BELIMUMAB (BMAB), A FULLY HUMAN MONOCLONAL ANTIBODY TO B-LYMPHOCYTE STIMULATOR (BLYS), SHOWS BIOACTIVITY AND REDUCES SYSTEMIC LUPUS ERYTHEMATOSUS DISEASE ACTIVITY

Background: BmAb inhibits the biological activity of soluble BLyS, a growth and survival factor for B-lymphocytes. Circulating levels of BLyS occur in human and murine SLE and correlate with disease activity.Objectives: To describe the efficacy and safety of BmAb in a multicenter SLE study.Methods: A prospective, randomized, double-blind, placebo-controlled trial tested BmAb added to standard of care SLE therapy. 449 subjects meeting ACR SLE criteria and screening SELENA SLEDAI (SS) score ≥ 4 were dosed (1, 4, 10 mg/kg BmAb or placebo) IV on days 0, 14, 28 then monthly for 52 wks at 59 sites in Canada/US. Efficacy was assessed every 1-2 months by SS score, SLE Flare Index and Physician's Global Assessment (PGA). Predefined primary efficacy endpoints were percent reduction in SS score at Wk 24 and time to flare over 52 wks as defined by SLE Flare Index. Biologic markers included ANA, anti-dsDNA antibody (Ab), C3/C4, Ig isotypes, and peripheral B cell FACS.Results: Means at baseline: age 42, SLE duration 8.8 yrs, SS 9.6. Demographics: 93% female, 70% Caucasian, 24% African American, 3% Asian, 18% Hispanic (categories overlap). Historical ANA+ 98%, ANA+ at entry (titer ≥ 1:80 and/or anti-dsDNA Ab+) 71.5%, 68% on steroids and 50% on immunosuppressants. There were no significant differences in baseline characteristics or completion rates across treatment arms (81% completed). BmAb (all treated combined) significantly reduced B-cell counts at Wk 52 (medians): CD20+ 54%, plasmacytoid 62% and activated B-cells 70% with preservation of plasma and memory cells. BmAb reduced anti-dsDNA Ab at Wk 52 by 30% (p<0.002, baseline positive) vs. 9% in placebo. Serum IgG decreased by 10% (p<0.0001) and C4 increased by 33% (p=0.0126, low baseline C4) in BmAb-treated arms. At Wk 52, 14.5% (24/165) of anti-dsDNA+ subjects receiving BmAb converted to negative compared with 3.5% (2/58) on placebo (p=0.012). Primary efficacy endpoints did not reach statistical significance, but SS score was significantly reduced at Wk 52 in ANA+ subjects (p=0.0435). SLE flares decreased in BmAb subjects during Wks 24-52 using a 24 wk baseline (log rank p= 0.036). The PGA improved by Wk 16 (p=0.016) through Wk 52 (p<0.002, all active vs placebo.) Improvements occurred despite increases of prednisone in placebo vs BmAb-treated (increases to >7.5mg/day, ∼15% vs ∼7%). There was no dose response in efficacy, suggesting all doses are equally active. No clinically significant differences were noted in safety, including adverse events (AE), AE severity, infections or lab toxicity in all BmAb arms vs placebo. Fewer subjects on BmAb had pleurisy (3.3% vs 8%, p<0.05), while more had urticaria (4% vs 0, p<0.05). Infusion reactions were rare, with only 1 severe event reported. Immunogenicity to BmAb was observed in 1 subject (1 mg/kg).Conclusion: BmAb was well tolerated and demonstrated significant bioactivity. BmAb improved PGA, increased C4 and reduced anti-dsDNA. BmAb delayed flare onset after 6 months. In subjects with ANA positivity at entry, the SS score improved significantly at Wk 52. The clinical efficacy and safety of BmAb support its further development as a novel therapy for SLE.Citation: Ann Rheum Dis, volume 65, supplement II, year 2006, page 62Session: SLE – clinical aspects