FRI0326 Efficacy and Safety of Tabalumab, an Anti-B Cell Activating Factor Monoclonal Antibody, in Patients with Rheumatoid Arthritis Who HAD an Inadequate Response to Methotrexate Therapy: Results from A Phase 3 Multicenter, Randomized, Double-Blind Study

Abstract

Background Tabalumab is a monoclonal antibody that neutralizes membrane-bound and soluble B cell activating factor (BAFF). Objectives Evaluate efficacy and safety of tabalumab, in RA pts who had an inadequate response to methotrexate (MTX) therapy, in a randomized, double-blind, placebo-controlled study. Methods 1041 RA pts (ITT population) were enrolled in this 52-wk study evaluating 2 subcutaneous (SQ) tabalumab doses (120mg every 4 wks [120/Q4W] or 90mg every 2 wks [90/Q2W]) vs placebo (PBO). At wk 0, pts received a SQ loading dose that was 2 times the treatment dose (240mg, 180mg, or PBO). Eligible pts had moderate-severely active RA despite ongoing MTX. Primary endpoints included ACR20 and HAQ-DI at 24 wks, and change in mTSS at 52 wks. This study was terminated early due to futility. Results The ITT population was mostly female (84.2%), and seropositive (RF and/or anti-CCP, 95%) with a mean age of 53.2 yrs, mean RA diagnosis of 6.8 yrs, and DAS28-CRP of 5.6±1.0 (mean ± SD). At wk 24 in the efficacy population (ITT population excluding pts on <10 mg/wk of MTX, n=997), there were no significant differences among the 120/Q4W, 90/Q2W, and PBO groups in the percentage of pts achieving ACR20 (NRI; 29.7%, 32.8%, 25.1%). There was no significant difference among the 120/Q4W, 90/Q2W, and PBO groups in structural progression defined as change from baseline in mTSS (mean ± SD) at wk 52 (1.5±4.9, 0.9±3.8, 1.7±5.3). A modest difference was observed in wk 24 HAQ-DI results (mean ± SD) in the 90/Q2W group (mBOCF; 1.2±0.6) vs PBO (mBOCF; 1.3±0.7) [p=0.005]; no difference was observed in the 120/Q4W group (mBOCF; 1.3±0.6). After 52 wks, changes in CD3-CD20+ B cells in the 120/Q4W, 90/Q2W, and PBO groups were −15.0%, −18.8%, and 5.3%. Changes in immunoglobulin levels in the 120/Q4W, 90/Q2W, and PBO groups were: IgM (−16.3%, −19.4%, −0.1%), IgA (−11.4%, −4.7%, 1.2%), and IgG (−8.6%, −7.8%, 0.1%). Safety was evaluated in all randomized pts who received ≥1 dose of study treatment (n=1038). Discontinuations due to an AE were similar across the 120/Q4W, 90/Q2W, and PBO groups (4.3%, 3.5%, 2.9%) as were TEAEs (54.2%, 50.7%, 53.7%) and SAEs (5.2%, 5.2%, 4.9%). For the 120/Q4W, 90/Q2W, and PBO groups, there was no difference in reports of AEs of interest: infections (24%, 23%, 26%); injection-site reactions (2.3%, 4.3%, 2.3%); and allergic/hypersensitivity events (4.3%, 3.5%, 4.6%). Three deaths occurred: 2 120/Q4W pts (sepsis, MI) and 1 PBO pt (MI). Conclusions In this phase 3 study, tabalumab demonstrated no clinical efficacy despite evidence of biologic activity. There were no differences in reports of AEs of interest and no new or unexpected safety findings for RA pts receiving tabalumab. Disclosure of Interest J. Smolen Grant/research support: Pfizer, Consultant for: Pfizer, Eli Lilly and Company, M. Weinblatt Consultant for: Eli Lilly and Company, Pfizer, Vertex, D. van der Heijde Consultant for: Eli Lilly and Company, AbbVie, Amgen, AstraZeneca, Augurex, BMS, Celgene, Centocor, Chugai, Covagen, Daiichi Sankyo Ltd, ...

BAFF System in Rheumatoid Arthritis: from Pathobiology to Therapeutic Targets

“…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]. 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].…”

“…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].…”

“…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.…”

“…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].…”