Safety and efficacy of ocrelizumab in patients with rheumatoid arthritis and an inadequate response to at least one tumor necrosis factor inhibitor: Results of a forty‐eight–week randomized, double‐blind, placebo‐controlled, parallel‐group phase III trial

Abstract

Objective. To evaluate the safety and efficacy of ocrelizumab plus methotrexate (MTX) or leflunomide (LEF) in patients with active rheumatoid arthritis (RA) and an inadequate response to tumor necrosis factor ␣ inhibitors.Methods. This was a multicenter randomized, double-blind, placebo-controlled, parallel-group study that continued over 48 weeks. Patients receiving stable doses of MTX or LEF were randomized to receive 2 infusions of placebo (n ‫؍‬ 277), ocrelizumab 200 mg (n ‫؍‬ 278), or ocrelizumab 500 mg (n ‫؍‬ 285) on days 1 and 15 as well as at weeks 24 and 26. Coprimary end points were the proportion of patients with response according to the American College of Rheumatology 20% improvement criteria (ACR20) at weeks 24 and 48. Secondary end points included the change from baseline in the modified Sharp/van der Heijde score (SHS) and the ACR50/70 responses.Results. ACR20 responses were 22.0% in the placebo group, 42.2% in the ocrelizumab 200 mg group, and 47.9% in the ocrelizumab 500 mg group at 24 weeks and 19.5%, 48.7%, and 50.7%, respectively, at 48 weeks (P < 0.0001 versus placebo for each comparison at each time point). At 48 weeks, patients receiving both doses of ocrelizumab showed significantly improved ACR50 and ACR70 responses of ϳ3-fold versus placebo. Only those in the ocrelizumab 500 mg group showed statistically significant (P ‫؍‬ 0.0017) inhibition of joint damage progression (mean change in the SHS) relative to placebo (61% inhibition) at 48 weeks. Overall adverse ClinicalTrials.gov identifier: NCT00476996.

Pathogenetic insights from the treatment of rheumatoid arthritis

“…obinutuzumab, ibrtumomab, ocaratuzumab) that could offer more potent depletion properties were considered but have either not started or advanced to larger scale trials in RA with the exception of the anti-CD20 antibody ocrelizumab which showed clinical efficacy in RA but was stopped due to increased infectious risk [55]. In contrast to complete B cell depletion a more subtle approach concerns inhibition of B cell modulatory cytokines.…”

Advances in the treatment of relapsing - Remitting multiple sclerosis

“…[15] A phase III trial in rheumatoid arthritis enrolling patients receiving concomitant immunosuppressive medications (such as methotrexate or leflunomide) reported high rates of infections, especially with the 500 mg regimen, and some of those infections resulted in death. [85][86][87] There were no reported opportunistic infections in the phase II trial. Adverse events reported were similar between the treatment groups; however, there was one death in the 2000 mg arm.…”

Biologic treatments in Sjögren's syndrome

“…Ocrelizumab is a fully humanized anti-CD-20 monoclonal antibody currently undergoing clinical trials in rheumatoid arthritis although its usage may be limited by an increased risk of infections in Asian patients receiving this therapy [49]. Biologic therapies are also potentially associated with an increased risk of one particularly severe side effect: progressive multifocal leucoencephalopathy (PML).…”