RESEARCH - Human anti-IL-1-beta monoclonal antibody ACZ885 is effective in joint inflammation models in mice and in a proof-of-concept study in patients with RA

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

Research article

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 , -Lorente8 , Gerardus JM Bruin8 , Thasia G Woodworth8

, Christiane Rordorf8 , Yannik Batard8 , M 8 and

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 lin,

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

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.

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http://arthritis-research.com/content/10/3/R67

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