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
1 Division of Rheumatology and Allergy-Clinical Immunology, North Shore Long Island Jewish Health System, Marcus Avenue, Lake Success, New York 11042, USA
2 Division of Rheumatology and Immunology, University of Southern California Keck School of Medicine, Zonal Avenue, Los Angeles, California 90033, USA
3 Division of Rheumatology, SUNY Downstate Medical Center, Clarkson Avenue, Brooklyn, New York 11203, USA
4 Department of Medicine/Section of Rheumatology, The University of Chicago Hospitals, South Maryland Avenue, Chicago, Illinois 60637, USA
5 Section of Rheumatology & Clinical Immunology, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, North Carolina 27157, USA
6 Division of Immunology and Rheumatology, University of Alabama at Birmingham, 510 20th Street, Birmingham, Alabama 35294, USA
7 Department of Medicine, Clinical Pharmacology Research Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, Oklahoma 73104, USA
8 Department of Medicine, Section of Rheumatology, Washington Hospital Center, Irving Street NW, Washington, Distric of Columbia 20010, USA
9 Division of Rheumatology, University of Michigan Health System, E Medical Center Drive, Taubman Center, Ann Arbor, Michigan 48109, USA
10 Biostatistics, Human Genome Sciences, Inc., Shady Grove Road, Rockville, Maryland 20850, USA
11 Pharmacology, Pharmacokinetics & Toxicology, Human Genome Sciences, Inc., Shady Grove Road, Rockville, Maryland 20850, USA
12 Clinical Research, Human Genome Sciences, Inc., Shady Grove Road, Rockville, Maryland 20850, USA
Arthritis Research & Therapy 2008, 10:R109 doi:10.1186/ar2506Published: 11 September 2008
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).
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. χ2 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.
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.
Belimumab was well tolerated and reduced peripheral B-cell levels in SLE patients. These data support further studies of belimumab in autoimmune disorders.