Use of multibiomarker disease activity scores in biosimilarity studies for the treatment of patients with rheumatoid arthritis

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.

Figures

Figure 1

Design of the comparative clinical studies of (A) IFX-qbtx and IFX-EU and (B) ADL-afzb and ADL-EU. (A) Comparative clinical study of IFX-qbtx and IFX-EU. (B) Comparative clinical study of ADL-afzb and ADL-EU. *Intravenous IFX-qbtx or IFX-EU (3 mg/kg) in combination with MTX (10–25 mg/week) were administered at weeks 0, 2 and 6 and then every 8 weeks thereafter. †ADL-afzb or ADL-EU 40 mg subcutaneously Q2W+MTX. ADL-afzb, adalimumab biosimilar PF-06410293; ADL-EU, adalimumab reference product sourced from the European Union; EOT, end of treatment; IFX-EU, infliximab reference product sourced from the European Union; IFX-qbtx, infliximab biosimilar PF-06438179/GP1111; MBDA, multi-biomarker disease activity; MTX, methotrexate; Q2W, every 2 weeks; TP, treatment period.

Figure 2

Mean (±SD) MBDA scores over time and ACR response rates and change from baseline in DAS28-CRP by study visit in patients with RA treated with IFX-qbtx or IFX-EU (ITT population). (A) Mean (±SD) MBDA scores over time up to week 30 in patients with RA treated with IFX-qbtx or IFX-EU (ITT population). (B) ACR response rates by study visit up to week 30 in patients with RA treated with IFX-qbtx or IFX-EU (ITT population). (C) Mean (±SE) change from baseline in DAS28-CRP by study visit up to week 30 in patients with RA treated with IFX-qbtx or IFX-EU (ITT population). *Baseline was defined as the measurement taken at the week 0 visit. For postbaseline visits, patients with both baseline and postbaseline data at each visit were counted. (B, C) ACR20/50/70, American College of Rheumatology criteria for ≥20%/50%/70% clinical improvement; DAS28-CRP, Disease Activity Score in 28 joints, four components based on C-reactive protein; IFX-EU, infliximab reference product sourced from the European Union; IFX-qbtx, infliximab biosimilar PF‑06438179/GP1111; ITT, intent-to-treat; MBDA, multi-biomarker disease activity; SD, standard deviation. Reproduced with permission from 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. https://doi.org/10.1186/s13075-018-1646-4.

Figure 3

Mean (±SD) MBDA scores over time and ACR response rates and change from baseline in DAS28-CRP by study visit in patients with RA treated with ADL-afzb or ADL-EU (ITT population). (A) Mean (±SD) MBDA scores over time up to week 26 in patients with RA treated with ADL-afzb or ADL-EU (ITT population). (B) ACR response rates by study visit up to week 26 in patients with RA treated with ADL-afzb or ADL-EU (ITT population). (C) Mean (±SE) change from baseline in DAS28-CRP by study visit up to week 30 in patients with RA treated with ADL-afzb or ADL-EU (ITT population). *Baseline was defined as the last non-missing measurement taken on or before study day 1. (B, C) ACR20/50/70, American College of Rheumatology criteria for ≥20%/50%/70% clinical improvement; ADL-afzb, adalimumab biosimilar PF‑06410293; ADL-EU, adalimumab reference product sourced from the European Union; DAS28-CRP, Disease Activity Score in 28 joints, four components based on C-reactive protein; ITT, intent-to-treat; MBDA, multi-biomarker disease activity; SD, standard deviation. Reproduced with permission from Fleischmann, R.M., 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. https://doi.org/10.1186/s13075-018-1676-y.

Figure 4

Mean (±SD) log biomarker values over time for (A) SAA (µg/mL), (B) TNF-R1 (ng/mL) and (C) VEGF-A (pg/mL) during TP1 (ITT population) of the comparative clinical study of IFX-qbtx and IFX-EU. (A) Mean (±SD) log biomarker values (µg/mL) over time for SAA. (B) Mean (±SD) log biomarker values (ng/mL) over time for TNF-R1. (C) Mean (±SD) log biomarker values (pg/mL) over time for VEGF-A. *Baseline was defined as the last non-missing measurement taken on or before study day 1. IFX-EU, infliximab reference product sourced from the European Union; IFX-qbtx, infliximab biosimilar PF-06438179/GP1111; ITT, intent-to-treat; SAA, serum amyloid A; TNF-R1, tumour necrosis factor receptor 1; TP1, treatment period 1; VEGF-A, vascular endothelial growth factor-A.

Figure 5

Mean (±SD) log biomarker values (pg/mL) over time for (A) SAA, (B) TNF-R1 and (C) VEGF-A during TP1 (ITT population) of the comparative clinical study of ADL-afzb and ADL-EU. (A) Mean (±SD) log biomarker values (pg/mL) over time for SAA. (B) Mean (±SD) log biomarker values (pg/mL) over time for TNF-R1. (C) Mean (±SD) log biomarker values (pg/mL) over time for VEGF-A. *Baseline was defined as the last non-missing measurement taken on or before study day 1. ADL-afzb, adalimumab biosimilar PF-06410293; ADL-EU, adalimumab reference product sourced from the European Union; ITT, intent-to-treat; SAA, serum amyloid A; TNF-R1, tumour necrosis factor receptor 1; TP1, treatment period 1; VEGF-A, vascular endothelial growth factor-A.