Conatus Reports Positive Results Of Preclinical Studies Of Liver Disease
Conatus Pharmaceuticals reported positive preclinical results on its lead compound, CTS-1027 in multiple models of hepatitis, an inflammatory liver disease. The results were presented in a poster session today at the American Association for the Study of Liver Diseases (AASLD) in Boston, MA.
CTS-1027 significantly reduced liver damage following oral administration in four different preclinical models of liver injury. CTS-1027 markedly reduced aminotransferase (ALT) activity and improved survival and liver histology in the TNFalpha/Gln model. CTS-1027 was equally effective dosed at the same time as the insult or post-insult in the LPS/Gln model. CTS-1027 significantly reduced ALT activity in the Fas and Con A models. Dosing was well below or equivalent to exposure levels previously tolerated in human clinical studies.
"CTS-1027 represents a potential new and exciting approach to treat patients infected with Hepatitis C Virus (HCV), and in the treatment of other liver diseases. Our initial goal for the development of CTS-1027 is to establish safety and efficacy in patients infected with HCV who have failed or can not tolerate standard of care," stated Alfred Spada, Ph.D., SVP Research and Development. "We plan to initiate a Phase 2 clinical trial within the next few months."
CTS-1027 is an oral, small molecule, matrix metalloproteinase (MMP) inhibitor under development for chronic use to protect the liver from damage due to a variety of insults including virus infection, obesity, alcohol use, and autoimmune diseases. Preclinical studies demonstrate strong efficacy in multiple models of liver disease. In previous clinical trials in other therapeutic areas, CTS-1027 was chronically administered to over 500 people, some for over 18 months.
Matrix metalloproteinases (MMPs) are a well studied family of proteolytic enzymes. In the liver, as in other solid organs, MMPs play a key role in maintaining the integrity of the extracellular matrix. Excessive MMP activity has been demonstrated to occur in the liver in response to a variety of acute and chronic insults. This results in the loss of scaffolding that maintains the normal architecture of the liver and the recruitment and activation of inflammatory cells that perpetuate liver damage. In addition, important cytokines in the progression of liver damage, such as TGF-beta, stimulate the expression of MMPs from hepatic stellate cells, the main cell type involved in the pathology of fibrosis. MMPs are also well recognized to play an important and direct role in regulating inflammation. These dual activities of tissue remodeling and modulating inflammatory networks make MMPs an attractive target in the setting of acute and chronic liver disease.