Ofatumumab, a human anti‐CD20 monoclonal antibody, for treatment of rheumatoid arthritis with an inadequate response to one or more disease‐modifying antirheumatic drugs: Results of a randomized, double‐blind, placebo‐controlled, phase I/II study

Abstract

Objective. To investigate the safety and efficacy of ofatumumab, a novel human anti-CD20 monoclonal antibody (mAb), in patients with active rheumatoid arthritis (RA) whose disease did not respond to >1 disease-modifying antirheumatic drug.Methods. This combined phase I/II study investigated the safety and efficacy of 3 doses of ofatumumab. In part A (phase I), 39 patients received 2 intravenous (IV) infusions of ofatumumab (300 mg, 700 mg, or 1,000 mg) or placebo in a 4:1 ratio 2 weeks apart, using a specified premedication and infusion regimen. In part B (phase II), 225 patients received study treatment as per phase I in a 1:1:1:1 ratio. Safety was assessed by adverse events (AEs) and laboratory parameters. Efficacy was assessed by the American College of Rheumatology 20% criteria for improvement (ACR20), the Disease Activity Score in 28 joints, and the European League Against Rheumatism (EULAR) response criteria. B cell pharmacodynamics were also investigated.Results. AEs were predominantly reported at the first infusion and were mostly mild to moderate in intensity. Rapid and sustained peripheral B cell depletion was observed in all dose groups. In phase II, patients in all ofatumumab dose groups had significantly higher ACR20 response rates (40%, 49%, and 44% for the 300 mg, 700 mg, and 1,000 mg doses, respectively) than did patients receiving placebo (11%) at week 24 (P < 0.001). Overall, 70% of patients receiving ofatumumab had a moderate or good response according to the EULAR criteria at week 24.Conclusion. Our findings indicate that ofatumumab, administered as 2 IV infusions of doses up to 1,000 mg, is clinically effective in patients with active RA.Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease characterized by symmetric inflammation of synovial joints, leading to progressive ClinicalTrials.gov identifier: NCT00291928.

Subcutaneously Administered Ofatumumab in Rheumatoid Arthritis: A Phase I/II Study of Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics

“…Infusion reactions, resulting from rapid B cell depletion and cytokine release, are commonly observed and may be severe following IV administration of anti-CD20 therapy, as has been reported in a phase I/II ofatumumab study in patients with RA 8 . Approaches including increased volume of infusion, increased infusion time, and use of IV gluco-corticoid premedication successfully reduced the incidence and severity of infusion reactions observed with ofatumumab, a highly potent monoclonal antibody with enhanced complement-dependent effector 8,9 .…”

“…In a previous randomized, placebo-controlled phase I/II study, IV ofatumumab doses of 300 mg, 700 mg, and 1000 mg administered as 2 infusions 2 weeks apart demonstrated significant clinical benefit compared with placebo in patients with active rheumatoid arthritis (RA) who had an inadequate response to disease-modifying antirheumatic drugs (DMARD) 8 .…”

“…Approaches including increased volume of infusion, increased infusion time, and use of IV gluco-corticoid premedication successfully reduced the incidence and severity of infusion reactions observed with ofatumumab, a highly potent monoclonal antibody with enhanced complement-dependent effector 8,9 . A study of ocrelizumab, a humanized anti-CD20 monoclonal antibody with enhanced antibody-dependent cell-mediated cytotoxicity and reduced complement-dependent cytotoxicity, administered IV to patients with RA who did not receive premedication with IV glucocorticoids, still demonstrated infusion-associated adverse events (AE) in 51% of ocrelizumab-treated patients on the first infusion compared with 27% with placebo 2 .…”

Humoral-Targeted Immunotherapies in Multiple Sclerosis

“…Ofatumumab demonstrated clinical efficacy in a phase 2 trial in RA patients (n020) without an increased risk of opportunistic infections. Phase 3 trials are underway in RA [45].…”

B-cell-targeted therapies in systemic lupus erythematosus and ANCA-associated vasculitis: current progress

“…Another humanised anti-CD20 mAb, ofatumumab, with improved antibody-dependent cellular cytotoxicity killing, has demonstrated clinical efficacy in Phase I/II trials in RA [29].…”