Pulmonary Fibrosis is a diffuse interstitial lung disease characterized by chronic inflammation and progressive fibrosis of unknown etiology. Pulmonary fibrosis affects five million people worldwide and in the United States there are over 200,000 patients with pulmonary fibrosis. Of these more than 40,000 expire annually. Typically, patients are in their forties and fifties when diagnosed. Median survival from time of diagnosis is 5.5 years. Pulmonary fibrosis is associated with pronounced morbidity and mortality and responds poorly to currently available therapy. While steroids and other immunosuppressive agents serve as the standard treatment for pulmonary fibrosis, these agents have proved inadequate and have deleterious side effects. Recent studies have identified hepatocyte growth factor (HGF) as an antifibrogenic agent that protects against transforming growth factor (TGFbeta) mediated apoptotic effects on epithelial cells and extracellular matrix accumulation in liver, kidney and lung fibrosis in animal models. In order to overcome the shortcomings and expense of protein therapy, we have developed a small molecule mimetic of HGF activity that was rationally designed through a novel combination of phage display and molecular modeling technology. In vitro, our lead HGF mimetic, Ang1170, activates the HGF receptor, c-Met, and induces its biological functions including activation of endothelial and bronchial epithelial cell proliferation, without stimulating SMC/fibroblasts and suppresses TGF beta expression similar to HGF. In vivo, Ang1170 inhibits collagen synthesis and decreases the liver and kidney fibrosis. Our recent preliminary PHASE-I studies suggest that Ang1170 treatment decreases collagen content in bleomycin induced pulmonary fibrosis in vivo. Quantitative histological evaluation demonstrated that Ang1170 treated mouse lung sections have reduced interstitial fibrosis, alveolar apoptosis, and damaged tissue compared with the vehicle-treated group. In the proposed studies, we will further evaluate the protective effects of Ang1170 (via delayed treatment and oral route) on lung from lung fibrosis in three different pre- clinical animal models of lung fibrosis. The objective of this application is the evaluation of our lead small molecule compound, Ang1170 in clinically relevant models of lung fibrosis to develop sufficient data to successfully file an investigational new drug (IND) application to the FDA to perform clinical trials of our lead small molecule antifibrotic therapy for pulmonary fibrosis. ? ? Pulmonary fibrosis affects five million people worldwide and over 200,000 patients in the United States. Median survival from time of diagnosis is 5.5 years. The objective of this application is to evaluate a lead small-molecule drug candidate in clinically relevant models of lung fibrosis to develop sufficient data to successfully file an investigational new drug (IND) application to the FDA to perform clinical trials. ? ? ? ? ? ?
