POS0467 DERSIMELAGON, A NOVEL ORAL MELANOCORTIN 1 RECEPTOR AGONIST, DEMONSTRATES DISEASE-MODIFYING EFFECTS IN PRECLINICAL MODELS OF SYSTEMIC SCLEROSIS

Abstract

BackgroundActivation of melanocortin 1 receptor (MC1R) is known to have broad anti-inflammatory and anti-fibrotic effects. The bleomycin (BLM)-induced skin fibrosis murine model is well-established for systemic sclerosis (SSc). α-melanocyte-stimulating hormone, an endogenous ligand of MC1R, inhibits skin fibrosis and MC1R knock-out enhances skin fibrosis in this model. These pieces of evidence suggest that MC1R agonism has potential in the treatment of SSc.ObjectivesDersimelagon phosphate (MT-7117) is an investigational small molecule that is an orally administered, selective agonist for MC1R. The purpose of this study is to investigate the potential of MT-7117 as a therapeutic agent for SSc by evaluating its efficacy and mechanism of action in complementary preclinical models. The expression and distribution of MC1R in the skin of SSc patients was investigated.MethodsThe effects of MT-7117 on skin fibrosis and lung inflammation were evaluated in BLM-induced SSc murine models that were optimized for prophylactic and therapeutic evaluation. Microarray-based gene expression analysis and serum protein profiling were performed to investigate the mechanism of action of MT-7117 in the BLM-induced SSc models. The effect of MT-7117 on TGF-β-induced activation of human dermal fibroblasts was evaluated in vitro. Immunohistochemical analyses of MC1R expression in skin samples from SSc patients were performed.ResultsProphylactic treatment with MT-7117 (≥0.3 mg/kg/day p.o.) significantly inhibited the increase in collagen content of the skin, the serum level of surfactant protein D, and the weight of the lungs from BLM-induced skin fibrosis and lung inflammation model. Therapeutic treatment with MT-7117 (≥3 mg/kg/day p.o.) significantly suppressed skin thickening and the numbers of myofibroblasts in pre-established BLM-induced skin fibrosis model. Gene array analysis using the BLM-induced SSc model demonstrated changes in numerous categories related to macrophages, monocytes, and neutrophils, followed by endothelial cell-related categories after treatment with MT-7117. In the analysis that focused on biological functions, categories of inflammatory response, activation of antigen-presenting cells, angiogenesis, atherosclerosis, vasculogenesis, and vaso-occlusion were suppressed by MT-7117. In the analysis that focused on molecular signaling pathways, triggering receptor expressed on myeloid cells-1, IL-6, and oncostatin M involved in inflammation, and peroxisome proliferator-activated receptor that is related to fibrosis were all affected by MT-7117. Serum protein profiling using BLM-induced SSc model revealed that multiple SSc-related biomarkers including P-selectin, osteoprotegerin, cystatin C, growth and differentiation factor-15 and S100A9 were suppressed by MT-7117. MT-7117 inhibited the activation of human dermal fibroblasts by suppressing TGF-β-induced ACTA2 (encoding α-smooth muscle actin) mRNA elevation in vitro. Immunohistochemical analyses showed that MC1R positivity was observed in 40 of 50 diffuse cutaneous SSc patients. MC1R was expressed by monocytes/macrophages, neutrophils, blood vessels (endothelial cells), fibroblasts, and epidermis (keratinocytes) in the skin of SSc patients.ConclusionMT-7117 demonstrates disease-modifying effects in preclinical models of SSc. Investigations of its mechanism of action and target expression analyses indicate that MT-7117 exerts its positive effects by affecting the pathologies of inflammation, vascular dysfunction, and fibrosis through inflammatory cells, endothelial cells, and fibroblasts. In view of its potent beneficial impact on all these three main pathologies of SSc, MT-7117 is a potential therapeutic agent for the treatment of clinically challenging SSc, which has diverse and difficult to treat symptoms. A phase 2 clinical trial investigating the efficacy and tolerability of MT-7117 in patients with early, progressive diffuse cutaneous SSc is currently in progress.Disclosure of InterestsMasahiro Kondo Employee of: Mitsubishi Tanabe Pharma Corporation, Tsuyoshi Suzuki Employee of: Mitsubishi Tanabe Pharma Corporation, Yuko Kawano Employee of: Mitsubishi Tanabe Pharma Corporation, Shinji Kojima Employee of: Mitsubishi Tanabe Pharma Corporation, Masahiko Miyashiro Employee of: Mitsubishi Tanabe Pharma Corporation, Atsuhiro Matsumoto Employee of: Mitsubishi Tanabe Pharma Corporation, Gabriela Kania: None declared, Przemyslaw Blyszczuk: None declared, rebecca ross: None declared, Panji Mulipa: None declared, Francesco Del Galdo Grant/research support from: Prof. F. Del Galdo received fees and research support from Abbvie, AstraZeneca, Boehringer-Ingelheim, Capella, Chemomab, Kymab, Janssen and Mitsubishi-Tanabe., Yun Zhang: None declared, Jörg H.W. Distler Grant/research support from: Prof. J.H.W. Distler received consulting fees, lecture fees, and/or honoraria from Actelion, Active Biotech, Anamar, ARXX, aTyr, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, JB Therapeutics, Medac, Pfizer, Sanofi-Aventis, RedX, RuiYi and UCB. J. H. W. Distler is stock owner of 4D Science and Scientific head of FibroCure.