Investigational SM04646 inhibits expression of TGF-beta-stimulated genes known to promote lung fibrosis, a new study shows.
The results will be presented in a poster titled “SM04646 Inhibited Wnt Pathway Gene Expression Stimulated in Response to Transforming Growth Factor-beta and was Effective in a Chronic Model of Bleomycin-induced Pulmonary Fibrosis,” at the upcoming 2018 American Thoracic Society (ATS) International Conference, May 18-23, 2018, in San Diego, California.
SM04646, developed by Samumed, is an inhibitor of the Wnt pathway previously found to promote idiopathic pulmonary fibrosis (IPF). The medicine is delivered as an inhaled aerosol, and was shown to inhibit the expression of fibrotic genes triggered by the pro-fibrotic factor TGF-beta.
In their study, researchers investigated SM04646’s potential to inhibit the TGF-beta-stimulated expression of Wnt pathway genes in primary human lung fibroblasts – the key cells promoting fibrosis – and in a mouse model of human IPF, namely the bleomycin-induced pulmonary fibrosis model.
The team focused on the Wnt pathway genes called Frizzled-8 (FZD-8) and Wnt inducible signalling pathway protein 1 (WISP-1).
In primary human lung fibroblasts, stimulation with TGF-beta led a potent activation of both FZD-8 and WISP-1 genes by more than 100-fold and five-fold, respectively.
Incubating these cells with SM04646 significantly inhibited the activation of these genes, while treatment with Esbriet and Ofev — the two main anti-fibrotic therapies used to treat IPF — showed limited effects.
Combining SM04646 with Esbriet or Ofev inhibited the gene expression stimulated by TGF-beta better than SM04646 alone, or both Esbriet and Ofev combined.
In the chronic bleomycin-induced fibrosis model, SM04646 significantly decreased pulmonary fibrosis scores (assessed with the Ashcroft scale) compared to control mice.
Overall, the results show that “SM04646 ameliorated pulmonary fibrosis induced by chronic bleomycin administration,” the researchers wrote, suggesting this is possible through a reduction in the crosstalk between TGF-beta and Wnt pathway genes.
“We look forward to sharing our findings which highlight SM04646’s unique mechanism of action at this year’s ATS conference. We believe that SM04646 may eventually be used as monotherapy or in combination with currently approved and other pipeline medications to help fight idiopathic pulmonary fibrosis,” Yusuf Yazici, MD, chief medical officer of Samumed, said in a press release.
According to the team, a Phase 1 study testing multiple ascending doses of SM04646 in IPF patients is ongoing in Australia.
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