Phase I Clinical Study Using an Antifibrotic Drug

DESCRIPTION (provided by applicant): Liver fibrosis, a disease affecting tens of millions of people worldwide, is the liver scarring response to chronic injury from excessive alcohol use, virus infection (hepatitis B and C), 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. Hepatic growth factor (HGF), also known as scatter factor (SF), has been shown to be efficacious in reducing liver fibrosis. The feasibility of 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 HGF in every assay tested to date. Particularly, BB3 possesses cell protective, anti-fibrotic, and regenerative activities and shows efficacy in reducing liver fibrosis. The overall objective of our program is to advance BB3 to the clinic as a first-in-class antifibrotic for liver fibrosis. From a clinical perspective, a Phase I safety and pharmacokinetic (PK) trial of intravenously administered BB3 has been completed successfully in healthy volunteers and BB3 was found to be well tolerated. In addition, a clinical study of intravenously administered BB3 for safety and PK in renal dialysis patients has been completed. While intravenous BB3 is being developed for acute indications, we are also developing oral BB3 for chronic indications. In this fast-track SBIR grant application, we propose to conduct a Phase 1 clinical study evaluating safety and PK of BB3 administered orally in healthy volunteers. PUBLIC HEALTH RELEVANCE: A small-molecule, hepatically protective and anti-fibrotic agent has significant clinical potential against both liver fibrosis.