Stimulators of the soluble guanylate cyclase ( sGC ) have recently been shown to inhibit transforming growth factor-beta ( TGF-beta ) signalling.
Researchers aimed to demonstrate that Riociguat ( Adempas ), the drug candidate for clinical trials in systemic sclerosis ( SSc ), is effective in experimental fibrosis and to compare its efficacy to that of phosphodiesterase V inhibitors that also increase the intracellular levels of cyclic guanosine monophosphate.
The antifibrotic effects of Riociguat and Sildenafil ( Revatio ) were compared in the tight-skin 1 model, in bleomycin-induced fibrosis and in a model of sclerodermatous chronic graft-versus-host-disease ( cGvHD ).
Doses of 0.1-3 mg/kg twice a day for Riociguat and of 3-10 mg/kg twice a day for Sildenafil were used.
Riociguat dose-dependently reduced skin thickening, myofibroblast differentiation and accumulation of collagen with potent antifibrotic effects at 1 and 3 mg/kg.
Riociguat also ameliorated fibrosis of the gastrointestinal tract in the cGvHD model.
The antifibrotic effects were associated with reduced phosphorylation of extracellular signal-regulated kinases.
Sildenafil at doses of 3 and 10 mg/kg exerted mild antifibrotic effects that were significantly less pronounced compared with 1 and 3 mg/kg Riociguat.
In conclusion, these data have demonstrated potent antifibrotic effects of Riociguat on experimental skin and organ fibrosis.
These findings suggest a role for Riociguat for the treatment of fibrotic diseases, especially for the treatment of systemic sclerosis. ( Xagena )
Dees C et al, Ann Rheum Dis 2015; Epub ahead of print