PHARMAIN CORPORATION — Department of Health and Human Services SBIR Phase I: 300

Description

DESCRIPTION provided by applicant The prevalence of all types of ascites irrespective of the cause is in with of these due to cirrhosis Ascites is treated with a salt restricted diet and pharmacologic therapy using diuretics However in to of patients with ascites the ascites becomes refractory to medical therapy Half of patients who develop refractory ascites due to advanced liver cirrhosis will die within a year without a liver transplan and therefore expedited referral for liver transplantation is recommended Temporary treatment while waiting includes large volume paracentesis transjugular intrahepatic portasystemic shunt TIPS and peritoneovenous shunt surgical procedures Complications from these procedures that can further increase mortality include paracentesis induced circulatory dysfunction PICD and chronic hepatic encephalopathy from TIPS Pharmacological therapies that can stop the progression or extend survival and act as a therapeutic bridge to liver transplantation are thus desperately needed Terlipressin tri glycyl lys vasopressin is a synthetic peptide drug that reduces portal vein pressure restores hemodynamic balance and is an effective treatment for portal hypertension ascites This prodrug is slowly converted to the vasoactive agent lys vasopressin in the blood it is well tolerated and has a far better safety profile than human nativ vasopressin Arg vasopressin Intravenous terlipressin has been available in Europe for the past twenty years and it is one of the most cost effective and economical drugs for treating bleeding varies and hepatorenal syndrome HRS with improvement in survival rates that is well documented Despite its good safety profile the use of terlipressin is currently limited to the acute care setting because the short half life min necessitates administration by IV bolus injection every h We believe that a formulation of a new terlipressin derivative that can be administered once daily ideally subcutaneously and would have a significant market opportunity in the U S in the outpatient setting which will reduce overall health care cost for the treatment of refractory ascites from cirrhosis induced portal hypertension We developed a new long acting terlipressin LAT based on a proprietary drug delivery technology invented by the PI that gives sustained release of modified terlipressin LAT demonstrated a substantially longer half life than unmodified terlipressin peptide hours vs hours respectively and was observed to maintain measurable blood concentrations for more than hours compared to hours for a rapid clearing of terlipressin This study will optimize the formulation determin pharmacokinetics of various metabolites to determine the optimum dose needed and test the efficacy of the formulation for the treatment of cirrhosis induced ascites in rat PUBLIC HEALTH RELEVANCE Half of patients who develop refractory ascites due to advanced liver cirrhosis will die within a year without a liver transplant This proposal will develop the desperately needed pharmacological therapies that can stop the progression or extend survival and act as a therapeutic bridge to liver transplantation for these patients The proposed study involves optimization of an advanced technology formulation of a new terlipressin derivative that can be delivered subcutaneously in an outpatient setting determine its pharmacokinetics and test its efficacy in cirrhosis induced ascites in rat