A loss for liver disease?

Conatus Pharmaceuticals’ pan-caspase inhibitor emricasan improves survival and portal hypertension in a mouse model of cirrhosis

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SAN DIEGO—Early July saw news from Conatus Pharmaceuticals Inc. on the publication of results from preclinical studies of its pan-caspase inhibitor emricasan that reportedly demonstrated improvements in portal hypertension (elevated blood pressure in the vein flowing into the liver) and survival in two bile duct ligation mouse models of induced secondary biliary 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 Journal of Molecular Medicine, were conducted in collaboration with Dr. Ariel E. Feldstein of the Department of Pediatrics and the School of Medicine at the University of California, San Diego. Dr. Al Spada, the executive vice president of research and development, chief scientific officer and co-founder of Conatus—as well as a co-author on the publication—said, “The current studies confirm and help explain the favorable effects of emricasan seen in other preclinical models and in observed clinically significant reductions in portal pressure in our pilot portal hypertension clinical trial. We understand that caspase inhibition drives multiple mechanisms of action both inside and outside the liver, which together can provide both symptomatic and structural improvements. We believe these data support continued clinical evaluation of emricasan in patients with chronic liver disease.”
In collaboration with Novartis, Conatus is conducting three randomized, double-blind, placebo-controlled Phase 2b clinical trials, the ENCORE trials, designed to evaluate emricasan in patients with fibrosis or cirrhosis caused by nonalcoholic steatohepatitis (NASH):
  • 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 Novartis, Conatus is developing its lead compound, emricasan, for the treatment of patients with chronic liver disease. Emricasan is a first-in-class, orally active pan-caspase inhibitor designed to reduce the activity of enzymes that mediate inflammation and apoptosis. Conatus believes that by reducing the activity of these enzymes, caspase inhibitors have the potential to interrupt the progression of a variety of diseases.

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