Development of PAR2 Inhibitors for the Treatment of Nonalcoholic steatohepatitis

DESCRIPTION provided by applicant Non alcoholic steatohepatitis NASH is characterized by fatty changes in the liver with inflammation and hepatocellular injury that in advanced stages leads to fibrosis and cirrhosis and high mortality rates NASH is frequently associated with other common metabolic abnormalities such as insulin resistance and visceral obesity Liver transplantation is currently the only therapeutic approach for severe NASH or other forms of liver fibrosis with no approved drug treatments Organ transplantation is a difficult risky and costly procedure with scarce organ availability and increased risk of developing cirrhosis in the transplanted liver from the original highlighting the major unmet need for new therapeutic options Protease activated receptor PAR is a signaling receptor that is highly abundant in liver cells and inflammatory cells which controls inflammatory and fibrotic processes that lead towards severe NASH and liver cirrhosis The cell penetrating lipidated PAR inhibitor PZ was developed using pepducin technology and offers a unique opportunity to target the intracellular surface of G protein coupled receptors GPCRs such as PAR with exquisite specificity potency and long half lives PZ is an advanced anti inflammatory anti fibrotic drug candidate that targets PAR and blocks PAR signaling in hepatic stellate and inflammatory cells PZ reduces fatty liver steatosis and hypertriglyceridemia by up to and suppresses lobular inflammation and systemic alanine aminotransferase ALT levels in mouse models of diet induced NASH similar to effects in a PAR deficient mouse strain PZ treatment gave a major improvement in NASH activity scores NAS in mice which corresponded to suppression of histologic disease progression PZ also significantly protected against severe pancreatitis a common sequela seen with several of the newly approved type II diabetes drugs Together these preclinical data identify PZ as a potent and potentially effective drug candidate for NASH treatment In Aim we will test the pharmacologic properties of PZ with the milestones of showing significant delivery into liver and efficacy data to demonstrate blockade of the late nd fibrotic hit in liver NASH mouse models and provide pilot safety tox data systemic parameters liver enzymes body weight injection site tolerability hematology in day repeat dose daily administration in rodents Aim will conduct GLP safety toxicology and PK PD studies of cGMP produced PZ in species with design of upcoming first in human phase I and II clinical trials in NASH patients with our gastroenterology and MR imaging clinical collaborators PUBLIC HEALTH RELEVANCE Nonalcoholic steatohepatitis NASH cirrhosis is one of the leading indications for liver transplantation in the United States with estimated million Americans suffering from NASH Protease activated receptor PAR has been identified as an emerging therapeutic opportunity for the effective and safe treatment of NASH as a non invasive pharmacologic therapy This proposal provides a drug development blueprint for the rapid evaluation of a first in class PAR Pepducin inhibitor for the treatment of NASH