SAT0190 A Phase I Trial Comparing PF-05280586 (A Potential Biosimilar) and Rituximab in Patients with Active Rheumatoid Arthritis

Background Rituximab is a genetically engineered chimeric murine/human monoclonal immunoglobulin (Ig) G1 κ-antibody directed against the CD20 antigen of B-cells. PF-05280586, a proposed biosimilar to rituximab, was studied in a double-blind phase I/II pharmacokinetic (PK) similarity trial (NCT01526057). Objectives To compare PF-05280586 to rituximab sourced from the European Union (rituximab-EU) and United States (rituximab-US) via clinical response, pharmacodynamic effects on CD19+ B-cell count, immunogenicity, and safety. Methods 220 subjects with active rheumatoid arthritis (RA) on a stable background regimen of methotrexate who had an inadequate response to one or more TNF antagonist therapies were randomized 1:1:1 to one course of IV PF-05280586, rituximab-US, or rituximab-EU 1000 mg on Days 1 and 15. After Week 17, subjects could enroll in an extension study and receive additional courses of treatment. Clinical response was assessed via Disease Activity Score in 28 joints-C-reactive protein (DAS28-CRP) and American College of Rheumatology (ACR) assessments. Blood and serum samples were collected at prespecified intervals for analysis of CD19+ B-cell counts and detection of anti-drug antibodies (ADA) and neutralizing antibodies (Nab). CD19+ B-cell counts were analyzed using a laser scanning cytometry procedure and analyzed by model-independent methods. ADA was detected using validated electrochemiluminescent immunoassays. Confirmed ADA-positive samples were further tested for Nab using a validated semi-quantitative cell-based assay and for ADA cross-reactivity. Safety analysis included adverse events, electrocardiograms, vital signs, and clinical laboratory data. Results Baseline demographics were generally similar among treatment arms, while measures of disease activity were numerically higher at baseline for patients randomized to rituximab-US. The primary objective of demonstrating PK similarity among the PF-05280586, rituximab-US, and rituximab-EU was achieved based on the 80-125% bioequivalence criteria. Although not designed to demonstrate similarity for efficacy, mean DAS28-CRP, mean number of tender/painful joint counts, mean number of swollen joint counts, and mean high-sensitivity C reactive protein values decreased over time, and improvement in ACR20, ACR50, and ACR70 scores were seen in all groups. All treatments resulted in rapid CD-19+ B-cell depletion by Week 2, which was sustained for the study duration. No differences in the incidence of ADA, time of ADA emergence, or ADA titers were observed. None of the ADA-positive samples tested positive for neutralizing activity. Safety was similar among treatment arms. A total of 11 subjects experienced serious adverse events (PF-05280586: 5; rituximab-US: 4; rituximab-EU: 2). Conclusions In this PK similarity study, improvement in clinical response occurred with PF-05280586, rituximab-US, and rituximab-EU. All 3 treatments had similar PD effect on CD19+ B-cell. All treatments were generally well-tolerated with similar AE profiles. These results are consistent with PK similarity evidence among treatments and support continued clinical development of PF-05280586 as a potential biosimilar to rituximab. Disclosure of Interest I. Jacobs Employee of: Pfizer Inc, D. Yin Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, L. A. Melia Employee of: Pfizer Inc, B. Gumbiner Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, M. Suster Employee of: Pfizer Inc, D. Thomas Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, X. Meng Employee of: Pfizer Inc