Genkyotex, the leading developer of NOX inhibitors to treat oxygen-radical mediated diseases, has reported successful results from studies of the NOX 1 and four inhibitor, GKT137831, in experimental models of liver fibrosis. The data, was published jointly with Professor David Brenner, MD, dean, School of Medicine, University of California San Diego online in Hepatology demonstrates the specificity of GKT137831 and its ability to attenuate development of fibrosis in the liver and production of reactive oxygen species (ROS) in two models of disease, as well as inhibiting messenger RNA expression of fibrotic and NOX genes.

“These data provide important validation of the role of NOX in liver fibrosis as well as demonstrating the robust activity of the NOX inhibitor GKT137831,” explained David A Brenner, MD. He further added, “Often called the silent disease due to the lack of symptoms, there is an unmet need for effective treatments for liver fibrosis as there are currently none available to patients.”

“The data also highlight the excellent pharmacological properties of GKT137831 and the broad potential for its use in fibrotic diseases,” said Dr Patrick Page, Chief Development Officer at Genkyotex. “As we have reported previously, GKT137831 has shown a good safety and PK profile to date in Phase I studies and we plan to develop the drug initially in diabetic nephropathy, where kidney fibrosis plays a major role in the progression to end stage renal disease. We are now considering the clinical evaluation of GKT137831 in additional fibrotic diseases, such as nonalcoholic steatohepatitis, a common liver disease, where there is high unmet need and large market potential.”

Most chronic liver diseases are associated with progressive fibrosis, which is triggered by the loss of hepatocytes and the activation of inadequate wound healing pathways. When the liver is injured, specific cell subsets including hepatic stellate cells (HSCs), are activated to become myofibroblasts, a major source of extracellular matrix (ECM) proteins including collagen. Myofibroblast derived chemokines also recruit macrophages to the liver, which contribute to the fibrotic response. The activation of myofibroblasts is triggered by intracellular signaling pathways involving NOX. By inhibiting NOX, the researchers believe myofibroblast activation and macrophage recruitment can be interrupted, preventing further fibrosis and potentially allowing regression of established fibrosis.

The role of NOX, and the efficacy of GKT137831, was evaluated in the carbon tetrachloride (CCL4) and bile duct ligation (BDL) models in mice. The CCL4 model was carried out in both wild type (WT) mice and in mice carrying the G37R mutation in the SOD1 gene (SOD1mu mice). This mutation leads to enhanced NOX activity and oxidative stress. Primary cultured HSCs isolated from WT and SOD1mu mice models were assessed for ROS production and NOX gene expression. Liver fibrosis developed in WT mice and was enhanced in SOD1mu mice, and ROS production and Rac1 activity were increased in SOD1mu HSCs. Treatment with the NOX1 and 4 inhibitor, GKT137831 suppressed ROS production and fibrotic gene expression in both SOD1mut and WT HSCs. In vivo, GKT137831 attenuated ROS production in both SOD1mu and WT mice as well as messenger RNA expression of fibrotic genes, resulting in reduced fibrosis. GKT137831 similarly prevented fibrosis in the BDLmodel, which mimics human cholestatic liver disease. GKT137831 was recently shown to be effective in the mouse BDL model, by an independent group of researchers lead by Ass. Professor Nathalie Torok at University of California Davis (Free Radic Biol Med. 2012 Jul 15;53(2):289-96. Epub 2012 May 19).

GKT137831 was found to be a potent inhibitor of human NOX4 (Ki =140 ±40 nM) and human NOX1 (Ki =110 ± 30 nM), with selectivity over other NOX isoforms.