Immunogenicity of Biosimilars for Rheumatic Diseases, Plaque Psoriasis, and Inflammatory Bowel Disease: A Review from Clinical Trials and Regulatory Documents
The goal of this narrative review was to summarize immunogenicity data of biosimilars or biosimilar candidates for rheumatic diseases, plaque psoriasis, or inflammatory bowel disease (IBD), available in peer-reviewed publications or regulatory documents. PubMed records and regulatory documents were searched for immunogenicity data of TNFα or CD20 inhibitor biosimilars or biosimilar candidates. Data collected included the proportion of patients positive for anti-drug antibodies (ADAbs), proportion with neutralizing antibodies (nAbs) among ADAb-positive patients, ADAb/nAb assay characteristics, cross-reactivity, and the effects of ADAbs on pharmacokinetics, pharmacodynamics, efficacy, and safety. We identified eight biosimilars or biosimilar candidates for adalimumab (BI 695501, SB5, ABP 501, GP2017, PF-06410293, MSB-11022, FKB-327, ZRC-3197) four for etanercept (SB4, GP2015, CHS-0214, LBEC0101), and three each for infliximab (SB2, CT-P13, GP1111) and rituximab (CT-P10, GP2013, PF-05280586) with immunogenicity data. Randomized, head-to-head trials with reference products varied in design and methodology of ADAb/nAb detection. The lowest proportions of ADAb-positive (0–13%) and nAb-positive patients (0–3%) were observed in the trials of etanercept and its biosimilars, and the highest with adalimumab, infliximab, and their biosimilars (ADAbs: ≤ 64%; nAbs: ≤ 100%). The most common method of ADAb detection was electrochemiluminescence, and ADAb positivity was associated with nominally inferior efficacy and safety. Overall, there were no significant immunogenicity differences between biosimilars and reference products. However, there are many discrepancies in assessing and reporting clinical immunogenicity. In conclusion, immunogenicity data of biosimilars or biosimilar candidates for TNFα or CD20 inhibitors were collected in trials that varied in design and procedures for ADAb/nAb detection. In general, immunogenicity parameters of biosimilars are similar to those of their reference products.
Medical writing assistance was provided by Vojislav Pejović, Ph.D., of Engage Scientific Solutions, and was funded by Pfizer.
The study was initially conceived by VS and LM; the initial concept was further refined and expanded by JG, JDI, TPH, and HEJ, LS, JG, JDI, and LM supervised data acquisition and analysis. All authors contributed to data interpretation, drafting, and critical revision of the drafts. All authors provided a final approval of the version to be published and agreed to be accountable for all aspects of the work.
Compliance with Ethical Standards
This review was sponsored by Pfizer.
Conflict of interest
Professor Isaacs and work in the Isaacs’ laboratory are supported in part by NIHR Newcastle Biomedical Research Centre, based at Newcastle Hospitals NHS Foundation Trust and Newcastle University and by the Research into Inflammatory Arthritis Centre Versus Arthritis. V. Strand has received consulting fees or honoraria from AbbVie, Amgen, Asana, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Celltrion, EMD Serono, Genentech/Roche, GSK, Janssen, Kezar, Kypha, Lilly, Merck, Novartis, Pfizer, Regeneron, Samsung Bioepis, Sandoz, Sanofi, and UCB. J. Gonçalves has received speaker fees from Amgen, Biogen, Celltrion, Libbs, Novartis, Pfizer, Samsung Bioepis, and Sandoz. J. D. Isaacs has received speaker or consulting fees from AbbVie, Biogen, BMS, Celltrion, Eli Lilly, Gilead, Janssen, Merck, Merck Serono, Pfizer, and Roche. T. P. Hickling is an employee of Pfizer and may own company stock. H. E. Jones and L. Marshall were employees of Pfizer during the development of the manuscript and may own company stock.
- 8.Guidelines on Evaluation of Similar Biotherapeutic Products (SBPs). 2009. http://www.who.int/biologicals/areas/biological_therapeutics/BIOTHERAPEUTICS_FOR_WEB_22APRIL2010.pdf.
- 9.Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues (EMEA/CHMP/BMWP/42832/2005 Rev1). 2014. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/01/WC500180219.pdf. Accessed 10 Apr 2019.
- 10.Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. Guidance for Industry. 2015. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. Accessed 10 Apr 2019.
- 12.Guideline on Immunogenicity assessment of therapeutic proteins (EMEA/CHMP/BMWP/14327/2006 Rev 1). 2017. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2017/06/WC500228861.pdf. Accessed 10 Apr 2019.
- 13.Immunogenicity Testing of Therapeutic Protein Products—Developing and Validating Assays for Anti-Drug Antibody Detection. Guidance for Industry. 2019. https://www.fda.gov/media/119788/download. Accessed 15 May 2019.
- 18.Rup B, Pallardy M, Sikkema D, Albert T, Allez M, Broet P, et al. Standardizing terms, definitions and concepts for describing and interpreting unwanted immunogenicity of biopharmaceuticals: recommendations of the Innovative Medicines Initiative ABIRISK consortium. Clin Exp Immunol. 2015;181(3):385–400.PubMedPubMedCentralCrossRefGoogle Scholar
- 19.Wynne C, Altendorfer M, Sonderegger I, Gheyle L, Ellis-Pegler R, Buschke S, et al. Bioequivalence, safety and immunogenicity of BI 695501, an adalimumab biosimilar candidate, compared with the reference biologic in a randomized, double-blind, active comparator phase I clinical study (VOLTAIRE(R)-PK) in healthy subjects. Expert Opin Investig Drugs. 2016;25(12):1361–70.PubMedCrossRefPubMedCentralGoogle Scholar
- 21.Kaur P, Chow V, Zhang N, Moxness M, Kaliyaperumal A, Markus R. A randomised, single-blind, single-dose, three-arm, parallel-group study in healthy subjects to demonstrate pharmacokinetic equivalence of ABP 501 and adalimumab. Ann Rheum Dis. 2017;76(3):526–33.PubMedPubMedCentralCrossRefGoogle Scholar
- 23.Assessment Report: Hyrimoz (Procedure No. EMEA/H/C/004320/0000). 2018. https://www.ema.europa.eu/documents/assessment-report/hyrimoz-epar-public-assessment-report_en.pdf. Accessed 10 Apr 2019.
- 26.Assessment Report: Erelzi (EMA/CHMP/302222/2017). 2017. https://www.ema.europa.eu/documents/assessment-report/erelzi-epar-public-assessment-report_en.pdf. Accessed 10 Apr 2019.
- 29.Park W, Lee SJ, Yun J, Yoo DH. 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):S25–31.PubMedCrossRefPubMedCentralGoogle Scholar
- 30.Cohen SB, Alonso-Ruiz A, Klimiuk PA, Lee EC, Peter N, Sonderegger I, et al. Similar efficacy, safety and immunogenicity of adalimumab biosimilar BI 695501 and Humira reference product in patients with moderately to severely active rheumatoid arthritis: results from the phase III randomised VOLTAIRE-RA equivalence study. Ann Rheum Dis. 2018;77(6):914–21.PubMedPubMedCentralGoogle Scholar
- 31.Weinblatt ME, Baranauskaite A, Niebrzydowski J, Dokoupilova E, Zielinska A, Jaworski J, et al. Phase III randomized study of SB5, an adalimumab biosimilar, versus reference adalimumab in patients with moderate-to-severe rheumatoid arthritis. Arthritis Rheumatol. 2018;70(1):40–8.PubMedCrossRefGoogle Scholar
- 32.Cohen S, Genovese MC, Choy E, Perez-Ruiz F, Matsumoto A, Pavelka K, et al. Efficacy and safety of the biosimilar ABP 501 compared with adalimumab in patients with moderate to severe rheumatoid arthritis: a randomised, double-blind, phase III equivalence study. Ann Rheum Dis. 2017;76(10):1679–87.PubMedPubMedCentralCrossRefGoogle Scholar
- 33.Assessment Report: Hulio (EMEA/H/C/004429/0000). 2018. https://www.ema.europa.eu/documents/assessment-report/hulio-epar-public-assessment-report_en.pdf. Accessed 11 Apr 2019.
- 34.Fleischmann RM, Alten R, Pileckyte M, Lobello K, Hua SY, Cronenberger C, et al. A comparative clinical study of PF-06410293, a candidate adalimumab biosimilar, and adalimumab reference product (Humira(R)) in the treatment of active rheumatoid arthritis. Arthritis Res Ther. 2018;20(1):178.PubMedPubMedCentralCrossRefGoogle Scholar
- 35.Jani RH, Gupta R, Bhatia G, Rathi G, Ashok Kumar P, Sharma R, et al. A prospective, randomized, double-blind, multicentre, parallel-group, active controlled study to compare efficacy and safety of biosimilar adalimumab (Exemptia; ZRC-3197) and adalimumab (Humira) in patients with rheumatoid arthritis. Int J Rheum Dis. 2016;19(11):1157–68.PubMedCrossRefPubMedCentralGoogle Scholar
- 36.Emery P, Vencovsky J, Sylwestrzak A, Leszczynski P, Porawska W, Baranauskaite A, et al. A phase III randomised, double-blind, parallel-group study comparing SB4 with etanercept reference product in patients with active rheumatoid arthritis despite methotrexate therapy. Ann Rheum Dis. 2017;76(1):51–7.PubMedCrossRefPubMedCentralGoogle Scholar
- 38.Matsuno H, Tomomitsu M, Hagino A, Shin S, Lee J, Song YW. Phase III, multicentre, double-blind, randomised, parallel-group study to evaluate the similarities between LBEC0101 and etanercept reference product in terms of efficacy and safety in patients with active rheumatoid arthritis inadequately responding to methotrexate. Ann Rheum Dis. 2018;77(4):488–94.PubMedCrossRefPubMedCentralGoogle Scholar
- 39.Choe JY, Prodanovic N, Niebrzydowski J, Staykov I, Dokoupilova E, Baranauskaite A, 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. 2017;76(1):58–64.PubMedCrossRefPubMedCentralGoogle Scholar
- 40.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. 2013;72(10):1605–12.PubMedPubMedCentralCrossRefGoogle Scholar
- 41.Park W, Yoo DH, Miranda P, Brzosko M, Wiland P, Gutierrez-Urena S, et al. Efficacy and safety of switching from reference infliximab to CT-P13 compared with maintenance of CT-P13 in ankylosing spondylitis: 102-week data from the PLANETAS extension study. Ann Rheum Dis. 2017;76(2):346–54.PubMedCrossRefPubMedCentralGoogle Scholar
- 42.Takeuchi T, Yamanaka H, Tanaka Y, Sakurai T, Saito K, Ohtsubo H, 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(6):817–24.PubMedPubMedCentralCrossRefGoogle Scholar
- 43.Tweehuysen L, van den Bemt BJF, van Ingen IL, de Jong AJL, van der Laan WH, van den Hoogen FHJ, et al. Subjective complaints as the main reason for biosimilar discontinuation after open-label transition from reference infliximab to biosimilar infliximab. Arthritis Rheumatol. 2018;70(1):60–8.PubMedCrossRefPubMedCentralGoogle Scholar
- 44.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. 2013;72(10):1613–20.PubMedPubMedCentralCrossRefGoogle Scholar
- 45.Yoo DH, Prodanovic N, Jaworski J, Miranda P, Ramiterre E, Lanzon A, 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. 2017;76(2):355–63.PubMedCrossRefPubMedCentralGoogle Scholar
- 46.Cohen SB, Alten R, Kameda H, Hala T, Radominski SC, Rehman MI, et al. A randomized controlled trial comparing PF-06438179/GP1111 (an infliximab biosimilar) and infliximab reference product for treatment of moderate to severe active rheumatoid arthritis despite methotrexate therapy. Arthritis Res Ther. 2018;20(1):155.PubMedPubMedCentralCrossRefGoogle Scholar
- 47.Park W, Bozic-Majstorovic L, Milakovic D, Berrocal Kasay A, El-Khouri EC, Irazoque-Palazuelos F, et al. Comparison of biosimilar CT-P10 and innovator rituximab in patients with rheumatoid arthritis: a randomized controlled Phase 3 trial. MAbs. 2018;10(6):934–43.PubMedPubMedCentralCrossRefGoogle Scholar
- 48.Park W, Suh CH, Shim SC, Molina FFC, Jeka S, Medina-Rodriguez FG, et al. Efficacy and safety of switching from innovator rituximab to biosimilar CT-P10 compared with continued treatment with CT-P10: results of a 56-week open-label study in patients with rheumatoid arthritis. Biodrugs. 2017;31(4):369–77.PubMedPubMedCentralCrossRefGoogle Scholar
- 49.Yoo DH, Suh CH, Shim SC, Jeka S, Cons-Molina FF, Hrycaj P, et al. A multicentre randomised controlled trial to compare the pharmacokinetics, efficacy and safety of CT-P10 and innovator rituximab in patients with rheumatoid arthritis. Ann Rheum Dis. 2017;76(3):566–70.PubMedPubMedCentralCrossRefGoogle Scholar
- 50.Smolen JS, Cohen SB, Tony HP, Scheinberg M, Kivitz A, Balanescu A, et al. A randomised, double-blind trial to demonstrate bioequivalence of GP2013 and reference rituximab combined with methotrexate in patients with active rheumatoid arthritis. Ann Rheum Dis. 2017;76(9):1598–602.PubMedPubMedCentralCrossRefGoogle Scholar
- 51.Tony HP, Kruger K, Cohen SB, Schulze-Koops H, Kivitz AJ, Jeka S, et al. Brief report: safety and immunogenicity of rituximab biosimilar GP 2013 after switch from reference rituximab in patients with active rheumatoid arthritis. Arthritis Care Res (Hoboken). 2019;71(1):88–94.PubMedCrossRefPubMedCentralGoogle Scholar
- 54.Papp K, Bachelez H, Costanzo A, Foley P, Gooderham M, Kaur P, et al. Clinical similarity of biosimilar ABP 501 to adalimumab in the treatment of patients with moderate to severe plaque psoriasis: a randomized, double-blind, multicenter, phase III study. J Am Acad Dermatol. 2017;76(6):1093–102.PubMedCrossRefPubMedCentralGoogle Scholar
- 56.Griffiths CEM, Thaci D, Gerdes S, Arenberger P, Pulka G, Kingo K, et al. The EGALITY study: a confirmatory, randomized, double-blind study comparing the efficacy, safety and immunogenicity of GP2015, a proposed etanercept biosimilar, vs. the originator product in patients with moderate-to-severe chronic plaque-type psoriasis. Br J Dermatol. 2017;176(4):928–38.PubMedCrossRefPubMedCentralGoogle Scholar
- 63.Jørgensen KK, Olsen IC, Goll GL, Lorentzen M, Bolstad N, Haavardsholm EA, et al. Switching from originator infliximab to biosimilar CT-P13 compared with maintained treatment with originator infliximab (NOR-SWITCH): a 52-week, randomised, double-blind, non-inferiority trial. Lancet. 2017;389(10086):2304–16.CrossRefGoogle Scholar
- 66.Smits LJ, Derikx LA, de Jong DJ, Boshuizen RS, van Esch AA, Drenth JP, et al. Clinical outcomes following a switch from Remicade(R) to the biosimilar CT-P13 in inflammatory bowel disease patients: a prospective observational cohort study. J Crohns Colitis. 2016;10(11):1287–93.PubMedCrossRefGoogle Scholar
- 67.CT-P13 (infliximab biosimilar). Briefing Document for the Arthritis Advisory Committee. 2016. https://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/arthritisadvisorycommittee/ucm484860.pdf. Accessed 9 Apr 2019.
- 68.CTP-10—a proposed biosimilar to Rituxan(R)—FDA Advisory Committee Meeting Briefing Document. 2018. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM622647.pdf. Accessed 9 Apr 2019.
- 69.Papp K, Bachelez H, Costanzo A, Foley P, Gooderham M, Kaur P, et al. Clinical similarity of the biosimilar ABP 501 compared with adalimumab after single transition: long-term results from a randomized controlled, double-blind, 52-week, phase III trial in patients with moderate-to-severe plaque psoriasis. Br J Dermatol. 2017;177(6):1562–74.PubMedCrossRefPubMedCentralGoogle Scholar
- 70.Weinblatt ME, Baranauskaite A, Dokoupilova E, Zielinska A, Jaworski J, Racewicz A, et al. Switching from reference adalimumab to SB5 (adalimumab biosimilar) in patients with rheumatoid arthritis: fifty-two-week phase iii randomized study results. Arthritis Rheumatol. 2018;70(6):832–40.PubMedPubMedCentralCrossRefGoogle Scholar
- 72.Gonczi L, Vegh Z, Golovics PA, Rutka M, Gecse KB, Bor R, et al. Prediction of short- and medium-term efficacy of biosimilar infliximab therapy do trough levels and antidrug antibody levels or clinical and biochemical markers play the more important role? J Crohns Colitis. 2017;11(6):697–705.PubMedGoogle Scholar
- 74.Park W, Yoo DH, Jaworski J, Brzezicki J, Gnylorybov A, Kadinov V, 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;20(18):25.CrossRefGoogle Scholar
- 76.Smits LJT, van Esch AAJ, Derikx L, Boshuizen R, de Jong DJ, Drenth JPH, et al. Drug survival and immunogenicity after switching from Remicade to biosimilar CT-P13 in inflammatory bowel disease patients: two-year follow-up of a prospective observational cohort study. Inflamm Bowel Dis. 2019;25(1):172–9.PubMedCrossRefGoogle Scholar
- 78.Smolen JS, Choe JY, Prodanovic N, Niebrzydowski J, Staykov I, Dokoupilova E, et al. Safety, immunogenicity and efficacy after switching from reference infliximab to biosimilar SB2 compared with continuing reference infliximab and SB2 in patients with rheumatoid arthritis: results of a randomised, double-blind, phase III transition study. Ann Rheum Dis. 2018;77(2):234–40.PubMedCrossRefGoogle Scholar
- 81.Gerdes S, Thaçi D, Griffiths CEM, Arenberger P, Poetzl J, Wuerth G, et al. Multiple switches between GP2015, an etanercept biosimilar, with originator product do not impact efficacy, safety and immunogenicity in patients with chronic plaque-type psoriasis: 30-week results from the phase 3, confirmatory EGALITY study. J Eur Acad Dermatol Venereol. 2018;32(3):420–7.PubMedCrossRefPubMedCentralGoogle Scholar
- 82.Yoo DH, Suh CH, Shim SC, Jeka S, Molina FFC, Hrycaj P, et al. Efficacy, safety and pharmacokinetics of up to two courses of the rituximab biosimilar CT-P10 versus innovator rituximab in patients with rheumatoid arthritis: results up to week 72 of a phase i randomized controlled trial. Biodrugs. 2017;31(4):357–67.PubMedPubMedCentralCrossRefGoogle Scholar
- 83.Girolomoni G, Feldman SR, Emery P, Ghil J, Keum JW, Cheong SY, et al. Comparison of injection-site reactions between the etanercept biosimilar SB4 and the reference etanercept in patients with rheumatoid arthritis from a phase III study. Br J Dermatol. 2018;178(3):e215–6.PubMedCrossRefPubMedCentralGoogle Scholar
- 84.Reinisch W, Jahnsen J, Schreiber S, Danese S, Panes J, Balsa A, et al. Evaluation of the cross-reactivity of antidrug antibodies to CT-P13 and infliximab reference product (Remicade): an analysis using immunoassays tagged with both agents. Biodrugs. 2017;31(3):223–37.PubMedPubMedCentralCrossRefGoogle Scholar
- 87.Benucci M, Gobbi FL, Bandinelli F, Damiani A, Infantino M, Grossi V, et al. Safety, efficacy and immunogenicity of switching from innovator to biosimilar infliximab in patients with spondyloarthritis: a 6-month real-life observational study. Immunol Res. 2017;65(1):419–22.PubMedCrossRefPubMedCentralGoogle Scholar