Presentation #PS-004, “The gut-liver axis is essential for disease progression in the Mdr2−/− mouse model of primary sclerosing cholangitis,” will be delivered by lead author Lijun Liao, Researcher in the Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany and at Renji Hospital, Shanghai Jiao Tong University, Department of Pain Management, in Shanghai, China. Conatus co-sponsored the research, which was conducted by a collaboration of academic researchers in Germany, China, Spain and Sweden.
The researchers noted that PSC, a disease affecting bile ducts in the liver which can lead to cirrhosis and liver failure, is strongly associated with inflammatory bowel disease, and that the gut-liver connection plays a critical role in PSC onset and progression. They investigated gut-liver interactions and inflammasome activation in the Mdr2−/− mouse model resembling PSC. Their results showed that inflammation in the Mdr2−/− mouse model showed characteristic increases in apoptotic cell death, progressive bile duct proliferation and periportal fibrosis development. The bile acid composition was abnormal and reflective of changes in intestinal bacteria.
Conatus’ pan-caspase inhibitor IDN-7314 was administered as a treatment to block caspase activation, resulting in reduced inflammasome activation and demonstrated beneficial effects on liver injury, periportal inflammation, serum bile acid profile as well as imbalance in the intestinal bacteria. The researchers confirmed the importance of the gut-liver connection in the Mdr2−/− mouse model of PSC, and concluded that blockage of bile ducts triggers an intestinal bacteria imbalance and migration of bacteria and related toxins to the portal vein of the liver, followed by increased inflammation and liver injury. They further concluded that this cascade of events can be blocked by pan-caspase inhibition.
“The confirmation of the links between liver and gut implications in PSC suggest that treatments addressing the underlying mechanisms may provide benefits in both organ systems,” said Al Spada, Ph.D., Executive Vice President of Research and Development and Chief Scientific Officer of Conatus, and a co-author on the publication. “We believe the demonstrated impact of IDN-7314 on these underlying mechanisms encourages further evaluation of caspase inhibition as a treatment for PSC.”
IDN-7314 is an orally active pan-caspase protease inhibitor designed to reduce the activity of enzymes that mediate inflammation and cell death (or apoptosis), which has demonstrated reduction of relevant biomarkers in two preclinical models of PSC. The Mdr2-/- mouse model is considered the current benchmark nonclinical model of PSC. IDN-7314 also reduced biochemical markers in a new acute preclinical model of PSC. These results suggest the involvement of caspases in the progression of PSC. IDN-7314 was granted Orphan Drug Designation for the treatment of PSC by the U.S. Food and Drug Administration (FDA) in June 2017 and by the European Medicines Agency (EMA) in October 2017. Conatus is evaluating the potential of IDN-7314 as a treatment for PSC.
About Conatus Pharmaceuticals
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. For additional information, please visit www.conatuspharma.com.