Mavrilimumab, a human monoclonal antibody targeting GM-CSF receptor-α, in subjects with rheumatoid arthritis: A randomised, double-blind, placebo-controlled, phase I, first-in-human study

Gerd Rüdiger Burmester, Eugen Feist, Matthew A. Sleeman, Bing Wang, Barbara White, Fabio Magrini

Research output: Contribution to journalArticle

Abstract

Objective: To evaluate the safety, tolerability, pharmacokinetic and pharmacodynamic profiles of mavrilimumab, a human monoclonal antibody targeting the granulocyte-macrophage colony-stimulating factor receptor-α, in subjects with rheumatoid arthritis (RA). Methods: A randomised, double-blind, placebo-controlled, dose-escalating phase I study in subjects with RA who received stable methotrexate treatment for ≥3 months before enrolment. Subjects received single intravenous escalating doses of mavrilimumab (0.01-10.0 mg/kg) or placebo. Results: 32 subjects were enrolled in this study (1 unblinded subject at 0.01 mg/kg and another at 0.03 mg/kg were followed by five sequential doubleblinded cohorts, n=6 each, treated with 0.1, 0.3, 1.0, 3.0 and 10.0 mg/kg, respectively). Adverse events were mild or moderate and were reported with similar frequency across all treatment cohorts. One subject (10.0 mg/kg) experienced moderate face and neck urticaria during infusion that resolved with symptomatic treatment. Systemic clearance of mavrilimumab approached that of endogenous IgG at doses >1.0 mg/kg; pharmacodynamic activity was confirmed in the 1.0 and 3.0 mg/kg cohorts by suppression of suppressor of cytokine signalling 3 mRNA transcripts. In exploratory analyses, reductions of acute phase reactants were observed in subjects with elevated C-reactive protein (>5 mg/l) and erythrocyte sedimentation rate (≥20.0 mm/h) at baseline. No significant change in Disease Activity Score 28-joint assessment (DAS28) was seen in any of the cohorts. In mavrilimumab-treated subjects (n=15) with baseline DAS28 >3.2, mean disease activity (DAS28) was significantly reduced at 4 weeks. Conclusion: In this first-in-human study, mavrilimumab showed preliminary evidence of pharmacodynamic activity. Importantly, the safety and pharmacokinetic profiles of mavrilimumab support further clinical studies in RA. Trial registration number: NCT00771420.

Original languageEnglish (US)
Pages (from-to)1542-1549
Number of pages8
JournalAnnals of the Rheumatic Diseases
Volume70
Issue number9
DOIs
StatePublished - Sep 2011
Externally publishedYes

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Granulocyte-Macrophage Colony-Stimulating Factor Receptors
Rheumatoid Arthritis
Monoclonal Antibodies
Placebos
Pharmacodynamics
Pharmacokinetics
Joints
Safety
Acute-Phase Proteins
Blood Sedimentation
Urticaria
Sedimentation
Methotrexate
C-Reactive Protein
mavrilimumab
Neck
Therapeutics
Immunoglobulin G
Cytokines
Messenger RNA

ASJC Scopus subject areas

  • Rheumatology
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Allergy

Cite this

Mavrilimumab, a human monoclonal antibody targeting GM-CSF receptor-α, in subjects with rheumatoid arthritis : A randomised, double-blind, placebo-controlled, phase I, first-in-human study. / Burmester, Gerd Rüdiger; Feist, Eugen; Sleeman, Matthew A.; Wang, Bing; White, Barbara; Magrini, Fabio.

In: Annals of the Rheumatic Diseases, Vol. 70, No. 9, 09.2011, p. 1542-1549.

Research output: Contribution to journalArticle

Burmester, Gerd Rüdiger ; Feist, Eugen ; Sleeman, Matthew A. ; Wang, Bing ; White, Barbara ; Magrini, Fabio. / Mavrilimumab, a human monoclonal antibody targeting GM-CSF receptor-α, in subjects with rheumatoid arthritis : A randomised, double-blind, placebo-controlled, phase I, first-in-human study. In: Annals of the Rheumatic Diseases. 2011 ; Vol. 70, No. 9. pp. 1542-1549.
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AU - Wang, Bing

AU - White, Barbara

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N2 - Objective: To evaluate the safety, tolerability, pharmacokinetic and pharmacodynamic profiles of mavrilimumab, a human monoclonal antibody targeting the granulocyte-macrophage colony-stimulating factor receptor-α, in subjects with rheumatoid arthritis (RA). Methods: A randomised, double-blind, placebo-controlled, dose-escalating phase I study in subjects with RA who received stable methotrexate treatment for ≥3 months before enrolment. Subjects received single intravenous escalating doses of mavrilimumab (0.01-10.0 mg/kg) or placebo. Results: 32 subjects were enrolled in this study (1 unblinded subject at 0.01 mg/kg and another at 0.03 mg/kg were followed by five sequential doubleblinded cohorts, n=6 each, treated with 0.1, 0.3, 1.0, 3.0 and 10.0 mg/kg, respectively). Adverse events were mild or moderate and were reported with similar frequency across all treatment cohorts. One subject (10.0 mg/kg) experienced moderate face and neck urticaria during infusion that resolved with symptomatic treatment. Systemic clearance of mavrilimumab approached that of endogenous IgG at doses >1.0 mg/kg; pharmacodynamic activity was confirmed in the 1.0 and 3.0 mg/kg cohorts by suppression of suppressor of cytokine signalling 3 mRNA transcripts. In exploratory analyses, reductions of acute phase reactants were observed in subjects with elevated C-reactive protein (>5 mg/l) and erythrocyte sedimentation rate (≥20.0 mm/h) at baseline. No significant change in Disease Activity Score 28-joint assessment (DAS28) was seen in any of the cohorts. In mavrilimumab-treated subjects (n=15) with baseline DAS28 >3.2, mean disease activity (DAS28) was significantly reduced at 4 weeks. Conclusion: In this first-in-human study, mavrilimumab showed preliminary evidence of pharmacodynamic activity. Importantly, the safety and pharmacokinetic profiles of mavrilimumab support further clinical studies in RA. Trial registration number: NCT00771420.

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