Rafael Muniz

Although treatment with biologic disease-modifying antirheumatic drugs (bDMARDs) has significantly improved clinical outcomes in patients with rheumatoid arthritis (RA), many patients do not have access to these treatments. As cost-effective alternatives to their reference products (RPs), biosimilars provide an opportunity to increase access to bDMARDs. The European Medicines Agency and the US Food and Drug Administration have detailed pathways for the approval of biosimilars based on establishing the similarity of the biosimilar to the RP in terms of structure and function, pharmacokinetics (PK), efficacy, safety, and immunogenicity. A number of biosimilars of adalimumab, infliximab, etanercept, and rituximab RPs have been approved in the United States and/or European Union. This article is focused on the seven adalimumab biosimilars. A review of the data for the biosimilars FKB327, ABP 501, BI 695501, GP2017, MSB11022, PF-06410293, and SB5 confirm that these products are highly similar to the adalimumab RP with regard to structure, physicochemical and biological properties, PK, safety, immunogenicity, and efficacy in the treatment of RA and other chronic immune-mediated, inflammatory conditions. Data from several switching studies showed no changes in efficacy, safety, trough serum drug concentration, or immunogenicity between the biosimilars and their RP. Trial registration: ClinicalTrials.gov identifiers: NCT02260791, NCT02405780, NCT01970475, NCT02137226, NCT02045979, NCT02744755, NCT02144714, NCT02167139, NCT03014947, NCT02114931, NCT02640612, NCT02167139, NCT03052322, NCT02480153. EudraCT numbers: 2012-005140-23, 2012-000785-37, 2013-003722-84, 2015-000579-28, 2014-002879-29, 2014-000662-21, 2013-004654-13, 2015-002634-41, 2014-005229-11, 2016-002852-26, 2014-000352-29

Aim This study, FKB327‐003, is a phase 3, open‐label extension (OLE) study comparing the long‐term immunogenicity of an adalimumab biosimilar, FKB327 (F), with the reference product (RP). Methods In the OLE, patients completing 24 weeks of an initial randomized, double‐blind (DB) study (Period 1) with clinical response and no safety concerns were rerandomized to F or RP, so that two‐thirds of patients remained on the same treatment and one‐third switched to the alternate treatment for weeks 24 through 54 (OLE weeks 0‐30; Period 2), then all received F through week 100 (OLE week 76; Period 3). Treatment sequences were F‐F‐F (no switch), RP‐F‐F and RP‐RP‐F (single switch), and F‐RP‐F (double switch). Patients who entered the OLE study were evaluated for immunogenicity across switching sequences. Results The proportion of patients with positive antidrug antibody (ADA) status at the end of Period 1 was 61.7% and 60.0% for F and RP, respectively. The proportion of patients with positive ADA status did not increase throughout Period 1, and was similar for F and RP at all time points. At the end of Period 3, the proportion of patients with positive ADA status was lower in all treatment sequences, at 51.1%, 54.4%, 48.1%, and 42.5% for F‐F‐F, F‐RP‐F, RP‐F‐F, and RP‐RP‐F, respectively. Conclusion The RP and F showed comparable immunogenicity characteristics after long‐term administration. Development of ADAs with the RP and F was similar, and was not impacted by switching and double switching between F and RP treatment.

FKB327 was approved by the European Medicines Agency as a biosimilar to European‐authorized adalimumab (Humira^®; AbbVie Inc). Adalimumab is a monoclonal antibody, binding and inhibiting tumor necrosis factor (TNF)‐α with use indicated for several immune‐mediated, chronic, and inflammatory disorders. The approval is based on high similarity in the physicochemical properties between FKB327 and adalimumab. The objective of this study is to assess the biological similarity, with regard to Fab‐ and Fc‐associated functions, and describe the relationship between physicochemical and biological characterization and functional activity. State‐of‐the‐art orthogonal techniques were implemented to assess the structure and function of FKB327. Peptide mapping with liquid chromatography and mass spectrometry, capillary electrophoresis–sodium dodecyl sulfate, ultraviolet circular dichroism, size‐exclusion high‐performance liquid chromatography (HPLC), and cation exchange HPLC were the techniques used to assess structure. Functional activity was assessed with enzyme‐linked immunosorbent assay, surface plasmon resonance, and cell‐based assays. The polypeptide sequence of FKB327 was identical to that of adalimumab. FKB327 also was demonstrated to have a similar secondary and tertiary structure to adalimumab. Posttranslational heterogeneities, along with size and charge variants, were not clinically meaningful. FKB327 binds to TNF‐α, FcγR, the neonatal Fc receptor, and C1q, and induces apoptosis, antibody‐dependent cellular cytotoxicity, and complement‐dependent cytotoxicity. The binding and activity of FKB327 were similar to that of adalimumab. FKB327 shares similar structure and activity with adalimumab. Based on characterization of physicochemical and biological properties, FKB327 is expected to have a similar safety, immunogenicity, and efficacy profile to adalimumab.

Background/Objective FKB327 is a biosimilar of the antitumour necrosis factor adalimumab reference product (RP). A randomised, double-blind (DB) phase 3 study compared the efficacy of FKB327 with the RP in patients with active rheumatoid arthritis (RA) inadequately controlled with methotrexate (MTX). A subsequent randomised open-label extension (OLE) study with treatment switching assessed long-term safety, efficacy, pharmacokinetics and immunogenicity of FKB327 compared with the RP. Methods Patients with moderate-to-severe, active RA on a stable dose of MTX were randomised 1:1 to receive FKB327 or the RP (40 mg subcutaneously every other week) for 24 weeks. Patients who completed the DB study were enrolled in the OLE and rerandomised 2:1 to receive FKB327 or the RP; two-thirds continued on the same treatment and one-third switched for 30 weeks. All patients received FKB327 through Week 76. Long-term efficacy, safety and immunogenicity were assessed. Results Of 728 patients in the DB study, 645 were enrolled in the FKB327-OLE study. The American College of Rheumatology (ACR)20 response rates for all treatment groups at Week 30 in the OLE ranged from 83.2% to 85.9%. ACR20 response rates remained stable for all patients regardless of single- or double-switching treatment and were similar for all treatment sequences through Week 76. The safety profile and incidence of antidrug antibodies were comparable across sequences. Conclusion Efficacy, safety and immunogenicity were similar among patients with RA treated with FKB327 or the RP for up to 2 years, and were not affected by single- or double-switching treatment.