Background/Purpose: Tabalumab is a monoclonal antibody that neutralizes membrane-bound and soluble B cell activating factor (BAFF). These interim analyses evaluated the efficacy and safety of 2 different subcutaneous (SQ) dosing regimens of tabalumab in RA patients (pts).

Methods: 1004 pts (ITT population) were enrolled in this phase 3, multicenter, randomized, double-blind study that evaluated 2 different SQ tabalumab doses (120 mg every 4 wks [120/Q4W] or 90 mg every 2 wks [90/Q2W]) vs. placebo over 24 wks. At wk 0, pts received an SQ loading dose that was 2 times the planned treatment dose (ie, 240 mg, 180 mg, or placebo). Eligible pts included those with or without background DMARDs having a Patient’s Global Assessment of Disease Activity ≥20/100 mm. Prespecified efficacy analyses were based on a subset of pts (n=849) with ≥5/68 tender and ≥5/66 swollen joints at baseline; the primary endpoint was ACR20 at 24 wks in this subset.

Results:  At baseline, the ITT population comprised mostly women (79%) who were seropositive (77%) with a mean age of 51 yrs, RA diagnosis of 6 yrs, and mean DAS28-CRP of 5.3±1.2; these baseline characteristics were similar to that of the efficacy population. For the efficacy population at wk 24, no significant differences in the percentage of pts who achieved ACR20 (NRI; range: 32%-34%) and ACR50 (NRI; range: 12%-13%), and no differences in mean DAS28-CRP (mLOCF; 4.6±1.5 to 4.7±1.5), mean HAQ-DI (mLOCF; range: 1.2±0.7 to 1.3±0.7), or percent with moderate/good EULAR28 response (mLOCF; range: 47%-50%) were observed. Efficacy results were similar between the efficacy and ITT populations. Discontinuation rates due to an AE were similar across all groups (range: 2%-4%) as were incidences of TEAEs (range: 58%-64%) and SAEs (range: 2%-4%). For the 120/Q4W, 90/Q2W, and placebo groups, incidences of events of interest were infection (23%, 26%, and 22%, respectively), injection-site reaction (6%, 10%, and 3%, respectively), and allergy/hypersensitivity reaction (2%, 5%, and 5%, respectively). Major adverse cardiovascular events were reported in two 120/Q4W pts and one 90/Q2W pt. Three deaths occurred (two 120/Q4W pts and one 90/Q2W pt). Changes in CD3-CD20+ B cells seen in the 120/Q4W and 90/Q2W groups were generally consistent with prior phase 2 results. Over the 24-wk treatment period, decreases in IgM, IgA, and IgG were also observed in both tabalumab groups vs. placebo (Table).

Conclusion: Tabalumab administration had biologic activity demonstrated by changes in B cells and immunoglobulins, but no significant changes in CRP were observed. Despite showing improvements in efficacy measures with intravenous and SQ treatment in three phase 2 trials, no clear clinical benefit and no new, unexpected safety findings were observed for the tabalumab doses evaluated in this larger phase 3 study. Post-hoc analyses to help understand the disparity in responses between phase 2 and phase 3 are planned.