Systemic Sclerosis Mouse Study of Nintedanib in Fibrotic and Vascular Manifestations Looks Promising

Nintedanib (OFEV) seems to inhibit the activation of fibroblasts and to exert an anti-fibrotic effect in mouse models of systemic sclerosis (SSc), according to data recently presented at the 4^th Systemic Sclerosis World Congress in Lisbon, Portugal, last week. The presentation, “Effects of Nintedanib on Fibrotic and Vascular Manifestation in Pre-clinical Models of Systemic Sclerosis,” was given by J. Distler from the Department of International Medicine 3 and the Institute for Clinical Immunology at the University of Erlangen-Nuremberg in Germany.

Nintedanib, which is marketed as Ofev by Boehringer Ingelheim, is a small molecule tyrosine kinase inhibitor approved for a rare lung disease called idiopathic pulmonary fibrosis (IPF). The drug has been shown to slow IPF disease progression as measured by annual rate of decline in lung function.

Systemic sclerosis is a rare disease characterized by the thickening and scarring of connective tissue in multiple organs in the body, including the lungs. The disease is typically seen in people ages 30 to 50, and women are four times more likely than men to be diagnosed with the condition. The symptoms and severity of systemic sclerosis can vary among individuals, and are dependent on the systems or organs involved.

The study evaluated whether nintedanib can have a beneficial impact on fibrotic manifestations in preclinical models of systemic sclerosis, and on the vascular mutations in the fos-related-antigen-2 (Fra2) model — a model of systemic sclerosis-associated pulmonary arterial hypertension.

In the presentation, Distler showed that nintedanib inhibited fibrotic manifestations more efficiently than selective inhibitors of platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), or fibroblast growth factor (FGF) receptors, all known to be involved in the fibrotic process.

Mice treated with nintedanib had a reduction in the proliferation of smooth muscle cells, which typically lead to thickening of the vessel walls and luminal occlusion of pulmonary arteries. Also in the transgenic mice, treatment with nintedanib was found to reduce skin and pulmonary fibrosis, and to inhibit vascular manifestations, namely capillary loss and dermal miscrovascular endothelial cells apoptosis (cell death).

Distler concluded that: “Treatment with nintedanib has antifibrotic effects in complementary mouse models of systemic sclerosis that mimic different stages, subtypes, and clinical situations of SSC.”

According to the researchers, these preclinical findings might have direct implications for the upcoming Phase 3 clinical trial assessing nintedanib in systemic sclerosis patients.