A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of belimumab in patients with active systemic lupus erythematosus

Abstract

Objective: To assess the safety, tolerability, biologic activity, and efficacy of belimumab in combination with standard of care therapy (SOC) in patients with active systemic lupus erythematosus (SLE).

Methods: Patients with a Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score >/=4 (n = 449) were randomly assigned to belimumab (1, 4, or 10 mg/kg) or placebo in a 52-week study. Coprimary end points were the percent change in the SELENA-SLEDAI score at week 24 and the time to first SLE flare.

Results: Significant differences between the treatment and placebo groups were not attained for either primary end point, and no dose response was observed. Reductions in SELENA-SLEDAI scores from baseline were 19.5% in the combined belimumab group versus 17.2% in the placebo group. The median time to first SLE flare was 67 days in the combined belimumab group versus 83 days in the placebo group. However, the median time to first SLE flare during weeks 24-52 was significantly longer with belimumab treatment (154 versus 108 days; P = 0.0361). In the subgroup (71.5%) of serologically active patients (antinuclear antibody titer >/=1:80 and/or anti-double-stranded DNA [anti-dsDNA] >/=30 IU/ml), belimumab treatment resulted in significantly better responses at week 52 than placebo for SELENA-SLEDAI score (-28.8% versus -14.2%; P = 0.0435), physician's global assessment (-32.7% versus -10.7%; P = 0.0011), and Short Form 36 physical component score (+3.0 versus +1.2 points; P = 0.0410). Treatment with belimumab resulted in a 63-71% reduction of naive, activated, and plasmacytoid CD20+ B cells, and a 29.4% reduction in anti-dsDNA titers (P = 0.0017) by week 52. The rates of adverse events and serious adverse events were similar in the belimumab and placebo groups.

Conclusion: Belimumab was biologically active and well tolerated. The effect of belimumab on the reduction of SLE disease activity or flares was not significant. However, serologically active SLE patients responded significantly better to belimumab therapy plus SOC than to SOC alone.

Trial registration: ClinicalTrials.gov NCT00071487.

Figure 1

Flow diagram of patient disposition during the study.

Figure 2. Time to first mild-moderate or severe flare as measured by the SLE Flare Index and subgroup analysis of response to 52-week SELENA-SLEDAI score

(A) All treated patients from weeks 0 to 52. Log-rank test for overall treatment effect; P=0.9683. (B) All patients from weeks 24–52. Log-rank test for combined belimumab vs placebo P= 0.0361. (C) Mean percent change from baseline in SELENA-SLEDAI score at week 52 in different subgroups. Each subgroup analyzed response rate between the all-belimumab-treatment group and the placebo group, where the absolute percent difference from placebo is set at 0 and the 95% confidence interval values are shown. SS = SELENA-SLEDAI; Pred = Prednisone; ANA = antinuclear antibodies; BLyS = B-lymphocyte stimulator; ALOD = above limit of detection (0.350 ng/mL); BLOD = below limit of detection

Figure 3. Percent change in B-cell subsets over 1 year of belimumab therapy or placebo added to standard of care therapy

(A) CD20⁺ B cells, (B) naive (CD20^+/27⁻) B cells, (C) activated (CD20⁺/69⁺), and (D) memory (CD20^+/27⁺) B cells. The baseline B-cell values in all 4 treatment groups were not significantly different. B-cell values are presented in absolute numbers for all patients combined: CD19 = 163.6/mm³, CD 20 = 157.3/mm³, naive = 120.4/mm³, activated = 25.1/mm³, memory = 36.6/mm³, plasmacytoid = 6.6/mm³ (not shown), and plasma cells = 3.9/mm³ (not shown). B-cell subsets were unaffected in the placebo group by week 52, except for plasmacytoid cells, which declined by 33% (data not shown).