RXC008 suppresses fibrosis in a DSS model as measured by histopathology and magnetic resonance imaging

Background: A common and untreatable complication of Crohn’s disease (CD) is the development of intestinal fibrostenosis; it is estimated that 50% of Crohn’s patients will experience fibrosis within 10 years of diagnosis and repeated surgical intervention is currently the only treatment option. ROCK is a serine/threonine kinase that plays a fundamental role in fibrosis and inhibitors of ROCK have been shown to suppress fibrosis in numerous animal models. RXC008 is a GI restricted, potent and selective ROCK1/2 inhibitor with the potential to treat fibrostenosis. Methods: RXC008 was examined for anti-fibrotic efficacy in a chronic 9-week DSS colitis model of intestinal fibrosis with RNAseq, histology, magnetization transfer (MT) and texture analysis entropy (TA-entropy) of magnetic resonance imaging (MRI) used to measure the extent of fibrosis. Results: The MT-MRI and TA-entropy assessments correlated with the histopathology scores with TA-entropy proving superior to MT-MRI for quantifying the progression of fibrosis throughout the experiment. RXC008 was able to strongly suppress fibrosis in the DSS colitis model as measured by both histology and TA-entropy; in addition, multiple pro-fibrotic and tissue remodelling genes were modulated by RXC008. Conclusions: MRI TA-entropy is a highly promising non-invasive surrogate markers of intestinal fibrosis that has the potential to revolutionise clinical assessment of fibrostenosis in Crohn’s patients and measure efficacious effects of new treatments. RXC008 shows great promise as an anti-fibrotic therapy to for fibrostenosis demonstrating strong efficacy as measured by both histopathology and MRI TA-entropy. RXC008 is being developed for phase I clinical assessment in H2 2023.