Pharmacokinetic Similarity and Comparative Pharmacodynamics, Safety, Efficacy, and Immunogenicity of DRL_RI Versus Reference Rituximab in Biologics-Naïve Patients with Moderate-to-Severe Rheumatoid Arthritis: A Double-Blind, Randomized, Three-Arm Study

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The aims were to demonstrate pharmacokinetic (PK) similarity between DRL_RI, a proposed rituximab biosimilar, and two reference innovator products (Rituxan ® [RTX-US] and MabThera ® [RTX-EU]) and compare their pharmacodynamics (PD), efficacy, safety, and immunogenicity in rheumatoid arthritis (RA) patients with inadequate response to methotrexate (MTX)-based therapy and no prior biologic administration. In this randomized, double-blind, parallel-group study, 276 patients with moderate-to-severe active RA were randomized to receive DRL_RI, RTX-US, or RTX-EU on days 1 and 15. The primary PK end points included area under the concentration–time curve from time 0 to 336 h after first infusion (AUC 0–14 days, first infusion ), AUC from day 1 through week 16 (AUC 0–∞, entire course ), and AUC from time 0 to time of last quantifiable concentration after the second dose (AUC 0– t , second infusion ). Secondary end points included other PK parameters, such as maximum concentration ( C max ), time to C max after each infusion, terminal half-life, systemic clearance, and volume of distribution after the second infusion; PD parameters and efficacy until week 24; safety and immunogenicity at week 24 and 52; and B cell recovery until week 52. AUC from time 0 to time of last quantifiable concentration after the first dose and over the entire course from day 1 through week 16 (AUC 0– t , entire course ) was analyzed as an exploratory end point. The 91% confidence intervals (CIs) of the geometric mean ratios (GMRs) for the primary end point of AUC 0–∞, entire course were within the bioequivalence limits of 80–125% for all comparisons: DRL_RI versus RTX-US 100.37% (92.30–109.14), DRL_RI versus RTX-EU 93.58% (85.98–101.85), and RTX-US versus RTX-EU 93.24% (85.62–101.54). PD outcomes (peripheral blood B-cell depletion and mean change in Disease Activity Score [28 joints]–C-reactive protein), efficacy, safety, and immunogenicity were also comparable between DRL_RI and the reference products. DRL_RI, a proposed biosimilar, demonstrated three-way PK similarity with RTX-EU and RTX-US, the reference innovator products, with comparable efficacy, PD, safety, and immunogenicity. ClinicalTrials.gov identifier: NCT02296775.