Conatus Pharmaceuticals’ Pan-caspase Inhibitor Emricasan Improves Survival and Portal Hypertension in a Mouse Model of Cirrhosis
In the first of the two current mouse studies, designed to evaluate treatment effect, emricasan decreased fibrosis, reduced portal hypertension and improved survival in mice with cirrhosis induced by bile duct ligation. The reductions in portal hypertension exceeded amounts that could be explained by the decreased fibrosis alone, indicating potential treatment effects both inside and outside the liver.
In the second study, designed to investigate mechanism of action, emricasan reduced liver damage, liver cell death and fibrosis in mice, and these changes were associated with a decrease in circulating microparticles. These microparticles, which are released from damaged cells, have been linked in previous studies to a cascade of detrimental effects in the liver, including inflammation, collagen production, restriction of blood flow through the liver, and restriction of blood flow in and out of liver cells responsible for toxin processing and removal and essential protein production. Previous studies also have shown that circulating microparticles above a threshold level can trigger increased blood flow toward the liver to compensate for the restricted blood flow through the liver, which exacerbates portal hypertension. In the current study, microparticles from placebo mice, but not from emricasan-treated mice, activated endothelial cells ex vivo. Endothelial cells lining the blood vessels inside the liver are the gateway between the blood stream and the toxin processing and protein synthesizing cells in the liver, and their activation directly restricts that exchange and thereby reduces liver function. Through these multiple mechanisms, emricasan’s suppression of microparticles could be a contributing factor both inside and outside the liver in reducing portal hypertension.
The studies, published in the peer-reviewed
In collaboration with
- ENCORE-PH (for Portal Hypertension), initiated in the fourth quarter of 2016, in approximately 240 NASH patients with compensated or early decompensated liver cirrhosis and severe portal hypertension, with top-line results expected in the fourth quarter of 2018;
- ENCORE-NF (for NASH Fibrosis), initiated in the first quarter of 2016, in approximately 330 NASH patients with fibrosis, with top-line results expected in the first half of 2019; and
- ENCORE-LF (for Liver Function), initiated in the second quarter of 2017, in approximately 210 NASH patients with decompensated cirrhosis, with top-line results expected in the second half of 2019.
Conatus is a biotechnology company focused on the development of novel medicines to treat liver disease. In collaboration with
This press release contains forward-looking statements within the meaning of Section 21E of the Securities Exchange Act of 1934, as amended. All statements other than statements of historical facts contained in this press release are forward-looking statements, including statements regarding: the preclinical data encouraging further evaluation of emricasan in chronic liver disease; the timeline for results from the ENCORE trials; and caspase inhibitors' potential to interrupt the progression of a variety of diseases. In some cases, you can identify forward-looking statements by terms such as “may,” “will,” “should,” “expect,” “plan,” “anticipate,” “could,” “intend,” “target,” “project,” “contemplates,” “believes,” “estimates,” “predicts,” “potential” or “continue” or the negative of these terms or other similar expressions. These forward-looking statements speak only as of the date of this press release and are subject to a number of risks, uncertainties and assumptions, including those risks described in the company’s prior press releases and in the periodic reports it files with the
1Eguchi, A., Koyama, Y., Wree, A. et al. Emricasan, a pan-caspase inhibitor, improves survival and portal hypertension in a murine model of common bile-duct ligation. J Mol Med (2018) 96:575-583. https://doi.org/10.1007/s00109-018-1642-9.
Source: Conatus Pharmaceuticals Inc.