Trinh-Minh Thuong, Tran-Manh Cuong, Györfi Andrea-Hermina, Dickel Nicholas, Liebel Christoph, Zhou Xiang, Wang Jiucun, Kunz Meik, Arozenius Helena, Pettersson Lars, Lindgren Sam, Wenglén Christina, Distler Jörg H W
Department of Rheumatology, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany; Hiller Research Center, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany.
Chair of Medical Informatics, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.
Arthritis Rheumatol. 2025 Aug;77(8):1063-1076. doi: 10.1002/art.43151. Epub 2025 Apr 17.
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.
The antifibrotic effects of AM1476 were evaluated in the mouse models of bleomycin-induced pulmonary fibrosis in Tsk-1 mice and in mice with sclerodermatous chronic graft-versus-host disease. For further validation, the antifibrotic effects of AM1476 were analyzed in precision cut skin (PCS) slices from patients with SSc.
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 lungs 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.
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. Because AM1476 also demonstrated good tolerability in a phase 1 trial, further clinical trials with AM1476 are currently in the planning stage.
系统性硬化症（SSc）是一种伴有皮肤和各种内脏器官纤维化重塑的结缔组织疾病。在所有风湿性自身免疫性疾病中，SSc的病例特异性死亡率最高，且抗纤维化治疗选择有限。在此，我们评估了高度选择性5-羟色胺2B受体（5-HTR）抑制剂AM1476的治疗效果。
在博来霉素诱导的Tsk-1小鼠肺纤维化模型和硬皮病样慢性移植物抗宿主病小鼠模型中评估AM1476的抗纤维化作用。为进一步验证，在SSc患者的精密切割皮肤（PCS）切片中分析AM1476的抗纤维化作用。
在体外，AM1476对5-HTR的选择性高于200多种其他受体，包括其他5-羟色胺受体。在所有三种小鼠模型中，AM1476以耐受性良好的剂量减少了羟脯氨酸的积累以及皮肤和/或肺部的纤维化组织重塑，其疗效与尼达尼布相当。在SSc皮肤的PCS中，用AM1476治疗可降低SSc特异性标志基因的表达。与霉酚酸酯相比，AM1476对与成纤维细胞活化和纤维化重塑相关术语的调节作用更为明显。
我们将AM1476描述为一种高度选择性的5-HTR抑制剂。用AM1476治疗可改善三种SSc小鼠模型中的纤维化，并直接使SSc皮肤中纤维化相关基因的表达正常化。由于AM1476在1期试验中也表现出良好的耐受性，目前正在计划开展进一步的AM1476临床试验。
