Acute liver failure (ALF) constitutes a challenge to clinicians and scientists alike. 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. Consequently, the field is ripe for translational studies that identify and develop new therapeutic strategies that attenuate hepatocyte death, promote hepatic regeneration and improve outcome. In a best-case scenario, such therapeutics will accelerate liver regeneration and preclude the need for transplantation;in the most severe cases, they will serve as a """"""""hepatic bridge"""""""" until transplantation. Significant evidence suggests that scatter factor / hepatocyte growth factor (SF/HGF), exerts direct hepatoprotective effects and can potentially be used as a therapeutic in ALF. However, the feasibility of using this growth factor in the form of gene or protein therapy is compounded by numerous logistical issues. Low molecular weight compounds that mimic the activity of SF/HGF could overcome these logistical difficulties and provide effective therapy. Based on the 3-dimensional structure of the ATP-binding site of the SF/HGF receptor c-Met's tyrosine kinase domain and using a product discovery engine combining rational drug design with preclinical biology, we have identified SF/HGF-like small molecules centered around a phthalazin-1 (2H)- one scaffold. Ang 1170, the lead member within this class, activates the SF/HGF receptor c-Met and has recapitulated the bioactivity of SF/HGF in every assay tested to date. Proof-of-principle studies conducted under our Phase I program indicate that Ang 1170 activates the hepatocyte SF/HGF/c-Met pathway, attenuates oxidative stress-induced hepatocyte death and accelerates regeneration in partially hepatectomized marginal livers. In a mammalian model of ALF, Ang 1170 systemic pretreatment reduces mortality, and attenuates hepatic injury. Of potentially significant clinical relevance is our preliminary findings that delayed treatment with Ang 1170, attenuates hepatocyte death, stimulates liver regeneration, decreases mortality and attenuates liver dysfunction in ALF. Importantly, Ang 1170 is therapeutic in the failing marginal liver. Pilot safety studies suggest that Ang 1170 treatment is safe and well-tolerated. Supported by separate funding, a formal and comprehensive set of regulatory studies profiling the genotoxicology, toxicology and safety pharmacology of Ang 1170 is underway. The present Phase II application, designed to complete the preclinical characterization of Ang 1170, will explore fully its therapeutic efficacy in preclinical models of ALF;a panel of acute, in vivo repeat dose, dose-escalating safety studies in two species will complement these efficacy studies. Successful completion of the proposed regulatory studies will support an Investigational New Drug application to Food and Drug Administration;approval of this application will allow the first clinical studies of our SF/HGF mimetic, Ang 1170.
Acute liver failure remains a significant cause of morbidity and mortality. A small molecule hepatocyte growth factor mimetic that is hepatoprotective and hepatoregenerative is of tremendous clinical benefit.
