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  • 30 July 2015
    Genkyotex’s NOX1&4 Inhibitor Strategy in Liver Fibrosis Supported by New Preclinical Results

    Genkyotex, the leading developer of selective NOX inhibitors, announced today publication of results from two independent studies confirming the important role played by both NOX1 and NOX4 enzymes in the development of liver fibrosis. This research, conducted at University of California, San Diego, and University of California, Davis, supports the use of dual NOX1&4 inhibitors for the treatment of liver fibrosis, such as nonalcoholic steatohepatitis (NASH). Genkyotex’s lead inhibitor, GKT137831, is in a Ph2 trial in diabetic nephropathy, the data from which is also being analyzed to support the company’s plan to evaluate the drug in a range of fibrotic diseases. 

    The first study, published in PLOS One (PLoS ONE 10(7): e0129743. doi:10.1371/ journal.pone.0129743) showed that deletion of either NOX1 or NOX4 genes in mice attenuates liver fibrosis induced by carbon tetrachloride treatment. The study also further elucidates the mechanism of action of GKT137831, by showing that in primary mouse hepatic stellate cell (HSCs) it suppressed signaling evoked by a number of ligands known to drive the fibrogenic process, including lipopolysaccharide (TLR4), platelet-derived growth factor, and sonic hedgehog.

    “For the first time, we have directly compared the role of NOX1 and NOX4 in the development and progression of liver fibrosis. While significant evidence supported a key role for NOX4 in liver fibrosis, data from this comparative gene deletion study demonstrates that both NOX1 and NOX4 drive the fibrogenic process,” explained senior author David A. Brenner, MD, Vice Chancellor, Health Sciences and Dean, School of Medicine at the University of California, San Diego. “This is in agreement with our finding that there is increased expression of NOX1 and NOX4 in liver tissue taken from patients with cirrhosis. In addition, we found that NOX1&4 inhibition with GKT137831in vitro prevents HSC activation through inhibition of multiple inflammatory and fibrogenic pathways. We believe this explains the marked efficacy observed with GKT137831 in multiple preclinical models, confirming the therapeutic potential of NOX1&4 inhibition in liver fibrosis.”

    The second study, with Professor Natalie Torok as senior author and published in Gastroenterology [j.gastro.2015.04.009], showed that selective NOX4 gene deletion in hepatocytes conferred marked protection in two mouse models of NASH. NOX1/4 inhibition with GKT137831 also produced marked anti-fibrotic effects in the fast food model of NASH. Importantly, GKT137831 displayed a favorable metabolic profile as it improved insulin sensitivity.

    “The data from these elegant studies answers a fundamental question by clearly showing that both NOX1 and NOX4 play important roles in liver fibrosis. The results also show that NOX1&4 inhibition attenuates multiple fibrogenic pathways in hepatic stellate cells and hepatocytes, and has positive metabolic effects. The overexpression of NOX 1 and 4 in tissue from patients with liver cirrhosis and NASH confirms the relevance of the preclinical models. Accordingly, we believe inhibiting both NOX1 and NOX4 provides a broad and powerful approach that we intend to investigate in further clinical settings,” commented Philippe Wiesel, MD, Chief Medical Officer at Genkyotex.