A PHASE III, RANDOMISED, DOUBLE-BLIND, ACTIVE-CONTROLLED CLINICAL TRIAL to COMPARE BAT1806/BIIB800, A PROPOSED TOCILIZUMAB BIOSIMILAR, with TOCILIZUMAB REFERENCE PRODUCT in SUBJECTS with MODERATE to SEVERE RHEUMATOID ARTHRITIS with AN INADEQUATE RESPONSE to METHOTREXATE THERAPY

ABSTRACT

Background: BAT1806/BIIB800 is a proposed biosimilar to reference tocili-zumab (TCZ). A Phase III randomised, double-blind, active-controlled clinical trial was conducted as part of a biosimilar development programme. Objectives: To evaluate the efficacy, pharmacokinetics (PK), safety and immu-nogenicity of BAT1806/BIIB800 in comparison with EU-sourced TCZ in subjects with moderate to severe rheumatoid arthritis with inadequate response to meth-otrexate (MTX). Methods: The study was conducted at 55 centres in China and Europe, between June 2018 and January 2021. Eligible subjects were randomised in a 211 ratio to one of three treatment groups (1) BAT1806/BIIB800 up to Week 48, (2) TCZ up to Week 48, or (3) TCZ up to Week 24, followed by BAT1806/BIIB800 from Week 24 to Week 48, administered intravenously every 4 weeks at a dose of 8mg/kg. The primary endpoint was the proportion of subjects achieving an ACR20 response at timepoints pre-specifed to meet the requirements of different Regulatory Agencies Week 12, for EMA;Week 24, for FDA and NMPA. Equivalence margins applied to differences in ACR20 response rates in the BAT1806/BIIB800 and TCZ treatment groups were pre-specifed as follows +/-14.5% for EMA (95% confdence interval (CI));-12.0%,15% for FDA (90% CI);+/-13.6% for NMPA (95% CI). Secondary endpoints included pharmacokinetics, safety and immunogenicity. The ICH E9(R1) estimands framework including intercurrent events (related or unrelated to the COVID19 pandemic) was implemented for the ACR20 evaluation. A logistic regression model including 'region' (China and Eastern Europe) and 'previous biologic or targeted synthetic DMARD use' (Yes/No) as captured in Interactive Web Response System as stratifcation factors was utilised to assess equivalence for the primary endpoint. The difference in response rates was estimated and corresponding confdence intervals were derived to assess equivalence for the primary endpoint. This presents results up to Week 24. Results: In total, 621 subjects were randomised to receive BAT1806/BIIB800 (N=312), TCZ (N=155), or TCZ followed by BAT1806/BIIB800 (N=154). The groups were comparable in terms of baseline demographics and disease characteristics, including age, gender, disease activity and disease duration. The estimated proportions of subjects achieving an ACR20 response in the BAT1806/BIIB800 vs. the TCZ groups, respectively, were 68.97% vs. 64.82% at Week 12 and 69.89% vs. 67.94% at Week 24. The estimated difference between ACR response rates was 4.15% (95% CI-3.63, 11.93) at week 12, and 1.94% (90% CI-4.04, 7.92;95% CI-5.18, 9.07) at Week 24. The CIs for the estimated differences between the treatment groups were within the pre-defned equivalence margins (Figure 1). The treatment groups were comparable in terms of serum trough levels, incidence of TEAEs and ADA/NAb positivity (Table 1). Conclusion: BAT1806/BIIB800 has demonstrated equivalent efficacy at Week 12 and Week 24 and a similar PK, safety and immunogenicity profile as reference tocilizumab up to Week 24.