Background PDGF (plateled derived growth factor) 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).
Objectives To investigate the efficacy of ARRY-768 in prevention 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 treated with ARRY-768 (kindly provided by Array Biopharma) 50mg/kg p.o. bid, group II and III with imatinib mesylate 50 and 200mg/kg i.p., respectively. Control groups, injected with NaCl (IV) and bleomycin (V) s.c., were treated p.o. with 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. bid, and groups III and IV with imatinib 50 and 200mg/kg i.p., respectively. 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 Treatment with ARRY-768 50mg/kg (I) in the prevention model (A) reduced dermal thickening by 67±2% (p<0.001), hydroxyproline content by 23±6% (p=0.642) and myofibroblast counts by 47±5% (p<0.001). Control treatment with imatinib (II, III) demonstrated comparable reduction of dermal fibrosis. In 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 counts 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 with no signs of toxicity such as weight loss, decreased activity or changes in the texture of the fur.
Conclusions 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 imatinib was not superior to that of ARRY-768, suggesting that the effects of imatinib might be mediated primarily via inhibition of PDGFR, whereas inhibitory effects on c-abl, a downstream mediator of TGFβ, seem to be less relevant. These data highlight the importance of PDGF signaling in fibrotic diseases.
Disclosure of Interest None Declared
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