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

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 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.

Conflict of interest statement

Competing interests GRB and EF received research funding from MedImmune to conduct this clinical study. MAS, B Wang and FM are employees of MedImmune. B White is a former employee of MedImmune.

Figures

Figure 1

Mean pharmacokinetic profiles of mavrilimumab (formerly known as CAM-3001) after a single intravenous dose in subjects with mild to moderate rheumatoid arthritis. Error bars represent SEM. Pharmacokinetic observations from the subject in the 10.0 mg/kg cohort who received partial infusion were excluded from mean concentration calculations. LLOQ, lower limit of quantification.

Figure 2

Effect of mavrilimumab on suppressor of cytokine signalling 3 (SOCS3) mRNA transcript levels induced by granulocyte-macrophage colony-stimulating factor ex vivo from peripheral blood leucocytes of subjects with mild to moderate rheumatoid arthritis. Data are presented as mean (SE). Asterisks indicate a significant change (*p

Figure 3

(A) Effect of mavrilimumab (formerly known as CAM-3001) on Disease Activity Score 28-joint assessment (DAS28) levels at baseline, week 4 and week 12. Data are presented as the mean (SD) for each visit. (B) Effect of mavrilimumab on DAS28 levels within the first 4 weeks after a single intravenous dose in subjects with moderate disease (DAS28 >3.2 at baseline). (C) Effect of mavrilimumab on C-reactive protein (CRP) level at baseline (week 0), week 2 and week 4. Data are presented as the mean (SD) for each visit. (D) Effect of mavrilimumab on CRP level within the first 4 weeks after a single intravenous dose in subjects with mild rheumatoid arthritis who had elevated (>5 mg/l) CRP levels at baseline. Legend: placebo (◊) and mavrilimumab 0.1 mg/kg (▲), 0.3 mg/kg (●), 1.0 mg/kg (■), 3.0 mg/kg (○) and 10.0 mg/kg (Δ).