Exploring the Therapeutic Potential of Dersimelagon in Systemic Sclerosis: Insights from Preclinical Studies

The activation of the melanocortin 1 receptor (MC1R) is recognized for its anti-inflammatory and anti-fibrotic properties. The study utilized a murine model induced by bleomycin (BLM), a common method for studying systemic sclerosis (SSc), and found that the natural MC1R ligand, α-melanocyte-stimulating hormone, can prevent skin fibrosis, while the absence of MC1R can exacerbate it. This suggests that MC1R agonists could be a promising treatment for SSc.

Dersimelagon phosphate, also known as MT-7117, is an experimental drug being studied for its potential as an MC1R agonist. This research aimed to explore MT-7117's effectiveness and mechanism in treating SSc, as well as to examine the receptor's expression in the skin of SSc patients.

The study assessed MT-7117's impact on skin fibrosis and lung inflammation in BLM-induced SSc models, which were designed for both preventive and therapeutic analysis. It included gene expression studies and serum protein profiling to understand how MT-7117 works. Additionally, the drug's effect on human dermal fibroblasts was tested in a laboratory setting, and MC1R expression was analyzed in skin samples from SSc patients.

The results showed that MT-7117, when administered as a preventive treatment, significantly reduced skin collagen, serum surfactant protein D levels, and lung weight in the BLM-induced model. As a therapeutic agent, it also reduced skin thickening and the presence of myofibroblasts. Gene array analysis indicated that MT-7117 influenced categories related to immune cells and endothelial cells, as well as biological functions and molecular signaling pathways associated with inflammation and fibrosis. Serum protein profiling revealed that several SSc-related biomarkers were reduced by MT-7117, and it was found to inhibit fibroblast activation in vitro. Immunohistochemical analysis showed MC1R expression in various skin components of SSc patients.

In conclusion, MT-7117 has shown to have disease-modifying effects in preclinical SSc models, affecting inflammation, vascular dysfunction, and fibrosis through various cell types. Given its impact on the main pathologies of SSc, it is considered a potential therapeutic agent. A phase 2 clinical trial is underway to evaluate its efficacy and safety in early-stage SSc patients.

The interests disclosed include affiliations with Mitsubishi Tanabe Pharma Corporation for several authors and various grants and research support for others from multiple pharmaceutical companies and organizations.