A 52-week, open-label study evaluating the safety and efficacy of tabalumab, an anti-B-cell-activating factor monoclonal antibody, for rheumatoid arthritis

Abstract

IntroductionThe objective of this study was to evaluate the long-term safety and efficacy of tabalumab, a monoclonal antibody that neutralizes membrane-bound and soluble B-cell-activating factor, in rheumatoid arthritis (RA) patients.MethodsPatients with RA who completed one of two 24-week randomized controlled trials (RCTs) participated in this 52-week, flexible-dose, open-label extension study. Patients in RCT1 received intravenous placebo, 30-mg tabalumab or 80-mg tabalumab every 3 weeks, and patients in RCT2 received subcutaneous placebo or 1-, 3-, 10-, 30-, 60- or 120-mg tabalumab every 4 weeks (Q4W). Regardless of prior treatment, all patients in this study received subcutaneous 60-mg tabalumab Q4W for the first 3 months, then a one-time increase to 120-mg tabalumab Q4W (60-mg/120-mg group) and a one-time decrease to 60-mg tabalumab Q4W per patient was allowed (60-mg/120-mg/60-mg group).ResultsThere were 182 patients enrolled: 60 mg (n = 60), 60/120 mg (n = 121) and 60/120/60 mg (n = 1). Pretabalumab baseline disease activity was generally higher in the 60-mg/120-mg group. There was a higher frequency of serious adverse events and treatment-emergent adverse events, as well as infections and injection-site reactions, in the 60-mg/120-mg group. One death unrelated to the study drug occurred (60-mg/120-mg group). In both groups, total B-cell counts decreased by approximately 40% from the baseline level in the RCT originating study. Both groups demonstrated efficacy through 52 weeks of treatment relative to baseline pretabalumab disease activity based on American College of Rheumatology criteria improvement ≥20%, ≥50% and ≥70%; European League against Rheumatism Responder Index in 28 joints; Disease Activity Score in 28 joints–C-reactive protein; and Health Assessment Questionnaire–Disability Index.ConclusionsWith long-term, open-label tabalumab treatment, no unexpected safety signals were observed, and B-cell reductions were consistent with previous findings. Despite differences in RCT originating studies, both groups demonstrated an efficacy response through the 52-week extension.Trial registrationClinicalTrials.gov Identifier: NCT00837811 (registered 3 February 2009).Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-014-0415-2) contains supplementary material, which is available to authorized users.

B cells biology in systemic lupus erythematosus—from bench to bedside

“…All these three biologics could block IL-6 mediated effects. In patients with rheumatoid arthritis, significant improvement of disease activity by blocking IL-6 signaling has been reported [175][176][177]. But till now no concrete data about efficacy in patients with SLE have been obtained and phase I studies indicate that adverse effects such as neutropenia and infection are worthy of attention [178,179].…”

BAFF System in Rheumatoid Arthritis: from Pathobiology to Therapeutic Targets

“…However, tabalumab received no further validation following two phase 3 randomized, double-blind, placebo-controlled studies aiming to demonstrate drug eicacy and safety in patients with moderate-tosevere RA with inadequate response to one or more TNF inhibitors [25,30,[34][35][36]. The interim analyses prompted the withdrawal of tabalumab due to lack of eicacy, not to safety concerns [2,4,25,[31][32][33][34][35]. Although the primary eicacy end point (ACR20 response) was not achieved in none of phase 2 studies, atacicept signiicantly reduced the immunoglobulin (IgM, IgG, and IgA) and rheumatoid factor levels in a dose-dependent manner.…”

“…Tabalumab, formerly LY2127399, is another fully human IgG4 anti-BAFF monoclonal antibody that binds to and neutralizes soluble and membrane-bound BAFF, but not to APRIL [2,4,25,[31][32][33][34][35].…”

“…Eicacy and safety of tabalumab in active RA despite ongoing methotrexate was assessed in several phase 2 and 3 randomized-controlled studies and their open-label extensions performed on diverse patient populations comprising either bio-naive or bio-experienced RA with an inadequate response to TNF inhibitors (non-responders or intolerant) [2,4,25,[31][32][33][34][35]. Clinical eicacy parameters included standardized measures such as ACR20, ACR50, and ACR70 improvement criteria, DAS28-C-reactive protein (DAS28-CRP), and Health Assessment Questionnaire-Disability Index (HAQ-DI), while total B-cell counts or CD3-CD20 B cells and serum immunoglobulins were used for biological impact [2,4,25,[31][32][33][34][35].…”

“…Clinical eicacy parameters included standardized measures such as ACR20, ACR50, and ACR70 improvement criteria, DAS28-C-reactive protein (DAS28-CRP), and Health Assessment Questionnaire-Disability Index (HAQ-DI), while total B-cell counts or CD3-CD20 B cells and serum immunoglobulins were used for biological impact [2,4,25,[31][32][33][34][35]. Of interest, each one of the four phase 2 clinical trials (identiier NCT00308282, NCT00689728, NCT00785928, and NCT00837811) provided encouraging results under lexible doses of anti-BAFF and a background of stable methotrexate, with meaningful clinical and biological RA improvement as compared to placebo, regardless of prior treatment [2,4,25,[31][32][33][34][35]. However, tabalumab received no further validation following two phase 3 randomized, double-blind, placebo-controlled studies aiming to demonstrate drug eicacy and safety in patients with moderate-tosevere RA with inadequate response to one or more TNF inhibitors [25,30,[34][35][36].…”