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ARD Online First, published on April 14, 2015 as 10.1136/annrheumdis-2014-207090 Clinical and epidemiological research

CONCISE REPORT

Efficacy and safety of tabalumab, an anti-B-cellactivating factor monoclonal antibody, in patients with rheumatoid arthritis who had an inadequate response to methotrexate therapy: results from a phase III multicentre, randomised, double-blind study Josef S Smolen,1 Michael E Weinblatt,2 Désirée van der Heijde,3 William F C Rigby,4 Ronald van Vollenhoven,5 Clifton O Bingham III,6 Melissa Veenhuizen,7 Anne Gill,7 Fangyi Zhao,7 Wendy J Komocsar,7 Pierre-Yves Berclaz,7 Robert Ortmann,7 Chin Lee7 Handling editor Tore K Kvien ▸ Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ annrheumdis-2014-207090). For numbered affiliations see end of article. Correspondence to Chin Lee, Eli Lilly and Company, Lilly Corporate Center (Drop Code 1534), Indianapolis, IN 46285, USA; [email protected] Received 4 December 2014 Revised 6 March 2015 Accepted 22 March 2015

ABSTRACT Objectives Randomised, double-blind, placebocontrolled study to evaluate efficacy and safety of tabalumab in patients with rheumatoid arthritis (RA) with inadequate responses to methotrexate (MTX-IR). Methods 1041 patients with moderate–severe RA despite ongoing MTX enrolled in a 52-week study evaluating subcutaneous tabalumab 120 mg every four weeks (120/Q4W) or 90 mg every two weeks (90/ Q2W) versus placebo. Primary endpoints were American College of Rheumatology 20% (ACR20) response rate and Health Assessment Questionnaire-Disability Index change from baseline at 24 weeks and modified Total Sharp Score (mTSS) change at 52 weeks. Results There were no significant differences in ACR20 responses at week 24 or mTSS change from baseline at week 52 among treatment groups. Declines were seen in CD20+ B cells and immunoglobulin levels in tabalumab groups, but not placebo: B cells (−15.0%, −18.8%, 5.3%, in the 120/Q4W, 90/Q2W, and placebo groups, respectively); IgM (−16.3%, −19.4%, −0.1%), IgA (−11.4%, −4.7%, 1.2%) and IgG (−8.6%, −7.8%, 0.1%). Discontinuations due to adverse events were similar between groups. Numerically more serious infections were reported in tabalumab groups (1.7%, 0.6%, 0.3%); numerically more injection-site reactions were reported in the 90/Q2W group (2.3%, 4.3%, 2.3%). Conclusions Neither clinical efficacy nor significant safety signals were observed with tabalumab despite evidence of biological activity. This study was terminated early due to insufficient efficacy. Trial registration number NCT01198002.

INTRODUCTION

To cite: Smolen JS, Weinblatt ME, van der Heijde D, et al. Ann Rheum Dis Published Online First: [please include Day Month Year] doi:10.1136/ annrheumdis-2014-207090

B-cell-activating factor (BAFF) is increased in patients with rheumatoid arthritis (RA). Therefore, neutralising BAFF may be an effective method of targeting B cells and treating RA. However, agents targeting BAFF including belimumab1 and atacicept2 3 have shown disappointing efficacy in RA. It is unclear whether this inadequate response is a target-specific or compound-specific issue. Tabalumab, a fully human anti-BAFF monoclonal

antibody that binds and neutralises both soluble and membrane-bound BAFF,4 reduced signs and symptoms of RA by up to 38% compared with placebo in phase II clinical trials of patients with active RA also taking methotrexate (MTX) treatment.5 6 The phase III study reported herein evaluated the efficacy and safety of tabalumab in RA.

METHODS This multicentre, randomised, double-blind, placebocontrolled, phase III study (NCT01198002) evaluated the efficacy and safety of tabalumab 120 mg every four weeks (120/Q4W) or 90 mg every two weeks (90/Q2W) compared with placebo in patients on background MTX with moderate–severe RA and inadequate responses to MTX (MTX-IR). Patients were enrolled from 23 countries in North America, Central and South America, Europe, Asia and Australia. The tabalumab doses were chosen based on data from phase II RA studies and pharmacokinetic modelling and simulations.5 6

Patient population Adults (≥18 years) with RA (≥6 months’ duration) with ≥8/68 tender and 8/66 swollen joints, positive rheumatoid factor (RF) and/or anticyclic citrullinated peptide antibody, regular use of MTX for ≥12 weeks with stable doses (10–25 mg/week) for ≥8 weeks before baseline, ≥1 RA-related joint erosion on hand or foot X-rays by central reading and screening C-reactive protein (CRP) >1.2 times the upper limit of normal or screening erythrocyte sedimentation rate >28 mm/h were eligible for enrolment. Patients who received any biological disease-modifying antirheumatic drug with discontinuation due to insufficient efficacy were excluded (see online supplementary text for more detailed information).

Study design Patients were randomised 1:1:1 to receive subcutaneous (SC) tabalumab 120/Q4W (240 mg SC loading dose, given as two SC injections of 120 mg), 90/Q2W (180 mg SC loading dose, given as two SC injections of 90 mg) or placebo (two SC

Smolen JS, et al. Ann Rheum Dis 2015;0:1–4. doi:10.1136/annrheumdis-2014-207090

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Clinical and epidemiological research placebo injections). Non-responders at week 16 (

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 III multicentre, randomised, double-blind study.

Randomised, double-blind, placebo-controlled study to evaluate efficacy and safety of tabalumab in patients with rheumatoid arthritis (RA) with inadeq...
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