Specific targeting of the 5-hydroxytryptamine 2B receptor (5-HTR) demonstrates antifibrotic effects in murine models and ex vivo models of scleroderma skin.

Objectives: Systemic sclerosis (SSc) is a connective tissue disease with fibrotic remodeling of the skin and various internal organs. SSc is associated with the highest case-specific mortality of all rheumatic autoimmune diseases with limited antifibrotic treatment options. Here, we evaluated the therapeutic effects of the highly selective 5-hydroxytryptamine 2B receptor (5-HTR) inhibitor AM1476.

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-HTR 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).

Conclusions: We describe AM1476 as a highly selective inhibitor of 5-HTR. 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.