Nonpeptide oral somatostatin agonists for congenital hyperinsulinemias

Project Summary Hyperinsulinemic hypoglycemia HH is one of the most frequent causes of persistent hypoglycemia in infants and can result in seizures developmental delays learning disabilities and even death The most severe form of HH is inherited and referred to as congenital hyperinsulinism CHI CHI largely results from mutations in key genes in the insulin secretion pathway in the islets of Langerhans in the pancreas Suspicion of CHI is confirmed by tests including the need to implement a high glucose infusion rate to maintain normal blood glucose levels Currently the only medical therapies used to treat CHI are used off label Typically diazoxide an insulin secretion inhibitor is tried first though it is often ineffective and has a side effect that causes abnormal and excessive hair growth over much of the body The peptide sst receptor agonist octreotide is also used off label for patients that are unresponsive to diazoxide or in conjunction with poor responders Its pharmacological profile sst andgt sst leads to a host of unwanted side effects including suppression of glucagon secretion which is detrimental to the CHI patientandapos s utmost need as well as inhibition of the growth hormone axis at the pituitary Despite their poor profiles these therapies are tried because the next line of treatment is typically a partial or full pancreatectomy Even when successful the result of this surgery is that the patient becomes diabetic and must actively manage glucose for the rest of their lives Therefore a significant unmet medical need exists for agents designed to specifically and effectively treat CHI Here we lay out our plan to develop orally available selective sst sst and or dual sst agonists for the treatment of infants and children with CHI and other hyperinsulinemic disorders Such a compound represents a major advance for infants with CHI and promises to provide specifically directed insulin control with the goal of preventing or delaying pancreatectomy without the excess of side effects that are carried along with current treatments Project Narrative Congenital hyperinsulinemia CHI is a severe endocrine disorder in infants in which the only treatment is often surgical pancreatectomy Currently available medical therapy is poor If successful this project will result in a novel drug candidate for the treatment of CHI with an improved safety and efficacy profile over existing options