A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus

Abstract

Objective: To assess the efficacy/safety of the B lymphocyte stimulator inhibitor belimumab plus standard therapy compared with placebo plus standard therapy in active systemic lupus erythematosus (SLE).

Methods: In a phase III, multicenter, randomized, placebo-controlled trial, 819 antinuclear antibody-positive or anti-double-stranded DNA-positive SLE patients with scores ≥6 on the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) version of the SLE Disease Activity Index (SLEDAI) were randomized in a 1:1:1 ratio to receive 1 mg/kg belimumab, 10 mg/kg belimumab, or placebo intravenously on days 0, 14, and 28 and then every 28 days for 72 weeks. The primary efficacy end point was the SLE Responder Index (SRI) response rate at week 52 (an SRI response was defined as a ≥4-point reduction in SELENA-SLEDAI score, no new British Isles Lupus Assessment Group [BILAG] A organ domain score and no more than 1 new BILAG B score, and no worsening in physician's global assessment score versus baseline).

Results: Belimumab at 10 mg/kg plus standard therapy met the primary efficacy end point, generating a significantly greater SRI response at week 52 compared with placebo (43.2% versus 33.5%; P = 0.017). The rate with 1 mg/kg belimumab was 40.6% (P = 0.089). Response rates at week 76 were 32.4%, 39.1%, and 38.5% with placebo, 1 mg/kg belimumab, and 10 mg/kg belimumab, respectively. In post hoc sensitivity analyses evaluating higher SELENA-SLEDAI score thresholds, 10 mg/kg belimumab achieved better discrimination at weeks 52 and 76. Risk of severe flares over 76 weeks (based on the modified SLE Flare Index) was reduced with 1 mg/kg belimumab (34%) (P = 0.023) and 10 mg/kg belimumab (23%) (P = 0.13). Serious and severe adverse events, including infections, laboratory abnormalities, malignancies, and deaths, were comparable across groups.

Conclusion: Belimumab plus standard therapy significantly improved SRI response rate, reduced SLE disease activity and severe flares, and was generally well tolerated in SLE.

Trial registration: ClinicalTrials.gov NCT00410384.

Figure 1

Flow diagram of patient disposition during study. * May count patients more than once if rescreened. † Multiple reasons for some patients.

Figure 2

Select clinical outcomes. A. Systemic Lupus Erythematosus Responder Index (SRI) response rate over 76 weeks. B. Durability of week-52 SRI response for 1 to 6 months before or after the week-52 visit. C. Modified SRI response rate (≥ 6-point reduction) over 76 weeks. D. Mean percent change in Safety of Estrogens in Lupus Erythematosus National Assessment– Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) (last-observation-carried-forward analysis). E. Percents of patients with corticosteroid dose reduced to ≤ 7.5 mg/d from > 7.5 mg/d at baseline (top; n = 376), and increased to > 7.5 mg/d from ≤ 7.5 mg/d at baseline (middle; n = 443), and with increased corticosteroid use over 76 weeks (bottom). F. Cumulative probability of severe systemic lupus erythematosus (SLE) flare. * P < 0.05. + P < 0.01. # P < 0.001.

Figure 3

Select biomarker analyses. A. Median percent change in anti-double-stranded DNA (anti-dsDNA) in patients positive for anti-dsDNA at baseline. B. Median percent change in complement 4 (C4) in patients with low values (< 16 mg/dL) at baseline. (Note: the median percent change values at week 76 in complement 3 in patients with low values [< 90 mg/dL] at baseline were 4.8%, 18.9%, and 21.1% for placebo, and belimumab 1 and 10 mg/kg, respectively.) C. Median percent change in CD20⁺ B-cell subset. D. Median percent change in CD20-/CD27^BRIGHT short-lived plasma B-cell subset. * P < 0.05. + P < 0.01. # P < 0.001.