverse reactions to biologicals: from pathogenic mechanisms to prophylactic management. Curr Opin Allergy Clin Immunol 2011;11(3):262–8, http:// dx.doi.org/10.1097/ACI.0b013e3283464bcd. Steenholdt C, Palarasah Y, Bendtzen K, Teisner A, Brynskov J, Teisner B, et al. Pre-existing IgG antibodies cross-reacting with the Fab region of infliximab predict efficacy and safety of infliximab therapy in inflammatory bowel disease. Aliment Pharmacol Ther 2013;37(12):1172–83, http://dx.doi.org/10. 1111/apt.12330 [http://dx.doi.org/10.1111/apt.12330]. Beck A, Wagner-Rousset E, Bussat MC, Lokteff M, Klinguer-Hamour C, Haeuw JF, et al. Trends in glycosylation, glycoanalysis and glycoengineering of therapeutic antibodies and Fc-fusion proteins. Curr Pharm Biotechnol 2008;9(6):482–501. Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther 2008;117(2):244–79, http:// dx.doi.org/10.1016/j.pharmthera.2007.10.001. Shealy D, Cai A, Staquet K, Baker A, Lacy ER, Johns L, et al. Characterization of golimumab, a human monoclonal antibody specific for human tumor necrosis factor alpha. mAbs Jul 8 2010;2(4).
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VIEWPOINT
Biosimilars: In support of extrapolation of indications Hans C. Ebbers ⁎ Utrecht University, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Department of Pharmaceutics, Utrecht, The Netherlands Utrecht University, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht, The Netherlands
Received 4 February 2014; accepted 11 February 2014 KEYWORDS Biosimilar; Extrapolation; Tumor necrosis factor alpha; Infliximab; Authorization; Safety
Abstract Biosimilars have the potential to lead to enormous cost savings in healthcare without reducing the level of care for patients. In Europe, biosimilars have to demonstrate comparability in an extensive biosimilarity exercise including analytical, preclinical and comparative clinical studies. By successfully completing the biosimilarity exercise, the biosimilar shows that all aspects that are considered relevant for the clinical activity of the product fall within the same range as observed for the innovator. It should be carefully considered whether the benefit of additional information from more comparative clinical studies weighs up to the additional barriers such studies create for biosimilars to enter clinical practice. © 2014 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.
1. Introduction In September 2013 a biosimilar version of Infliximab (Remicade®) received marketing authorization in the European Union. The product is developed by Celltrion as CT-P13 and sold as Remsima® by Celltrion and Inflectra® by Hospira. In Europe, in order to obtain marketing authorization as a biosimilar, a stepwise approach should be followed. Generally this means starting with a comparison of physicochemical characteristics, followed by in vitro and (possibly) in vivo data, and finally ⁎ P.O. Box 80 082, 3508 TB Utrecht, The Netherlands. Tel.: + 31 6 2029 6884; fax: +31 30 253 7839. E-mail address: [email protected].
comparative clinical studies that should be performed in the most ‘sensitive’ patient population. It should always be so that applicants provide sufficient data to support that a product is comparable to the reference product in all indications.1 Much debate has centered on which data is required to grant an approval for all indications of the reference product.2 European guidance states that — if adequately justified — biosimilars may receive all authorized indications of the reference product, even though comparative clinical data is only provided for a subset of authorized indications, so-called ‘extrapolation of indications’. In Europe, all indications belonging to Remicade® were granted to the biosimilar product based on comparative clinical studies in rheumatoid arthritis and ankylosing spondylitis only.3 Various learned societies have taken the position that extrapolation of
http://dx.doi.org/10.1016/j.crohns.2014.02.007 1873-9946/© 2014 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.
432 indications should never be allowed and that clinical data should be required for all indications.4–7 Others have generally supported extrapolation and advocated for careful postauthorization monitoring of the biosimilar.8 Here some considerations are presented to support the extrapolation of data to allow marketing authorization based on a tailored clinical development program.
2. Preclinical According to European guidance, products that do not have the identical primary structure as their reference product cannot follow the biosimilar pathway. The activity of tumor necrosis factor-α inhibitors (TNFIs) can be assessed in various assays, although the exact contribution of the various functions to the clinical efficacy and safety is not fully elucidated. TNFα binding affinity is determined by the complementarity determining region of the antibody and the TNFα receptor-domain, in the case of etanercept. Effector functions are mainly mediated by the Fc-portions, whereas certolizumab lacks effector functions. For infliximab, glycosylation is limited to the Fc region and has been shown to influence Fc-mediated effector functions, including antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). For CT-P13 physicochemical characterization demonstrated that the product is highly similar to Remicade® (Table 1). The TNFα binding properties of CT-P13 were indistinguishable from Remicade® and consistent throughout various batches.9 A small difference in the amount of afucosylation was observed for CT-P13 that translated to a slightly lower binding affinity towards FcγRIIIa receptor. However, this did not lead to differences in CDC or ADCC assays and was not considered to be clinically relevant by the EMA. All effector functions of CT-P13 fell within the range observed for Remicade®.3,10 CT-P13 demonstrated comparable dose-dependent suppression of cytokine secretion in various human cell lines including intestinal epithelial cells to support activity in inflammatory bowel disease. Differences in glycosylation are not known to have a relevant impact on the pharmacokinetic (PK) behavior of monoclonal antibodies, so it is unlikely that microheterogeneiety will affect PK behavior of the biosimilar.11 Indeed, the PK properties of CT-P13 were comparable to Remicade® both in rodent in vivo models and in patients.9
3. Clinical comparability If analytical and non-clinical studies demonstrate that a product is sufficiently similar to the reference product, comparative clinical studies are required to establish comparable safety and efficacy.12 These studies are not intended to demonstrate efficacy per se, but to confirm that the similarity observed in analytical, preclinical and PK studies translate into comparable clinical results. For CT-P13, rheumatoid arthritis patients were chosen (Table 1). Although RA patients are the largest patient population receiving TNFIs, from a regulatory standpoint this is somewhat surprising as RA patients usually receive concomitant methotrexate therapy. Immunosuppressants such as methotrexate and azathioprine are known to reduce the incidence of anti-drug antibodies (ADAs) although
H.C. Ebbers Table 1 CT-P13.
Attributes of the comparability exercise of
Analytical
Primary structure, higher order structures, glycosylation, content, purity, charge variants
Binding studies Fab related
TNFα (monomeric, trimeric and transmembrane), TNF-β, different species TNFα, tissue cross reactivity Fc receptor related FcγRI, FcγRIIa, FcγRIIb, FcγRIIIa, FcγRIIIb and FcRn hTNFα neutralization assay, ADCC, Biological activity a CDC, C1q binding affinity, T-cell proliferation, apoptosis, cytokine secretion, reverse signaling, FcγRIIIa and FcγRIIIb binding of NK cells and neutrophils, macrophage function Non-clinical PK Single dose IV comparison in rats Toxicity 3 repeat dose toxicity studies in rats Clinical CT-P13 1.2 PK study (n = 19) in RA patients (pilot study) receiving concomitant MTX (102 weeks) CT-P13 1.1 PK and long-term efficacy study (PLANET AS) (n = 250) in AS patients undergoing monotherapy (54 weeks) CT-P13 3.1 Long-term efficacy and safety study (PLANET RA) (n = 606) in RA patients receiving concomitant MTX (54 weeks) ADCC = antibody-dependent cellular cytotoxicity, CDC = complement dependent cytotoxicity, MTX = methotrexate, PK = pharmacokinetic. From the European public assessment report.3 a Most assays were performed in cells derived from both healthy donors and Crohn's disease patients.
the lower dose investigated in the PLANETRA study may make the assay to assess ADAs less susceptible to drug interference.13 Furthermore, the efficacy of infliximab vs. placebo in rheumatoid arthritis as determined by its preferred endpoint (ACR20 response, 50% vs. 20%) is less pronounced than for example psoriasis (PASI75, 80% vs. 3%).14,15 Nevertheless, the therapeutic efficacy was highly similar the proportion of patients achieving an ACR20 response were 60.9% and 58.6% for CT-P13 and Remicade® respectively for the intention to treat population. Also several pharmacodynamic markers related to the disease activity were measured, including erythrocyte sedimentation rate, C-reactive protein levels and rheumatoid factors, all of which showed a similar decrease for CT-P13 and Remicade®. The number of serious infections reported for CT-P13 was slightly higher than Remicade®, but the numbers were low and were considered to be a chance finding.3 The incidences of ADAs in both studies were comparable. At week 14, ADAs were detected in 25.4% of patients receiving CT-P13 and 25.8% of patients receiving Remicade®. At week 30 this was 48.4% and 48.2% for patients receiving CT-P13 and Remicade® respectively.10 In ankylosing spondylitis patients ADAs were detected in 9.1% (n = 11) and 11.0% (n = 13) of patients for CT-P13 and Remicade® at week 14 and 27.4% (n = 32) and 22.5% (n = 25) of patients for CT-P13
Biosimilars: In support of extrapolation of indications and Remicade®, respectively, at week 30.9 Despite that the patient population chosen may not have been the most sensitive, the incidence of ADA was sufficiently high in both CT-P13 and Remicade® to conclude that it is similar for the two products. The company also provided preliminary clinical data from an observational study in 23 inflammatory bowel disease patients that showed comparable efficacy to historical Remicade® data.3
4. Post authorization To obtain marketing authorization a risk management plan should be submitted for every biosimilar MAB. The following data were considered to be ‘missing information’ for CT-P13: long-term safety in not studied indications (including pediatric indications), use during lactation, lack of efficacy and hypersensitivity reactions (HSRs). The labels of biosimilars contain a black triangle to make prescribers aware that the product is subject to additional post authorization monitoring by the
433 EMA, which should encourage them to report adverse drug reactions. In addition to ‘routine pharmacovigilance’ activities, like collecting adverse event reports, the risk management plan for CT-P13 includes various long term extensions of pre-authorization studies, two additional randomized controlled trials in Japan and Russia and additional postauthorization observational studies to assess the incidence of serious infections (including tuberculosis) with a total targeted enrollment of 6200 patients (Supplementary info Table 1). The companies will also contribute to various existing European registries, like the Rheumatoid Arthritis Observation of Biologic Therapy (RABBIT) and British society for rheumatology biologics register. European regulators granted all indications, including CD and UC, based on literature data, in vitro data and preliminary observational data in a limited number of patients, stating that this evidence is convincing and sufficient to support extrapolation. It is therefore somewhat contradictory that a randomized controlled trial is included to study the efficacy and safety of CT-P13 in Crohn's disease. The question arises
Table 2 Characteristics of currently authorized tumor necrosis factor-α inhibitors. Adapted from Tracey et al.19 Infliximab
Etanercept
Adalimumab
Certolizumab-PEGol Golimumab
Class
MAB
Fc-fusion protein
MAB
Structure
Chimeric IgG1κ
TNFR2-Fc fusion protein
Human IgG1κ
Production cell line Molecular weight (kDa) Specificity Administration route EU approvals
Sp2/0 150 TNF IV RA, PsA, AS, CD, UC, Pso 3–5 mg/kg wk 0, 2, 6 Q8W
CHO 150 TNF/LT SC RA, PsA, AS, JIA, Pso
PEGylated Fab fragment PEGylated Fab fragment human IgG1 E. coli ~ 95 TNF SC RA, CD a
CHO 150 TNF SC RA, PsA, AS, CD, Pso, UC 80 mg, 40 mg 400 mg at wk 0, 2, EOW (except UC, 4 and 200 mg EOW 160 mg wk0, 80 mg wk 1, 40 mg EOW)
Sp2/0 150 TNF SC, IV a RA, PsA, AS, UC b
8–9.5 days ++
~ 3 days −c
~ 14 days +
14 days +
50 mg/month (except UC: 200 mg wk 0, 100 mg wk 2, 50 mg/4 wk ~ 12 days +
+++ +++
+++ +
+++ +++
+++ +++
+++ +++
+++ +++
+/− +/−
+++ +++
− +++
+++ +++
+++ +++
+/− +/−
+++ +++
− −
+++ +++
Dosing
Half-life (t1/2) Immunogenicity Neutralization potency Soluble TNF Trans membrane TNF neutralization Reverse signaling (apoptosis) Reverse signaling (cytokine suppression) FcγR function CDC ADCC
25 mg TIW or 50 mg QW
MAB Human IgG1κ
MAB = monoclonal antibody, PEG = poly-ethylene glycol, CHO = Chinese hamster ovary cell line, Sp2/0 = mouse myeloma cell line, TNF = tumor necrosis factor α, LT = lymphotoxin, IV = intravenous, SC = subcutaneous, RA = rheumatoid arthritis, PsA = psoriatic arthritis, AS = ankylosing spondylitis, CD = Crohn's disease, Pso = psoriasis, EOW = every other week, TIW = twice a week, QW = per week, CDC = complement dependent cytotoxicity, ADCC = antibody dependent cellular cytotoxicity, wk = week. −, not; +/−, very weak; +, weak; ++, moderate; +++, strong. a Authorized in the US only. b Has not been studied in CD. c Isolated cases of non-neutralizing antibodies against etanercept have been reported, but without loss of clinical response.
434 what would happen in the (hypothetical) case that this study does not show comparability.
5. Residual risk of immunogenicity If the potency of the product is similar both in the lab and in the clinic and the incidence of ADAs can be reliably assessed pre-authorization and is highly similar, there is no reason to assume that the long-term safety differs from the innovator product. The residual uncertainty is largely limited to a potential increase in hypersensitivity reactions (HSRs). HSRs to the product substance are contraindications in all authorized TNFIs and non-serious reactions occur commonly in all currently authorized TNFI. In Study CT-P13 3.1, 23 (8%) patients in the CT-P13 arm and 31 (10%) patients in the Remicade® arm experienced HSRs and infusion-related reactions.3 Serious HSRs such as anaphylaxis are included as safety warnings in all TNFIs with a labeled frequency of uncommon (b100 and N 1000) or rare (b 1000–N 10,000). Although it has it has been reported that murine glycosylation sequences may elicit immune responses, most serious HSRs to infliximab are the result of IgG and/or IgM antibodies against the murine part Fab portion of the antibody and thus its incidence is unlikely to differ significantly from Remicade®.16–18
6. How do biosimilars compare to currently available TNFIs? One argument against the extrapolation of clinical data for TNFIs is that, even though they all target TNFα, different products vary in their efficacy in different indications. For example, etanercept and certolizumab are not authorized for treating inflammatory bowel disease in the EU, while the full length antibodies are. This has been used as an argument supporting the need for comparative clinical data in all indications before a biosimilar can be granted marketing authorization.2 Currently authorized TNFIs have widely differing characteristics, in terms of structure, binding affinity, elimination half-life and frequency of administration, which clearly differentiates them from biosimilars19,20 (Table 2). Even so, taking only the full length MABs into account, despite considerable differences in characteristics, such as TNFα binding affinity and half-life they all show efficacy in those rheumatology, gastroenterology and dermatology indications that they have been studied in. While differences in efficacy of TNFIs may support the view that product attributes contribute differently to the efficacy in different indications, this cannot be applied to disqualifying biosimilars, which are designed to be highly similar to a product which has demonstrated efficacy in a given indication.
7. Conclusion Currently authorized TNFIs differ in many aspects that all may affect their efficacy across different indications and differentiate them from biosimilars. Biosimilars are designed to be used exactly the same way as their reference products. Before a biosimilar is authorized in the EU all aspects that are considered relevant for its biological activity are thoroughly assessed and fall within the variation observed for the originator.
H.C. Ebbers Furthermore, comparable clinical efficacy, safety and immunogenicity are established in a sensitive patient population. For such products, extrapolating the clinical safety and efficacy to all authorized indications of the reference product based on the overall evidence of comparability provided from the comparability exercise is justified. Supplementary data to this article can be found online at http://dx.doi.org/10.1016/j.crohns.2014.02.007.
Conflict of interest No competing interests to declare.
Acknowledgments and funding No funding was received for the preparation of this article. The Division of Pharmacoepidemiology & Clinical Pharmacology, has received unrestricted funding from the Netherlands Organisation for Health Research and Development (ZonMW), the Dutch Health Care Insurance Board (CVZ), the Royal Dutch Pharmacists Association (KNMP), the private–public funded Top Institute Pharma (www.tipharma.nl, which includes co-funding from universities, government, and industry), the EU Innovative Medicines Initiative (IMI), the EU 7th Framework Program (FP7), and the Dutch Ministry of Health and Industry (including GlaxoSmithKline, Pfizer, and others).
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