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

Authors

  • Richard Furie,

    Corresponding author
    1. North Shore–Long Island Jewish Health System, Lake Success, New York
    • Division of Rheumatology and Allergy–Clinical Immunology, North Shore–Long Island Jewish Health System, 2800 Marcus Avenue, Lake Success, NY 11042
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    • Dr. Furie has received research or grant support, travel support, and payment for review activities, board membership, and consultancy from Human Genome Sciences and GlaxoSmithKline (more than $10,000 each) and is a member of the BLISS-76 steering committee; he has served as a paid consultant to the investment analysts Gerson Lehrman Group, Guidepoint Global, and Lazard Ltd. (less than $10,000 each).

  • Michelle Petri,

    1. Johns Hopkins University School of Medicine, Baltimore, Maryland
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    • Dr. Petri has received research or grant support, travel support, and payment for review activities, board membership, and consultancy from Human Genome Sciences and GlaxoSmithKline (more than $10,000 each) and is a member of the BLISS-76 steering committee; she has served as a paid consultant to the investment analyst Gerson Lehrman Group (less than $10,000).

  • Omid Zamani,

    1. Rheumazentrum Favoriten, Vienna, Austria
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  • Ricard Cervera,

    1. Hospital Clínic, Barcelona, Spain
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    • Dr. Cervera has received payment for board membership and consultancy from Human Genome Sciences and GlaxoSmithKline (less than $10,000 each) and is a member of the BLISS-76 steering committee.

  • Daniel J. Wallace,

    1. Cedars-Sinai Medical Center/David Geffen School of Medicine at University of California, Los Angeles
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    • Dr. Wallace has received consulting fees, speaking fees, and/or honoraria from Human Genome Sciences and GlaxoSmithKline (less than $10,000 each).

  • Dana Tegzová,

    1. Charles University, Prague, Czech Republic
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  • Jorge Sanchez-Guerrero,

    1. Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubrián, Delegacion Tlalpan, Mexico
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  • Andreas Schwarting,

    1. Universitatsklinik Mainz, Mainz, Germany, and Sana-Rheumazentrum Rheinland-Pfalz AG, Bad Kreuznach, Germany
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  • Joan T. Merrill,

    1. Oklahoma Medical Research Foundation, Oklahoma City
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    • Dr. Merrill has received consulting fees and grant support from Human Genome Sciences and GlaxoSmithKline (less than $10,000 each); she has served as a paid consultant to the investment analysts Gerson Lehrman Group, Leerink Swann, and Sionna (less than $10,000 each).

  • W. Winn Chatham,

    1. University of Alabama at Birmingham
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    • Dr. Chatham has received research or grant support and travel support from Human Genome Sciences (less than $10,000).

  • William Stohl,

    1. Los Angeles County and University of Southern California Medical Center and University of Southern California Keck School of Medicine, Los Angeles
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    • Dr. Stohl has received research or grant support and consulting fees from Human Genome Sciences and GlaxoSmithKline (less than $10,000 each).

  • Ellen M. Ginzler,

    1. State University of New York Downstate Medical Center, Brooklyn
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    • Dr. Ginzler has received consulting fees, speaking fees, and/or honoraria from Human Genome Sciences, Genentech, Vifor Pharma, MedImmune, and Wyeth (less than $10,000 each); she has served as a paid consultant to the investment analysts Guidepoint Global and Gerson Lehrman Group (less than $10,000 each).

  • Douglas R. Hough,

    1. Human Genome Sciences, Rockville, Maryland
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    • Drs. Hough, Zhong, and Freimuth own stock or stock options in Human Genome Sciences.

  • Z. John Zhong,

    1. Human Genome Sciences, Rockville, Maryland
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    • Drs. Hough, Zhong, and Freimuth own stock or stock options in Human Genome Sciences.

  • William Freimuth,

    1. Human Genome Sciences, Rockville, Maryland
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    • Drs. Hough, Zhong, and Freimuth own stock or stock options in Human Genome Sciences.

  • Ronald F. van Vollenhoven,

    1. Karolinska Institute, Stockholm, Sweden
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    • Dr. van Vollenhoven has received consulting fees and honoraria from Human Genome Sciences and GlaxoSmithKline (less than $10,000 each) and is a member of the BLISS-76 steering committee.

  • BLISS-76 Study Group


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.

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