# Subcutaneous Drug Development for Portal Hypertension Ascites

> **NIH NIH R44** · PHARMAIN CORPORATION · 2022 · $982,292

## Abstract

ABSTRACT: The prevalence of all types of ascites, irrespective of the cause, is 41.7 in 100,000 with
80% of these due to cirrhosis. Ascites is treated with a salt restricted diet and pharmacologic therapy using
diuretics. However, in 5% to 10% of patients with 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
transplant 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 [8-lys]
vasopressin, is an inactive pro-drug of Lysine-vasopressin (LVP) that releases active LVP slowly to
minimize LVP spike that can cause ischemic side effect. LVP reduces portal vein pressure, restores
hemodynamic balance, and is an effective treatment for portal hypertension ascites. Because of slow LVP
release, terlipressin is well tolerated and has a far better safety profile than human native vasopressin ([8-
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 varices 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 (26
min) that necessitates administration by IV bolus injection every 4-6h. We developed a new terlipressin
derivative (dTer) that has much slower LVP release and found to be effective rat model of cirrhosis induced
portal hypertension ascites when administered subcutaneously as once-daily bolus. This product can have
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. This product (dTer) provides sustained release of active LVP and
demonstrated a substantially longer blood presence with lower LVP Cmax (eliminating ischemic side effect)
than terlipressin. This proposal is intended to collect IND enabling data package for submission to the FDA
to begin clinical trial. We already secured an orphan drug status for the use of dTer in patient with cirrhosis
induced ascites.
PharmaIN Corp. Confidential Information

## Key facts

- **NIH application ID:** 10469005
- **Project number:** 5R44DK103553-04
- **Recipient organization:** PHARMAIN CORPORATION
- **Principal Investigator:** Gerardo M. Castillo
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $982,292
- **Award type:** 5
- **Project period:** 2014-09-22 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10469005

## Citation

> US National Institutes of Health, RePORTER application 10469005, Subcutaneous Drug Development for Portal Hypertension Ascites (5R44DK103553-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10469005. Licensed CC0.

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