Objectives Evaluate efficacy and safety of tabalumab, a human IgG4 monoclonal antibody that binds and neutralises membrane and soluble B-cell activating factor (BAFF) versus placebo plus standard of care (SoC) in patients with systemic lupus erythematosus (SLE).

Methods This phase III, 52-week study randomised 1164 patients with moderate-to-severe SLE (Safety of Estrogens in Lupus Erythematosus National Assessment—SLE Disease Activity Index ≥6 at baseline). Patients received SoC plus subcutaneous injections of tabalumab or placebo, starting with a loading dose (240 mg) at week 0 and followed by 120 mg every two weeks (120 Q2W, n=387), 120 mg every four weeks (120 Q4W, n=389) or placebo Q2W (n=388). Primary endpoint: proportion of patients achieving SLE Responder Index 5 (SRI-5) response at week 52.

Results Similar proportions of patients in each group achieved SRI-5 response at week 52 (120 Q2W: 31.8%; 120 Q4W: 35.2% and placebo: 29.3%). Key secondary endpoints were not met. In a sensitivity analysis not excluding patients who decreased antimalarials or immunosuppressants, SRI-5 response was achieved with 120 Q4W (37.0% vs 29.8% placebo; p=0.021), but not 120 Q2W (34.1%; p=0.171). Significant reductions in anti-dsDNA antibodies, increases in C3 and C4, and reductions in total B cells and immunoglobulins were observed with tabalumab. No differences were observed between treatment groups in percentage of deaths (120 Q2W: 0.8%; 120 Q4W: 0.5%; placebo: 0.5%), serious adverse events (AEs) (range 11.1–14.4%) or treatment-emergent AEs (range 81.1–82.3%).

Conclusions Tabalumab had biological activity—changes in anti-dsDNA, complement, B cells and immunoglobulins—consistent with BAFF pathway inhibition. Key clinical efficacy endpoints did not achieve statistical significance. Safety profiles were similar with tabalumab and placebo.

Trial registration number NCT01196091.