The human anti-IL-1β monoclonal antibody ACZ885 is effective in joint inflammation models in mice and in a proof-of-concept study in patients with rheumatoid arthritis

Rieke Alten¹ , Hermann Gram² , Leo A Joosten³ , Wim B van den Berg³ , Joachim Sieper⁴ , Siegfrid Wassenberg⁵ , Gerd Burmester⁶ , Piet van Riel⁷ , Maria Diaz-Lorente⁸ , Gerardus JM Bruin⁸ , Thasia G Woodworth⁸ , Christiane Rordorf⁸ , Yannik Batard⁸ , Andrew M Wright⁸ and Thomas Jung⁸

¹Department of Internal Medicine II, Rheumatology, Schlosspark-Klinik Teaching Hospital Charité University Medicine Berlin, Heubnerweg, D-14059 Berlin, Germany

²Novartis Institutes of Biomedical Research, Basel, CH-4002 Basel, Switzerland

³Rheumatology Research and Advanced Therapeutics, Radboud University Nijmegen Medical Centre, Nijmegen 6500 HB, The Netherlands

⁴Department of Rheumatology, Klinikum Benjamin Franklin, Hindenburgdamm, D-12200 Berlin, Germany

⁵Department of Rheumatology, Evangelisches Fachkrankenhaus, Rosenstraße, D-40882 Ratingen, Germany

⁶Department of Rheumatology, Charité, Charitéplatz, D-10117 Berlin, Germany

⁷Department of Rheumatology, University Medical Center St Radboud, Nijmegen 6500 HB, The Netherlands

⁸Novartis Exploratory Development, Werk St. Johann, Forum 1, CH-4002 Basel, Switzerland

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Arthritis Research & Therapy 2008, 10:R67doi:10.1186/ar2438


Published:	5 June 2008

Abstract

Introduction

IL-1β is a proinflammatory cytokine driving joint inflammation as well as systemic signs of inflammation, such as fever and acute phase protein production.

Methods

ACZ885, a fully human monoclonal antibody that neutralizes the bioactivity of human IL-1β, was generated to study the potent and long-lasting neutralization of IL-1β in mechanistic animal models as well as in a proof-of-concept study in patients with rheumatoid arthritis (RA).

Results

The mouse IL-1 receptor cross-reacts with human IL-1β, and it was demonstrated that ACZ885 can completely suppress IL-1β-mediated joint inflammation and cartilage destruction in mice. This observation prompted us to study the safety, tolerability and pharmacodynamic activity of ACZ885 in RA patients in a small proof-of-concept study – the first to be conducted in humans. Patients with active RA despite treatment with stable doses of methotrexate were enrolled in this dose escalation study. The first 32 patients were split into four cohorts of eight patients each (six were randomly assigned to active treatment and two to placebo). ACZ885 doses were 0.3, 1, 3 and 10 mg/kg, administered intravenously on days 1 and 15. To explore efficacy within 6 weeks of treatment, an additional 21 patients were randomly assigned to the 10 mg/kg cohort, resulting in a total of 20 patients dosed with 10 mg/kg and 15 patients treated with placebo. There was clinical improvement (American College of Rheumatology 20% improvement criteria) at week 6 in the 10 mg/kg treatment group; however, this did not reach statistical significance (P = 0.085). A statistically significant reduction in disease activity score was observed after 4 weeks in the 10 mg/kg group. Onset of action was rapid, because most responders exhibited improvement in their symptoms within the first 3 weeks. C-reactive protein levels decreased in patients treated with ACZ885 within 1 week. ACZ885 was well tolerated. Three patients receiving ACZ885 developed infectious episodes that required treatment. No anti-ACZ885 antibodies were detected during the study.

Conclusion

ACZ885 administration to methotrexate-refractory patients resulted in clinical improvement in a subset of patients. Additional studies to characterize efficacy in RA and to determine the optimal dose regimen appear warranted.

Trial Registration

ClinicalTrials.gov identifier NCT00619905.