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

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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. CLINICAL TRIALS REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT02296775. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s40259-020-00406-1) contains supplementary material, which is available to authorized users.