Research Project
8781386
DESCRIPTION (provided by applicant): Chronic Pancreatitis (CP) is characterized by continuous or recurrent inflammation of the pancreas that leads to permanent destruction of the pancreas resulting in exocrine and endocrine insufficiency. CP is a common disorder associated with significant morbidity and mortality with an incidence of 8.2 and a prevalence of 27.4 per 100 000 population. The etiology of CP is complex and about 70% of cases are due to excessive alcohol consumption. Alcoholic chronic pancreatitis is one of the more painful and serious consequences of alcohol, and the role of alcohol as a predisposing factor in severe pancreatitis is underappreciated. The most critical step for development of chronic pancreatitis is activation of pancreatic stellate cells (PSCs) and increased extracellular matrix (ECM) deposition that leads to fibrosis. Several growth factors, cytokines and alcohol can induce PSCs activation. Pancreatic fibrosis is a constant histopathological feature of chronic pancreatitis of all etiologis. In a recent survey it was found that approximately 17.6 million adult Americans are alcoholic. Alcohol-related problems cost society approximately $185 billion per year11. The direct medical cost of hospitalization for pancreatitis is estimated to be $2.2 billion. Thus, chronic pancreatiti is a major burden for both the patient and health care system. Any intervention that can reduce the length of stay and severity of the disease is likely to be cost-effective. Hence there is an unmet medical need CP including alcoholic chronic pancreatitis. There is no effective therapeutic strategy for CP apart from dietetic and analgesic concepts, endoscopy and pancreatic surgery. There is an urgent need for therapies that could mitigate chronic pancreatic disease progression. Recent studies indicate that growth factors and angiogenic activity are increased in chronic pancreatitis. Platelet derived growth factor (PDGF) and vascular endothelial cell growth factor (VEGF) was strongly expressed in pancreatic cells in CP patients. From review of literature, we concluded that inhibiting both PDGFR and VEGFR (KDR) could be a novel therapeutic strategy to benefit patients with CP. Using a product discovery engine comprising 3-D molecular modeling and preclinical biology, rational drug design, medicinal chemistry and in vitro biology, Angion Biomedica has synthesized an orally bioavailable, small molecule PDGFR+KDR inhibitor, ANG3070. This novel, dual kinase inhibitor has shown efficacy in animal models of chronic injury and fibrosis including pancreatitis as shown in our preliminary studies. We will conduct further preclinical studies with the ultimate goal of advancing our novel therapeutic to clinical trials for CP including alcoholic pancreatitis patients.
