Subcutaneous Drug Development for Portal Hypertension Ascites

ABSTRACT: Approximately 2.2 million Americans suffer from liver cirrhosis [1, 2]. Approximately 60%
of cirrhosis patients will progress into advanced stage cirrhosis with ascites, an accumulation of fluid in the
peritoneal cavity, which is associated with a poor quality of life, increased risk of infection, and decreased
survival [4-8]. Ascites is treated with a salt restricted diet and pharmacologic therapy using diuretics,
however, 5% to 10% of these patients become refractory to medical therapy [7]. Half of patients who
develop refractory ascites due to advanced liver cirrhosis will die within a year without a liver transplant and
therefore expedited referral for liver transplantation is recommended. Temporary treatment while waiting
includes large volume paracentesis, transjugular intrahepatic portosystemic shunt (TIPS), and
peritoneovenous shunt surgical procedures. Complications from these procedures that can further increase
mortality include paracentesis-induced circulatory dysfunction (PICD), bacterial peritonitis, and chronic
hepatic encephalopathy from TIPS. Pharmacological therapies that can stop the progression or extend
survival and function as a therapeutic bridge to liver transplantation are thus desperately needed.
Terlipressin is an inactive pro-drug of Lysine-vasopressin (LVP, a V1a full agonist) that releases active LVP
slowly to minimize LVP spike that can cause ischemic side effect. In a tightly controlled dosing and
monitoring this V1a agonist can reduce portal vein pressure, restores hemodynamic balance, and is an
effective treatment for portal hypertension driven ascites. Terlipressin is better tolerated and has a far
better safety profile than human native vasopressin ([8-Arg] vasopressin). Terlipressin has been available
in Europe for the past twenty years and more recently in the US; it is one of the most cost-effective drugs
for treating bleeding varices and hepatorenal syndrome (HRS), with well documented improvement in
survival rates. Despite its good safety profile, the use of terlipressin is currently limited to the acute care
setting because the short half-life (reports vary from 8-50 min average) that necessitates administration by
IV bolus injection every 4-6h. We developed a new terlipressin derivative, PHIN-214, which slowly releases
V1a partial agonist into the blood, and to a much lesser extent under the skin. PHIN-214 is effective in
reducing portal pressure in a rat model of portal hypertension and can be administered subcutaneously as
a bolus once a day without causing skin necrosis (in animals and human patients). Along with a wider
therapeutic index than Terlipressin, PHIN-214 significantly increases glomerular filtration rate (GFR) on
Child’s Pugh A patients and highly anticipated to prevent progression of the disease to Hepatorenal
Syndrome (HRS). This product has the potential to be a significant market opportunity in the U.S.,
especially in an outpatient setting (which will reduce overall health care cost by eliminating cost of
hospitalization) for the treatment of refractory ascites from cirrhosis-induced portal hypertension ascites.
PHIN-214 demonstrated a substantially longer blood presence than terlipressin, without causing severe
vasoconstriction that can affect the heart. This proposal is intended to request additional funding to
produce more GMP materials and additional chronic or extended animal toxicology studies that are needed
to enable the upcoming Phase 2 efficacy and pivotal clinical trials.
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Grant Number: 5R44DK103553-06
NIH Institute/Center: NIH
Principal Investigator: Gerardo Castillo