Safety and PK Study in Hepatic Impairment Patients

DESCRIPTION (provided by applicant): Liver fibrosis, a disease affecting tens of millions of patients worldwide, is the liver scarring response to chronic injury from viral hepatitis B or C, excessive alcohol use, iron overload or extrahepatic obstructions and can progress to liver cirrhosis, liver failure and death. In fact, deaths from complications of liver fibrosis/cirrhosis are expected to triple over the next decade as a result of the hepatitis C epidemic and the growing incidence of liver disease associated with non-alcoholic steatohepatitis. Currently available therapies, including antivirals, are largely ineffective in treating the underlying fibrosis, and in the majority of cases, liver transplantation is the only effective cure. Acute liver failure (ALF) is commonly associated with the alcohol-acetaminophen syndrome, its clinical course is unpredictable and polarizing, with death as the outcome in a large percentage of cases. Given the lack of specific therapy, organ transplantation is the only clinically effective strategy. Hepatic growth factor (HGF), as known as scatter factor (SF), has been shown to be efficacious in reducing both liver fibrosis (chronic) and acute liver failure (acute). The feasibility of SF/HGF as gene or protein therapy however is limited by issues relating to immune and inflammatory responses evoked by adenoviral proteins, inherent instability of proteins in solution, their limited tissue half-life and the exorbitant costs associated with such therapy. Supported by the National Institutes of Health (NIH) Small Business Innovative Research (SBIR) and Rapid Access to Interventional Development (RAID) programs, we have identified and developed BB3, a novel small molecule HGF mimetic. BB3 duplicates the bioactivities of the native protein in every assay tested to date. Particularly, BB3 possesses cell protective, anti-fibrotic, and regenerative activities and shows efficacy in reducing liver fibrosis and acute liver injury. The overall objective of our program is to advance BB3 to the clinic as a first-in-class antifibrotic for liver fibrosis and cyto-protective agent for acute liver injury. From a clinical perspective, a Phase I acute safety trial of intravenously administered BB3 has been successfully completed in healthy volunteers and BB3 was found to be well tolerated. Absorption, distribution, metabolism and elimination studies indicate that BB3 is eliminated via its conversion to metabolites, with the liver and kidneys being the primary routes of metabolite elimination. Prior to evaluating BB3 efficacy in any patient population, including patients presenting with liver fibrosis, it is necessary to evaluate BB3 PK and safety in renally and/or hepatically compromised patients. A Phase IIA clinical trial is currently underway evaluating BB3 PK and safety in patients with renal impairment. The present proposal seeks to evaluate BB3 PK and tolerance in patients with moderate but stable hepatic impairment. Successful completion of the proposed studies will enable us to evaluate the efficacy and safety of BB3 in larger Phase IIB studies in liver fibrosis or acute liver injury. PUBLIC HEALTH RELEVANCE: Liver fibrosis, a disease affecting tens of millions of patients worldwide, is the liver scarring response to chronic injury from viral hepatitis B or C, excessive alcohol use, iron overload or extrahepatic obstructions and can progress to liver cirrhosis, liver failure and death. In fact, deaths from complications of liver fibrosis/cirrhosis are expected to triple over the next decade as a result of the hepatitis C epidemic and the growing incidence of liver disease associated with non-alcoholic steatohepatitis. Currently available therapies, including antivirals, are largely ineffective in treating the underlying fibrosis, and in the majority of cases, liver transplantation is the only effective cure. Acute liver failure (ALF) is commonly associated with the alcohol-acetaminophen syndrome, its clinical course is unpredictable and polarizing, with death as the outcome in a large percentage of cases. Given the lack of specific therapy, organ transplantation is the only clinically effective strategy. Hepatic growth factor (HGF), as known as scatter factor (SF), has been shown to be efficacious in reducing both liver fibrosis (chronic) and acute liver failure (acute). The feasibility of SF/HGF as gene or protein therapy however is limited by issues relating to immune and inflammatory responses evoked by adenoviral proteins, inherent instability of proteins in solution, their limited tissue half-life and the exorbitant costs associated with such therapy. Supported by the National Institutes of Health (NIH) Small Business Innovative Research (SBIR) and Rapid Access to Interventional Development (RAID) programs, we have identified and developed BB3, a novel small molecule HGF mimetic. BB3 duplicates the bioactivities of the native protein in every assay tested to date. Particularly, BB3 possesses cell protective, anti-fibrotic, and regenerative activities and shows efficacy in reducing liver fibrosis and acute liver injury. The overall objective of our program is to advance BB3 to the clinic as a first-in-class antifibrotic for liver fibrosis and cyto-protective agent for acute liver injury. From a clinical perspective, a Phase I acute safety trial of intravenously administered BB3 has been successfully completed in healthy volunteers and BB3 was found to be well tolerated. Absorption, distribution, metabolism and elimination studies indicate that BB3 is eliminated via its conversion to metabolites, with the liver and kidneys being the primary routes of metabolite elimination. Prior to evaluating BB3 efficacy in any patient population, including patients presenting with liver fibrosis, it is necessary to evaluate BB3 PK and safety in renally and/or hepatically compromised patients. A Phase IIA clinical trial is currently underway evaluating BB3 PK and safety in patients with renal impairment. The present proposal seeks to evaluate BB3 PK and tolerance in patients with moderate but stable hepatic impairment. Successful completion of the proposed studies will enable us to evaluate the efficacy and safety of BB3 in larger Phase IIB studies in liver fibrosis or acute liver injury.