• Open Access

Sifalimumab, a Human Anti–Interferon-α Monoclonal Antibody, in Systemic Lupus Erythematosus: A Phase I Randomized, Controlled, Dose-Escalation Study

Authors

  • Michelle Petri,

    Corresponding author
    1. Johns Hopkins University School of Medicine, Baltimore, Maryland
    • Johns Hopkins University School of Medicine, 1830 East Monument Street, Suite 7500, Baltimore, MD 21205

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    • Dr. Petri has received consulting fees from GlaxoSmithKline and Human Genome Sciences (less than $10,000 each).

  • Daniel J. Wallace,

    1. Cedars-Sinai Medical Center and David Geffen School of Medicine, University of California, Los Angeles
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  • Alberto Spindler,

    1. Centro Medico Privado de Reumatologia, Tucumán, Argentina
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  • Vishala Chindalore,

    1. Pinnacle Research Group, Anniston, Alabama
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    • Dr. Chindalore has received speaking fees from Pfizer, Roche, and Eli Lilly (more than $10,000 each).

  • Kenneth Kalunian,

    1. University of California at San Diego, La Jolla
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    • Dr. Kalunian has received consulting fees from Genentech, Merck Serono, Anthera, Questcor, Ambit, and Novo Nordisk (less than $10,000 each).

  • Eduardo Mysler,

    1. Organización Médica de Investigación, Buenos Aires, Argentina
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  • C. Michael Neuwelt,

    1. East Bay Rheumatology Research Institute, San Leandro, California
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  • Gabriel Robbie,

    1. MedImmune, LLC, Gaithersburg, Maryland
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    • Drs. Robbie, White, Higgs, Yao, Wang, and Greth are employees of MedImmune, LLC and own stock or stock options in AstraZeneca.

  • Wendy I. White,

    1. MedImmune, LLC, Gaithersburg, Maryland
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    • Drs. Robbie, White, Higgs, Yao, Wang, and Greth are employees of MedImmune, LLC and own stock or stock options in AstraZeneca.

  • Brandon W. Higgs,

    1. MedImmune, LLC, Gaithersburg, Maryland
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    • Drs. Robbie, White, Higgs, Yao, Wang, and Greth are employees of MedImmune, LLC and own stock or stock options in AstraZeneca.

  • Yihong Yao,

    1. MedImmune, LLC, Gaithersburg, Maryland
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    • Drs. Robbie, White, Higgs, Yao, Wang, and Greth are employees of MedImmune, LLC and own stock or stock options in AstraZeneca.

    • Dr. Yao is a coinventor on a diagnostic patent for sifalimumab in systemic lupus erythematosus filed by MedImmune, LLC.

  • Liangwei Wang,

    1. MedImmune, LLC, Gaithersburg, Maryland
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    • Drs. Robbie, White, Higgs, Yao, Wang, and Greth are employees of MedImmune, LLC and own stock or stock options in AstraZeneca.

  • Dominique Ethgen,

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    • Dr. Ethgen is deceased.

  • Warren Greth

    1. MedImmune, LLC, Gaithersburg, Maryland
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    • Drs. Robbie, White, Higgs, Yao, Wang, and Greth are employees of MedImmune, LLC and own stock or stock options in AstraZeneca.


  • ClinicalTrials.gov identifier: NCT00482989.

Abstract

Objective

To evaluate the safety and tolerability of multiple intravenous (IV) doses of sifalimumab in adults with moderate-to-severe systemic lupus erythematosus (SLE).

Methods

In this multicenter, double-blind, placebo-controlled, sequential dose-escalation study, patients were randomized 3:1 to receive IV sifalimumab (0.3, 1.0, 3.0, or 10.0 mg/kg) or placebo every 2 weeks to week 26, then followed up for 24 weeks. Safety assessment included recording of treatment-emergent adverse events (AEs) and serious AEs. Pharmacokinetics, immunogenicity, and pharmacodynamics were evaluated, and disease activity was assessed.

Results

Of 161 patients, 121 received sifalimumab (26 received 0.3 mg/kg; 25, 1.0 mg/kg; 27, 3.0 mg/kg; and 43, 10 mg/kg) and 40 received placebo. Patients were predominantly female (95.7%). At baseline, patients had moderate-to-severe disease activity (mean SLE Disease Activity Index score 11.0), and most (75.2%) had a high type I interferon (IFN) gene signature. In the sifalimumab group versus the placebo group, the incidence of ≥1 treatment-emergent AE was 92.6% versus 95.0%, ≥1 serious AE was 22.3% versus 27.5%, and ≥1 infection was 67.8% versus 62.5%; discontinuations due to AEs occurred in 9.1% versus 7.5%, and death occurred in 3.3% (n = 4) versus 2.5% (n = 1). Serum sifalimumab concentrations increased in a linear and dose-proportional manner. Inhibition of the type I IFN gene signature was sustained during treatment in patients with a high baseline signature. No statistically significant differences in clinical activity (SLEDAI and British Isles Lupus Assessment Group score) between sifalimumab and placebo were observed. However, when adjusted for excess burst steroids, SLEDAI change from baseline showed a positive trend over time. A trend toward normal complement C3 or C4 level at week 26 was seen in the sifalimumab groups compared with baseline.

Conclusion

The observed safety/tolerability and clinical activity profile of sifalimumab support its continued clinical development for SLE.

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