Clara Dees1, Christian Beyer1, Alfiya Distler1, Alina Soare2, Yun Zhang1, Katrin Palumbo-Zerr1, Oliver Distler3, Georg Schett1, Peter Sandner4, Jörg H W Distler1. 1. Department of Internal Medicine 3,Institute for Clinical Immunology, University of Erlangen-Nuremberg, Germany. 2. Department of Internal Medicine 3,Institute for Clinical Immunology, University of Erlangen-Nuremberg, Germany Internal Medicine and Rheumatology Department, Dr. I. Cantacuzino Clinical Hospital, Bucharest, Romania Carol Davila University of Medicine and Pharmacy, Bucharest, Romania. 3. Center of Experimental Rheumatology, Research of Systemic Autoimmune Diseases, University Hospital Zurich, Switzerland. 4. Bayer Health Care, Global Drug Discovery-Common Mechanism Research, Wuppertal, Germany Hannover Medical School, Institute of Pharmacology, Hannover, Germany.
Abstract
OBJECTIVES: Stimulators of the soluble guanylate cyclase (sGC) have recently been shown to inhibit transforming growth factor-β signalling. Here, we aimed to demonstrate that riociguat, 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. METHODS: The antifibrotic effects of riociguat and sildenafil 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. RESULT: 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. CONCLUSIONS: These data 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 SSc. A phase II study with riociguat in patients with SSc is currently starting. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
OBJECTIVES: Stimulators of the soluble guanylate cyclase (sGC) have recently been shown to inhibit transforming growth factor-β signalling. Here, we aimed to demonstrate that riociguat, 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. METHODS: The antifibrotic effects of riociguat and sildenafil 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. RESULT: 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. CONCLUSIONS: These data 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 SSc. A phase II study with riociguat in patients with SSc is currently starting. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Authors: Clara Dees; Sebastian Pötter; Yun Zhang; Christina Bergmann; Xiang Zhou; Markus Luber; Thomas Wohlfahrt; Emmanuel Karouzakis; Andreas Ramming; Kolja Gelse; Akihiko Yoshimura; Rudolf Jaenisch; Oliver Distler; Georg Schett; Jörg Hw Distler Journal: J Clin Invest Date: 2020-05-01 Impact factor: 14.808
Authors: Andrea-Hermina Györfi; Alexandru-Emil Matei; Maximilian Fuchs; Chunguang Liang; Aleix Rius Rigau; Xuezhi Hong; Honglin Zhu; Markus Luber; Christina Bergmann; Clara Dees; Ingo Ludolph; Raymund E Horch; Oliver Distler; Jiucun Wang; Bertram Bengsch; Georg Schett; Meik Kunz; Jörg H W Distler Journal: J Exp Med Date: 2021-07-14 Impact factor: 14.307