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

• Published in: Annals of the rheumatic diseases Vol. 70; no. 9; pp. 1542 - 1549
• Main Authors: Burmester, Gerd R, Feist, Eugen, Sleeman, Matthew A, Wang, Bing, White, Barbara, Magrini, Fabio
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd and European League Against Rheumatism 01.09.2011; BMJ Publishing Group; BMJ Group
• Series: Extended report
• Subjects: Adolescent; Adult; Aged; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal - blood; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized; Antirheumatic Agents - administration & dosage; Antirheumatic Agents - adverse effects; Antirheumatic Agents - blood; Antirheumatic Agents - therapeutic use; Arthritis, Rheumatoid - blood; Arthritis, Rheumatoid - drug therapy; Biological and medical sciences; Clinical and Epidemiological Research; Diseases of the osteoarticular system; Dose-Response Relationship, Drug; Double-Blind Method; Gene Expression Regulation - drug effects; Humans; Inflammatory joint diseases; Injections, Intravenous; Medical sciences; Middle Aged; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor - antagonists & inhibitors; RNA, Messenger - genetics; Severity of Illness Index; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins - biosynthesis; Suppressor of Cytokine Signaling Proteins - genetics; Treatment Outcome; Young Adult; Human; Immunopathology; Chronic; Targeting; Rheumatoid arthritis; Diseases of the osteoarticular system; Rheumatology; Phase I trial; Autoimmune disease; Inflammatory joint disease; Monoclonal antibody; Granulocyte macrophage colony stimulating factor
• ISSN: 0003-4967; 1468-2060; 1468-2060
• DOI: 10.1136/ard.2010.146225

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 double-blinded 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.