OP0012 A Phase 3, Randomized, Double-Blind, Active Comparator Study of the Efficacy and Safety of Bow015, A Biosimilar Infliximab, in Patients with Active Rheumatoid Arthritis on Stable Methotrexate Doses

Background Comparative effectiveness trials using suitable endpoints are necessary to demonstrate therapeutic equivalence of biosimilar molecules. Objectives This phase 3 double-blind, active comparator, clinical trial compared the efficacy and safety of a biosimilar infliximab (IFX), BOW015, to innovator IFX (iIFX). Methods 189 subjects with active rheumatoid arthritis (RA) diagnosed according to the 2010 ACR/EULAR criteria, on stable doses of oral methotrexate (MTX) 10-20 mg/wk, were randomized 2:1 to receive either BOW015 or iIFX 3 mg/kg iv on wks 0, 2, 6, and 14. Subjects had CRP ≥10 mg/L at screening and were tested for TB by PPD, QuantiFERON-TB Gold, and chest radiographs. The primary endpoint was ACR20 response at Wk 16, within a 23% equivalence margin. Responders to BOW015 were continued on treatment and responders to iIFX were crossed over to BOW015 during an open-label phase in which all subjects are being treated every 8 wks through Wk 46. Efficacy and safety were assessed at each visit and immunogenicity at Wks 0 and 14. Twelve subjects were not included in the per protocol (PP) analysis due to study drug discontinuation prior to Wk 16 (n=9), dosing error (n=2) or missing data (n=1). In serum from each patient, antibodies to IFX were assayed using sensitive bridge ELISAs against BOW015 and iIFX. Results The ACR20 responses at Wk 16 for BOW015 and iIFX, respectively, were 89.9% and 86.4% in the PP population (95% CI for the difference, -6.9% to 13.7%) and 85.0% and 85.5% in the intention-to-treat (ITT) population (95% CI for the difference, -11.2% to 10.3%). Kinetics of the ACR20 response was similar for both treatments over the first 16 wks of the trial in both the PP and ITT populations. The maximum treatment difference for the PP population was 3.4% and that for the ITT population was 6.4%, each at Wk 2. Overall, 43.3% of BOW015-treated and 50.0% of iIFX-treated subjects had at least one treatment emergent adverse event (AE). There was no significant difference in AE incidence by body system. Infectious AEs occurred in 15.8% of BOW015-treated and 9.7% of iIFX-treated subjects (p=0.368). Anti-IFX antibodies were detected in 22.1% of BOW015-treated and 35.5% of iIFX-treated subjects at Wk 14 (p=0.055). There was high concurrence between the BOW015-specific and iIFX-specific immunoassays among all subjects, regardless of treatment (κ=0.96). Conclusions This is the first clinical trial of a biosimilar IFX to demonstrate and report the kinetics of