A randomised, double-blind trial to demonstrate bioequivalence of GP2013 and reference rituximab combined with methotrexate in patients with active rheumatoid arthritis

Josef S Smolen, Stanley B Cohen, Hans-Peter Tony, Morton Scheinberg, Alan Kivitz, Andra Balanescu, Juan Gomez-Reino, Liyi Cen, Peijuan Zhu, Tamas Shisha, Josef S Smolen, Stanley B Cohen, Hans-Peter Tony, Morton Scheinberg, Alan Kivitz, Andra Balanescu, Juan Gomez-Reino, Liyi Cen, Peijuan Zhu, Tamas Shisha

Abstract

Objectives: The aim of this report is to demonstrate pharmacokinetic (PK) and pharmacodynamic (PD) equivalence as well as similar efficacy, safety and immunogenicity between GP2013, a biosimilar rituximab, and innovator rituximab (RTX) in patients with rheumatoid arthritis (RA) with inadequate response or intolerance to tumour necrosis factor inhibitor (TNFi) treatment.

Methods: In this multinational, randomised, double-blind, parallel-group study, 312 patients with active disease despite prior TNFi therapy were randomised to receive GP2013 or either the EU (RTX-EU) or the US (RTX-US) reference product, along with methotrexate (MTX) and folic acid. The primary endpoint was the area under the serum concentration-time curve from study drug infusion to infinity (AUC0-inf). Additional PK and PD parameters, along with efficacy, immunogenicity and safety outcomes were also assessed up to week 24.

Results: The 90% CI of the geometric mean ratio of the AUCs were within the bioequivalence limits of 80% to 125% for all three comparisons; GP2013 versus RTX-EU: 1.106 (90% CI 1.010 to 1.210); GP2013 versus RTX-US: 1.012 (90% CI 0.925 to 1.108); and RTX-EU versus RTX-US: 1.093 (90% CI 0.989 to 1.208). Three-way PD equivalence of B cell depletion was also demonstrated. Efficacy, safety and immunogenicity profiles were similar between GP2013 and RTX.

Conclusions: Three-way PK/PD equivalence of GP2013, RTX-EU and RTX-US was demonstrated. Efficacy, safety and immunogenicity profiles were similar between GP2013 and RTX.

Trial registration number: NCT01274182; Results.

Keywords: B cells; DMARDs (biologic); Rheumatoid arthritis.

Conflict of interest statement

Competing interests: PZ, LC and TS are employees of Sandoz/Hexal. JSS, HPT, AK, AB, JG-R and MS received investigator fees from Sandoz, a Novartis Division.

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Figures

Figure 1
Figure 1
Arithmetic mean of B cell count relative to baseline up to week 24 (pharmacokinetic set).
Figure 2
Figure 2
(A) Box whiskers plot of DAS28(CRP) up to week 24 (per protocol set). (B) ACR20 response rate up to week 24 (per protocol set). (C) Box whiskers plot of CDAI up to week 24 (per protocol set). (D) Box whiskers plot of SDAI up to week 24 (per protocol set). ACR, American College of Rheumatology; CDAI, Clinical Disease Activity Index; CRP, C reactive protein; DAS, Disease Activity Score in 28; RTX, rituximab; SDAI, Simplified Disease Activity Index.

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