Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.


Platelet Derived Growth Factor Receptor Inhibitor ARRY-768 Prevents Experimental Dermal Fibrosis and Induces Regression of Pre-Established Dermal Fibrosis.

Tomcik1,  Michal, Reich2,  Nicole, Palumbo2,  Katrin, Zerr2,  Pawel, Avouac3,  Jérôme, Akhmetshina2,  Alfiya, Dees2,  Clara

Institute of Rheumatology, Department of Clinical and Experimental Rheumatology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic
Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
Paris Descartes University, Rheumatology A department, Cochin Hospital, Paris, France
University of Erlangen-Nuremberg, Erlangen, Germany
Institute of Rheumatology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic
University Hospital Zurich, Zurich, Switzerland

Background/Purpose:

Platelet derived growth factor (PDGF) is one of the key profibrotic cytokines in pathogenesis of systemic sclerosis. ARRY-768 is a highly selective, orally active, small molecule inhibitor of PDGF receptors, which targets PDGFR more potently than imatinib (IC50 of 3 vs. 69 nM, respectively). The aim of this study was to investigate the efficacy of ARRY-768 in prevention of dermal fibrosis and treatment of pre-established dermal fibrosis induced by bleomycin.

Methods:

Design for prevention of dermal fibrosis (A) comprised 3 treatment groups injected with bleomycin s.c. for 3 weeks: group I was treated with ARRY-768 50mg/kg p.o., group II and III with imatinib mesylate 50 and 200mg/kg i.p., respectively, twice a day. Control groups, injected with NaCl (IV) and bleomycin (V) s.c., were treated p.o. with a vehicle (water). Design for the treatment of pre-established dermal fibrosis (B) consisted of 4 treatment groups injected with bleomycin s.c. for 6 weeks. During the last 3 weeks, groups I and II were treated with ARRY-768 30 and 100mg/kg p.o., whereas groups III and IV with imatinib mesylate 50 and 200mg/kg i.p., respectively, twice a day. Control groups, injected s.c. with NaCl (V) or bleomycin (VI) for 6 weeks or bleomycin for the first 3 and NaCl the last 3 weeks (VII), were treated p.o. with water for the last 3 weeks. A total of 40+56 (A+B) DBA/2 mice were examined weekly for weight, activity and the texture of the fur.

Results:

In the standard model of bleomycin-induced dermal fibrosis (A), treatment with ARRY-768 50mg/kg (I) reduced dermal thickening by 67±2% (p<0.001), hydroxyproline content by 23±6% (p=0.642) and myofibroblast count by 47±5% (p<0.001). Control treatment with imatinib (II, III) demonstrated comparable reduction of dermal fibrosis. Similarly in the model of bleomycin-induced pre-established dermal fibrosis (B), treatment with ARRY-768 30 (I) and 100mg/kg (II) decreased dermal thickening by 45±2% (p<0.01) and 56±1% (p<0.01), hydroxyproline content by 52±4% (p<0.001) and 55±5% (p<0.001), and myofibroblast count by 75±6% (p<0.001) and 88±8% (p<0.001), respectively. Control treatment with imatinib (III, IV) showed similar regression of pre-established dermal fibrosis. ARRY-768 demonstrated significant antifibrotic effects in both prevention and treatment of pre-established dermal fibrosis. The treatment with ARRY-768 was well tolerated for 3 weeks at all dosing regimens (30, 50 or 100mg/kg) and no signs of toxicity such as weight loss, decreased activity or changes in the texture of the fur were observed.

Conclusion:

This is the first study on the anti-fibrotic effects of the selective PDFGR inhibitor ARRY-768. ARRY-768 did not only prevent experimental fibrosis, but also induced regression of pre-established bleomycin-induced fibrosis without toxic side effects. The efficacy of ARRY-768 was comparable to that of imatinib, suggesting that the effects of imatinib might be mediated primarily via inhibition of PDGFR, whereas inhibitory effects on c-abl, a downstream mediator of TGFb, seem to be less relevant. These data highlight the importance of PDGF signaling in fibrotic diseases.

To cite this abstract, please use the following information:
Tomcik, Michal, Reich, Nicole, Palumbo, Katrin, Zerr, Pawel, Avouac, Jérôme, Akhmetshina, Alfiya, et al; Platelet Derived Growth Factor Receptor Inhibitor ARRY-768 Prevents Experimental Dermal Fibrosis and Induces Regression of Pre-Established Dermal Fibrosis. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :2321
DOI:

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