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.
A Multi-Center, Open-Label, Proof of Concept Study of Imatinib Mesylate Demonstrates No Benefit for the Treatment of Fibrosis in Patients with Early, Diffuse Systemic Sclerosis.
Distler8, Oliver, Distler9, Jorg H. W., Varga4, John, Denton7, Christopher P., Lafyatis1, Robert A., Wigley3, Fredrick M., Schett2, Georg
Boston University School of Medicine, Arlington, MA
University of Florence, Firenze, Italy
Friedrich Alexander Univ, Erlangen, Germany
Johns Hopkins University, Baltimore, MD
Northwestern Univ Feinberg School, Chicago, IL
Novartis Institutes for Biomedical Research, Cambridge, MA
Novartis Institutes for Biomedical Research
Royal Free Hospital, London, United Kingdom
University Hospital Zurich, Zurich, Switzerland
University of Erlangen, Erlangen, Germany
Background and Purpose:
Preclinical evidence and preliminary clinical data have suggested that imatinib mesylate may beneficially influence disease course in systemic sclerosis (SSc) mainly by suppressing TGFbeta and PDGF mediated fibrosis through the selective inhibition of the PDGFR and c-abl kinases. A multi-center, open-label, Proof of Concept (PoC) phase IIa study was conducted to evaluate the efficacy and tolerability of imatinib for the treatment of fibrosis in patients with early diffuse SSc.
Twenty-seven diffuse cutaneous SSc patients, older than 18 years, with disease duration less than 18 months and with modified Rodnan Skin Score (mRSS) of 16 36 were enrolled. Imatinib was initiated at an oral dose of 200 mg/day for 4 weeks then up-titrated to 400 mg/day for 2 weeks followed by 600 mg/day until Week 24, if safety and tolerability permitted. After discontinuation of imatinib, patients were followed for additional 24 weeks. Concomitant treatment with high-dose corticosteroids or immunosuppressants was not allowed. Primary outcomes were efficacy as assessed by the change in the mRSS and safety and tolerability. A 25% or greater decrease in mean mRSS with at least 50% level of proof after 24 weeks of treatment was pre-defined as a positive PoC. Further important efficacy assessments included lung functions and patient and physician global assessments. For biomarker assessments, immunohistochemistry and gene expression profiling of skin biopsy samples and assays for soluble markers were performed.
Of the 27 patients enrolled, 16 completed 24 weeks of treatment with imatinib and 13 patients were followed up until week 48. Discontinuations were due to adverse events (6 patients, 22%), informed consent withdrawn (3 patients, 11 %) and other causes (5 patients, 19%). There were 5 patients with serious adverse events which included generalized edema, erosive gastritis, anemia, peripheral and facial edema, upper respiratory tract infection, viral infection, neutropenia and neutropenic infection, nausea and vomiting. No meaningful clinical improvement was observed during the treatment period for any endpoint. Positive PoC was not achieved as the mean change in mRSS at Week 24 was +9.9 %. No significant changes were observed in pulmonary function tests. Trends towards improvement in mRSS, patients and physicians global assessments were observed in the follow up period by Week 48. Biomarker analyses demonstrated a reduction of the mRNA levels of col1a1 and fibronectin.
The adverse events and tolerability in this study were as expected for imatinib and for the diffuse SSc population. Despite preclinical and some preliminary clinical evidence, inhibition of PDGFR/c-abl/c-kit tyrosine kinases by imatinib had no major effect on the disease course of early diffuse systemic sclerosis in our study.
To cite this abstract, please use the following information:
Distler, Oliver, Distler, Jorg H. W., Varga, John, Denton, Christopher P., Lafyatis, Robert A., Wigley, Fredrick M., et al; A Multi-Center, Open-Label, Proof of Concept Study of Imatinib Mesylate Demonstrates No Benefit for the Treatment of Fibrosis in Patients with Early, Diffuse Systemic Sclerosis. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :560