Exploring the Therapeutic Potential of MT-5562 in Mitigating Fibrosis in Systemic Sclerosis: Insights from Preclinical Models

The study investigates the effectiveness and safety of MT-5562, a newly developed oral medication that targets the enzyme autotaxin (ATX), which is linked to systemic sclerosis (SSc). MT-5562 and its free form (MT-5562F) were tested alongside other ATX inhibitors like ziritaxestat and cudetaxestat. The research involved measuring ATX activity, assessing the impact of MT-5562F on IL-6 and CTGF production in fibroblasts, and evaluating cell toxicity in various lung cell types. In vivo tests were conducted on mice to assess plasma concentration of MT-5562F and its effects on LPA levels, as well as its impact on fibrosis in skin and lung models induced by bleomycin.

The results indicated that MT-5562F, along with ziritaxestat and cudetaxestat, effectively inhibited human ATX activity with varying IC50 values. MT-5562F showed a concentration-dependent reduction in TGF-beta-induced IL-6 and CTGF production in fibroblasts from both healthy individuals and those with idiopathic pulmonary fibrosis (IPF). MT-5562 demonstrated low toxicity in lung structural cells, whereas ziritaxestat had a more pronounced cytotoxic effect. MT-5562 did not exhibit off-target inhibition in receptor binding and kinase profiling assays.

In mice, both MT-5562F and ziritaxestat reduced plasma LPA concentration in a dose-dependent manner, with MT-5562F showing more sustained effects. Therapeutic administration of MT-5562F significantly alleviated skin thickening and myofibroblast numbers in a skin fibrosis model and reduced fibrosis severity in a lung fibrosis model, along with a decrease in the biomarker LPA. MT-5562F also significantly lowered the expression of various inflammatory and fibrotic mediators in bronchoalveolar lavage fluid.

The findings suggest that MT-5562 is a selective and potent ATX inhibitor with potential as a safer alternative to other ATX inhibitors and may be a promising treatment for lung and skin fibrosis associated with SSc.