Immunogenicity of an adalimumab biosimilar, FKB327, and its reference product in patients with rheumatoid arthritis

Abstract

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.

Keywords: TNF inhibitors; adalimumab; biosimilars; immunogenicity; rheumatoid arthritis; switching.

Figure 1

Study design. DB, double‐blind study; EOW, every other week; F, FKB327; OLE, open‐label extension study; R, randomized; RA, rheumatoid arthritis; RP, reference product (US‐approved); SC, subcutaneous; w, week. 730 patients were initially enrolled in the study, but 2 patients dropped out prior to randomization and receipt of study drug

Figure 2

Summary of antidrug antibody development over time. ADA, antidrug antibody; ADA+ve, antidrug antibody positive; F, FKB327; RP, reference product (US‐approved). Week 80 indicates overall; Week 0, beginning of open‐label extension; Week 24, end of Period 2; Week 76, end of Period 3. Percentages are based on the number of patients in the Safety Analysis Set with an assay result obtained each week. See Figure 1 for explanation of treatment sequences. At each sampling point, electrochemiluminescence assays were used to assess the development of ADAs. The proportion of patients with positive ADA status is represented for each treatment sequence at each time point

Figure 3

Drug serum trough concentrations and ADA status over time. ADA, antidrug antibody; DB, double‐blind; F, FKB327; OLE, open‐label extension; RP, reference product (US‐approved). Baseline indicates the beginning of the DB study; Week 24, beginning of OLE; Week 54, end of Period 2, OLE; Week 76, end of Period 3, OLE; Week 100, Week 76, OLE. See Figure 1 for full explanation of treatment sequences. Low, less than or equal to the lower quartile (0.0625); moderate, between the lower and upper quartile; high, greater than or equal to the upper quartile (17 600). Circles indicate outlier points; rectangles, the upper and lower quartiles; horizontal line inside rectangle, median; vertical lines extending from rectangles, highest and lowest values; diamonds, means. *Indicates time points where an analysis of variance model including maximum ADA titer category as the only covariate had a significant (P < .05) overall F test. Validity of assumptions was evaluated via diagnostic plots (histograms, scatterplots, and quantile‐quantile plots)