Biologic activity and safety of belimumab, a neutralizing anti-B-lymphocyte stimulator (BLyS) monoclonal antibody: a phase I trial in patients with systemic lupus erythematosus

Abstract

Introduction: This trial evaluated the safety, biologic activity, and pharmacokinetics of belimumab, a fully human monoclonal antibody that inhibits the biologic activity of the soluble form of the essential B-cell survival factor B-lymphocyte stimulator (BLyS) in patients with systemic lupus erythematosus (SLE).

Methods: Seventy patients with mild-to-moderate SLE were enrolled in a phase I, double-blind, randomized study and treated with placebo (n = 13) or belimumab (n = 57) at four different doses (1.0, 4.0, 10, and 20 mg/kg) as a single infusion or two infusions 21 days apart. Patients were followed for 84 to 105 days to assess adverse events, pharmacokinetics, peripheral blood B-cell counts, serology, and SLE disease activity. Data from the study were summarized using descriptive statistics. chi2 type tests were used to analyze discrete variables. The Kruskal-Wallis test, the Wilcoxon test, and the analysis of covariance were used to analyze the continuous variables, as appropriate. The analysis was performed on all randomized patients who received study agent.

Results: The incidences of adverse events and laboratory abnormalities were similar among the belimumab and placebo groups. Belimumab pharmacokinetics were linear across the 1.0 to 20 mg/kg dose range. Long terminal elimination half-life (8.5 to 14.1 days), slow clearance (7 ml/day per kg), and small volume of distribution (69 to 112 ml/kg) were consistent with a fully human antibody. Significant reductions in median percentages of CD20+ B cells were observed in patients treated with a single dose of belimumab versus placebo (day 42: P = 0.0042; and day 84: P = 0.0036) and in patients treated with two doses of belimumab versus placebo (day 105: P = 0.0305). SLE disease activity did not change after one or two doses of belimumab.

Conclusions: Belimumab was well tolerated and reduced peripheral B-cell levels in SLE patients. These data support further studies of belimumab in autoimmune disorders.

Trial registration: ClinicalTrials.gov NCT00657007.

Figures

Figure 1

Belimumab concentrations. (a) Concentrations in the single-dose cohort. (b) Concentrations in the double-dose cohort. Arrows indicate time of belimumab administration. Values are expressed as mean ± standard deviation.

Figure 2

Changes in CD20+ B cells. Median percentage change from baseline in CD20+ B cells in (a) single-dose cohorts and (b) double-dose cohorts. Arrows indicate time of belimumab administration.

Figure 3

Change in anti-dsDNA antibodies. Mean percentage change from baseline in 31 patients whose anti-dsDNA antibody levels were 10 IU/ml or greater. dsDNA, double-stranded DNA.

Figure 4

SELENA SLEDAI scores. The SELENA SLEDAI scores in the single-dose and double-dose cohorts over time are presented, stratified by baseline SELENA SLEDAI score (≥4 or <4). Values are expressed as mean ± standard error. SELENA, Safety of Estrogens in Lupus Erythematosus National Assessment; SLEDAI, Systemic Lupus Erythematosus Disease Activity Index.

Figure 5

PGA scores. The PGA scores in the single-dose and double-dose cohorts over time are presented, stratified by baseline SELENA SLEDAI score (≥4 or <4). Values are expressed as mean ± standard error. SELENA, Safety of Estrogens in Lupus Erythematosus National Assessment; SLEDAI, Systemic Lupus Erythematosus Disease Activity Index; PGA, Physician's Global Disease Assessment.

Figure 6

SF-36 PCS scores. The SF-36 PCS scores in single-dose and double-dose cohorts for over time are presented, stratified by baseline SS score (≥4 or <4). Values are expressed as mean ± standard error. PCS, Physical Component Score; SELENA, Safety of Estrogens in Lupus Erythematosus National Assessment; SF-36, 36-item Short Form; SLEDAI, Systemic Lupus Erythematosus Disease Activity Index.