Background: Fibrosis, characterized by excessive tissue scarring, represents a major healthcare challenge accounting for up to 40% of deaths in industrialized countries. Systemic sclerosis (SSc) stands out as a particularly severe form of fibrotic disease, affecting multiple organs and having the highest mortality rate among autoimmune rheumatic diseases. The condition involves myofibroblasts, which are activated fibroblasts that produce excess collagen and extracellular matrix components. Recent research has identified the serotonin (5-HT) pathway, specifically through 5-HT _2B receptor activation, as a key mechanism in both fibroblast activation and macrophage regulation. However, developing effective treatments remains challenging due to the lack of suitable selective inhibitors for clinical use.

Objectives: Here, we evaluated the therapeutic effects of the highly selective 5-hydroxytryptamine 2B receptor (5-HT _2B R) inhibitor AM1476 on fibrotic models.

Methods: The antifibrotic effects of AM1476 were evaluated in the mouse models of bleomycin-induced pulmonary fibrosis, in tight-skin-1 (Tsk-1) mice and in mice with sclerodermatous chronic graft-versus-host disease (cGvHD). For further validation, the antifibrotic effects of AM1476 were analyzed in precision cut skin (PCS) slices from SSc patients.

Results: AM1476 demonstrated high selectivity for 5-HT _2B R over more than 200 other receptors including other 5-HT receptors in vitro . AM1476 reduced accumulation of hydroxyproline and fibrotic tissue remodeling of skin and/or lung in all three mouse models at well tolerated doses with a comparable efficacy to that of Nintedanib. In PCS of SSc skin, treatment with AM1476 reduced the expression of SSc-specific signature genes. AM1476 demonstrated more pronounced regulation of terms related to fibroblast activation and fibrotic remodeling than mycophenolate mofetil (MMF).

Conclusion: We describe AM1476 as a highly selective inhibitor of 5-HT _2B R. Treatment with AM1476 ameliorated fibrosis in three mouse models of SSc and normalized the expression of fibrosis-related genes directly in SSc skin. As AM1476 also demonstrated good tolerability in a phase I trial, further clinical trials with AM1476 are currently in the planning stage.

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Acknowledgements: We thank Wolfgang Espach, and Regina Kleinlein for excellent technical assistance.

Disclosure of Interests: Thuong Trinh-Minh: None declared, Cuong Tran-Manh: None declared, Andrea-Hermina Györfi Boehringer Ingelheim, Abbvie, Nicholas Dickel: None declared, Christoph Liebel: None declared, Xiang Zhou: None declared, Jiucun Wang: None declared, Meik Kunz: None declared, Helena Arozenius AnaMar AB, Lars Pettersson AnaMar AB, Sam Lindgren AnaMar AB, AnaMar AB; Vicore Pharma; Hansa Biopharma, Christina Wenglén AnaMar AB, Jörg Distler AbbVie, Active Biotech, Anamar, ARXX, AstraZeneca, Bayer Pharma, Boehringer, Ingelheim, Celgene, Galapagos, Genentech, GSK, Inventiva, Janssen, Novartis, Pfizer, Roche and UCB, AbbVie, Active Biotech, Anamar, ARXX, AstraZeneca, Bayer Pharma, Boehringer, Ingelheim, Celgene, Galapagos, Genentech, GSK, Inventiva, Janssen, Novartis, Pfizer, Roche and UCB, AbbVie, Anamar, Argenx, ARXX, BMS, Bayer Pharma, Boehringer Ingelheim, Cantargia, Celgene, CSL Behring, ExoTherapeutics, Galapagos, GSK, Inventiva, Kiniksa, Lassen, Novartis, Sanofi-Aventis, RedX, UCB, Zenasbio.

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