Use of multibiomarker disease activity scores in biosimilarity studies for the treatment of patients with rheumatoid arthritis
Jonathan Kay, Amy E Bock, Muhammad Rehman, Wuyan Zhang, Min Zhang, Noriko Iikuni, Daniel F Alvarez, Jonathan Kay, Amy E Bock, Muhammad Rehman, Wuyan Zhang, Min Zhang, Noriko Iikuni, Daniel F Alvarez
Abstract
Objectives: This exploratory analysis investigated the potential use of the multibiomarker disease activity (MBDA) score to support biosimilarity assessments using data from two randomised controlled trials (RCTs) of biosimilar infliximab (IFX-qbtx) and biosimilar adalimumab (ADL-afzb) versus EU-sourced infliximab (Remicade; IFX-EU) and adalimumab (Humira; ADL-EU) reference products, respectively, both conducted in adult patients with active rheumatoid arthritis.
Methods: In one study, patients (N=650) were randomised 1:1 to IFX-qbtx or IFX-EU (3 mg/kg intravenous at weeks 0, 2 and 6, then every 8 weeks). In the other, patients (N=597) were randomised 1:1 to ADL-afzb or ADL-EU (40 mg subcutaneous every other week). All treatments were given with MTX. Mean values of MBDA scores were calculated at baseline (BL), based on the concentrations of 12 serum proteins using the Vectra disease activity algorithm, and at timepoints throughout treatment period 1 (TP1) of the IFX (weeks 6, 14, 30) and ADL (weeks 6, 12, 26) studies. Data were summarised using descriptive statistics for the intent-to-treat population, without imputation for missing data.
Results: At BL, mean (±SD) MBDA scores were 61.3 (±12.5) and 58.8 (±13.2) for IFX-qbtx (n=236) and IFX-EU (n=248), respectively, and 57.2 (±14.44) and 58.3 (±15.34) for ADL-afzb (n=292) and ADL-EU (n=293), respectively. Mean MBDA scores were highly comparable between IFX-qbtx and IFX-EU and between ADL-afzb and ADL-EU at all measured timepoints during TP1 in each study.
Conclusions: These RCTs are the first to incorporate MBDA score as an exploratory assessment of biosimilarity. MBDA scores may provide objective, quantitative evidence of biosimilarity using an assessment of disease activity that is independent of the potential subjectivity inherent in joint counts, or in patient or physician global assessments.
Trial registration numbers: NCT02222493 and NCT02480153.
Keywords: Adalimumab; Arthritis, Rheumatoid; Biosimilar Pharmaceuticals; Infliximab.
Conflict of interest statement
Competing interests: JK reports grant support (paid to his institution) from Aker BioMarine, Alliance for Lupus Research, AMPEL BioSolutions, Gilead Sciences, Inc., Novartis Pharmaceuticals Corp., Pfizer and UCB Inc; royalty fees from UpToDate; consulting fees from AbbVie, Alvotech Suisse AG, Arena Pharmaceuticals, Inc., Boehringer Ingelheim GmbH, Celltrion Healthcare Co. Ltd., Horizon Therapeutics PLC, Jubilant Radiopharma, Merck Sharp & Dohme Corp., Mylan Inc., Novartis AG, Pfizer, Samsung Bioepis, Sandoz Inc., Scipher Medicine, and UCB Inc.; and fees for participation in data monitoring boards from Bristol Myers Squibb Co., Inmagene Biopharmaceuticals and Kolon TissueGene Inc. DFA, AEB, MR and MZ are full-time employees of, and declare shareholdings, stock holdings and/or stock options from, Pfizer. NI was a full-time employee of Pfizer at the time of the studies and declares shareholdings, stock holdings and/or stock options from Pfizer. WZ is a full-time employee of Pfizer and declares shareholdings, stock holdings and/or stock options from Abbot, AbbVie and Pfizer.
© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
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References
- US Food and Drug Administration . Scientific considerations in demonstrating biosimilarity to a reference product, 2015. Guidance for industry. Available: [Accessed 11 Nov 2019].
- European Medicines Agency . Amsparity (adalimumab) Eurpoean public assessment report, 2020. Available: [Accessed 17 Sep 2020].
- European Medicines Agency . Zessly (infliximab) European public assessment report, 2020. Available: [Accessed 16 Sep 2020].
- Pfizer Inc . ABRILADA (adalimumab-afzb) US prescribing information, 2020. Available: [Accessed 17 Sep 2020].
- Pfizer Ireland Pharmaceuticals . IXIFI (infliximab-qbtx) US prescribing information, 2017. Available: [Accessed 16 Sep 2020].
- . A study of PF-06410293 (adalimumab-Pfizer) and adalimumab (Humira) in healthy subjects (reflections B538–07)) (B538–07), 2014. Available: [Accessed 17 Sep 2020].
- Cohen SB, Alten R, Kameda H, 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;20:155. 10.1186/s13075-018-1646-4
- Derzi M, Johnson TR, Shoieb AM, et al. . Nonclinical evaluation of PF-06438179: a potential biosimilar to Remicade® (Infliximab). Adv Ther 2016;33:1964–82. 10.1007/s12325-016-0403-9
- Derzi M, Shoieb AM, Ripp SL, et al. . Comparative nonclinical assessments of the biosimilar PF-06410293 and originator adalimumab. Regul Toxicol Pharmacol 2020;112:104587. 10.1016/j.yrtph.2020.104587
- Fleischmann RM, Alten R, Pileckyte M, et al. . A comparative clinical study of PF-06410293, a candidate adalimumab biosimilar, and adalimumab reference product (Humira®) in the treatment of active rheumatoid arthritis. Arthritis Res Ther 2018;20:178. 10.1186/s13075-018-1676-y
- Palaparthy R, Udata C, Hua SY, et al. . A randomized study comparing the pharmacokinetics of the potential biosimilar PF-06438179/GP1111 with Remicade® (infliximab) in healthy subjects (reflections B537-01). Expert Rev Clin Immunol 2018;14:329–36. 10.1080/1744666X.2018.1446829
- Centola M, Cavet G, Shen Y, et al. . Development of a multi-biomarker disease activity test for rheumatoid arthritis. PLoS One 2013;8:e60635. 10.1371/journal.pone.0060635
- Segurado OG, Sasso EH. Vectra dA for the objective measurement of disease activity in patients with rheumatoid arthritis. Clin Exp Rheumatol 2014;32:S-29–34.
- Schiff M, Weinblatt ME, Valente R, et al. . Head-To-Head comparison of subcutaneous abatacept versus adalimumab for rheumatoid arthritis: two-year efficacy and safety findings from AMPLE trial. Ann Rheum Dis 2014;73:86–94. 10.1136/annrheumdis-2013-203843
- Weinblatt ME, Schiff M, Valente R, et al. . Head-To-Head comparison of subcutaneous abatacept versus adalimumab for rheumatoid arthritis: findings of a phase IIIB, multinational, prospective, randomized study. Arthritis Rheum 2013;65:28–38. 10.1002/art.37711
- US Food and Drug Administration . Biosimilars action plan: balancing innovation and competition, 2018. Available: [Accessed 17 September 2020].
- Li J, Florian J, Campbell E, et al. . Advancing Biosimilar development using pharmacodynamic biomarkers in clinical pharmacology studies. Clin Pharmacol Ther 2020;107:40–2. 10.1002/cpt.1653
- European Medicines Agency . Pelmeg (pegfilgrastim) European public assessment report, 2018. Available: [Accessed 6 September 2022].
- US Food and Drug Administration . Udenyca (pegfilgrastim-cbqv) summary review, 2018. Available: [Accessed 25 July 2022].
- Alten R, Batko B, Hala T, et al. . Randomised, double-blind, phase III study comparing the infliximab biosimilar, PF-06438179/GP1111, with reference infliximab: efficacy, safety and immunogenicity from week 30 to week 54. RMD Open 2019;5:e000876. 10.1136/rmdopen-2018-000876
- Cohen SB, Radominski SC, Kameda H, et al. . Long-Term efficacy, safety, and immunogenicity of the infliximab (IFX) biosimilar, PF-06438179/GP1111, in patients with rheumatoid arthritis after switching from reference IFX or continuing biosimilar therapy: week 54-78 data from a randomized, double-blind, phase III trial. BioDrugs 2020;34:197–207. 10.1007/s40259-019-00403-z
- Fleischmann RM, Alvarez DF, Bock AE, et al. . Randomised study of PF-06410293, an adalimumab (ADL) biosimilar, compared with reference ADL for the treatment of active rheumatoid arthritis: results from weeks 26-52, including a treatment switch from reference ADL to PF-06410293. RMD Open 2021;7:e001578. 10.1136/rmdopen-2021-001578
- Fleischmann RM, Alvarez DF, Bock AE, et al. . Long-Term efficacy, safety, and immunogenicity of the adalimumab biosimilar, PF-06410293, in patients with rheumatoid arthritis after switching from reference adalimumab (Humira®) or continuing biosimilar therapy: week 52-92 data from a randomized, double-blind, phase 3 trial. Arthritis Res Ther 2021;23:248. 10.1186/s13075-021-02626-4
- Kay J, Alvarez D, Rehman M. Use of Multi-Biomarker Disease Activity Scores to Assess Biosimilarity in a Phase 3 Randomized Controlled Trial Comparing Biosimilar Infliximab-qbtx (PF-06438179/GP1111) with EU-Sourced Reference Infliximab in Patients with Active RA [abstract]. Arthritis Rheumatol 2020;72
- Kay J, Bock AE, Iikuni N. Use of Multi-Biomarker Disease Activity Scores to Compare Biosimilar Adalimumab-afzb (PF-06410293) with EU-Sourced Reference Adalimumab in a Phase 3, Randomized, Double-Blind Trial in Patients with Active RA [abstract]. Arthritis Rheumatol 2020;72
- Bathon JM, Martin RW, Fleischmann RM, et al. . A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 2000;343:1586–93. 10.1056/NEJM200011303432201
- Keystone E, Genovese MC, Klareskog L, et al. . Golimumab in patients with active rheumatoid arthritis despite methotrexate therapy: 52-week results of the GO-FORWARD study. Ann Rheum Dis 2010;69:1129–35. 10.1136/ard.2009.116319
- Keystone E, Heijde Dvander, Mason D, et al. . Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis: findings of a fifty-two-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheum 2008;58:3319–29. 10.1002/art.23964
- Keystone EC, Kavanaugh AF, Sharp JT, et al. . Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis Rheum 2004;50:1400–11. 10.1002/art.20217
- Lipsky PE, van der Heijde DM, St Clair EW, et al. . Infliximab and methotrexate in the treatment of rheumatoid arthritis. anti-tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy Study Group. N Engl J Med 2000;343:1594–602. 10.1056/NEJM200011303432202
- Maini R, St Clair EW, Breedveld F, et al. . Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. attract Study Group. Lancet 1999;354:1932–9. 10.1016/s0140-6736(99)05246-0
- Smolen JS, Kay J, Landewé RBM, et al. . Golimumab in patients with active rheumatoid arthritis who have previous experience with tumour necrosis factor inhibitors: results of a long-term extension of the randomised, double-blind, placebo-controlled GO-AFTER study through week 160. Ann Rheum Dis 2012;71:1671–9. 10.1136/annrheumdis-2011-200956
- Fleischmann R, Connolly SE, Maldonado MA, et al. . Brief report: estimating disease activity using multi-biomarker disease activity scores in rheumatoid arthritis patients treated with abatacept or adalimumab. Arthritis Rheumatol 2016;68:2083–9. 10.1002/art.39714
- Kay J, Smolen JS. Biosimilars to treat inflammatory arthritis: the challenge of proving identity. Ann Rheum Dis 2013;72:1589–93. 10.1136/annrheumdis-2012-203198
Source: PubMed