Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of the Monoclonal Antibody ASK8007 Blocking Osteopontin in Patients with Rheumatoid Arthritis in a Randomized, Placebo-Controlled, Combined First-in-Man and Proof-of-Concept Study.
Boumans5, M., Houbiers1, J., Verschueren10, P., Ishikura2, A., Westhovens10, R., Brouwer4, E., Rojkovich8, B.
Astellas Pharma Global Development, the Netherlands and Japan, Leiderdorp, The Netherlands
University Hospital Leuven, Leuven, Belgium
Astellas Pharma Global Development, the Netherlands and Japan
Centre for Experimental Medicine and Rheumatology, Queen Mary's School of Medicine, London
Department Rheumatology, University Medical Center Groningen, Groningen, The Netherlands
Division of Clinical Immunology and Rheumatology, Academic Medical Center / University of Amsterdam, Amsterdam, Noord-Holland, The Netherlands
Division of Clinical Immunology and Rheumatology, Academic Medical Center / University of Amsterdam, Amsterdam, The Netherlands
Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
Rheumatology, Buda Charity Hospital, Budapest, Hungary
Rheumatology, Hospital Clinico Universitario, Santiago de Compostela, Spain, Santiago, Spain
Osteopontin (OPN) is an extracellular matrix protein that is constitutively expressed in bone and epithelial tissues and upregulated in activated T cells, macrophages, synoviocytes and chondrocytes. OPN has diverse functions including chemotaxis, immunomodulation and activation of osteoclasts. High levels of OPN in serum, synovial fluid and tissue have been reported in rheumatoid arthritis (RA) patients. OPN-blockade improves arthritis in animal models of RA. In this study we assessed the safety, tolerability, pharmacokinetics, pharmacodynamics and initial efficacy of the humanized monoclonal antibody ASK8007 which binds to the SVVYGRL epitope of OPN in patients with active RA receiving methotrexate (MTX), leflunomide (LEF) or sulfasalazine (SSZ).
In this combined first-in-man single dose escalation study (part A) and multiple dose proof-of-concept study (part B), patients meeting the American College of Rheumatology (ACR) criteria for RA who had been taking MTX, LEF or SSZ for 4 months with active disease were randomly assigned to receive either ASK8007 or matching placebo intravenously while continuing to receive MTX, LEF or SSZ. In Part A, patients were treated with a single dose of 0.3, 1.25, 5 or 20 mg/kg ASK8007 intravenously in four consecutive dose cohorts of 8 patients each. In part B, patients received 3 consecutive infusions of 20 mg/kg ASK8007 or matching placebo on day 1, day 8 and day 29. Safety monitoring, pharmacokinetic and pharmacodynamic analyses and clinical assessments were performed throughout the study. Synovial tissue was obtained at baseline and after 43 days of treatment, and was analyzed by immunohistochemistry and digital image analysis. The two co-primary efficacy endpoints were the change from baseline in the disease activity score evaluated in 28 joints (DAS28) and the change from baseline in the number of CD68 positive sublining macrophages in the synovium as assessed on day 43.
ASK8007 was well tolerated up to the highest studied dose of 20 mg/kg in both parts of the study. No anti-ASK8007 antibodies were detected and no renal clearance of ASK8007 was observed. In part B, in the intention-to-treat population, no difference was observed in the delta DAS28 between the ASK8007 treated patients (n=33) and the placebo-treated patients (n=16, P= 0.95). Results were similar for the per protocol population. In addition, no difference was observed in the delta CD68 positive sublining macrophages between the ASK8007-treated patients (n=9) and the placebo-treated patients (n=4, P= 0.61). Paired analysis also did not show a clear cut decrease in sublining macrophages within the ASK8007 treatment group. Although quantifiable ASK8007 concentrations were obtained in synovial fluid samples which indicates that it reaches the target site, there was also no effect of multiple doses of ASK8007 on the biomarkers for bone and cartilage metabolism and for inflammation in any of the matrices tested (blood, urine, synovial fluid and synovial tissue).
The results of this trial consistently show that blocking the extracellular matrix protein osteopontin is unlikely to be a feasible strategy for the treatment of RA.
To cite this abstract, please use the following information:
Boumans, M., Houbiers, J., Verschueren, P., Ishikura, A., Westhovens, R., Brouwer, E., et al; Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of the Monoclonal Antibody ASK8007 Blocking Osteopontin in Patients with Rheumatoid Arthritis in a Randomized, Placebo-Controlled, Combined First-in-Man and Proof-of-Concept Study. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :2170