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Subcutaneous Drug Development for Portal Hypertension Ascites

Award Number: R44DK103553
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/22/2014
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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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. PharmaIN Corp. Confidential Information


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $0 )
2026	2025	PHARMAIN CORPORATION	11812 N CREEK PKWY N STE 101	BOTHELL	WA	98011	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	6/4/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $2,638,464 )
2025	2025	PHARMAIN CORPORATION	11812 N CREEK PKWY N STE 101	BOTHELL	WA	98011	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	8/20/2025	NON-COMPETING CONTINUATION	$2,638,464
														Subtotal = $2,638,464

Issue Date FY: 2024 ( Subtotal = $2,145,275 )
2024	2024	PHARMAIN CORPORATION	11812 N CREEK PKWY N STE 101	BOTHELL	WA	98011	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	9/17/2024	COMPETING CONTINUATION	$2,145,275
2024	2022	PHARMAIN CORPORATION	11812 N CREEK PKWY N STE 101	BOTHELL	WA	98011	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/21/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,145,275

Issue Date FY: 2022 ( Subtotal = $982,292 )
2022	2022	PHARMAIN CORPORATION	11812 N CREEK PARKWAY N STE 101	BOTHELL	WA	98011	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	7/26/2022	NON-COMPETING CONTINUATION	$982,292
														Subtotal = $982,292

Issue Date FY: 2021 ( Subtotal = $992,469 )
2021	2021	PHARMAIN CORPORATION	11812 N CREEK PARKWAY N STE 101	BOTHELL	WA	98011	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	8/26/2021	COMPETING CONTINUATION	$0
2021	2021	PHARMAIN CORPORATION	11812 N CREEK PARKWAY N STE 101	BOTHELL	WA	98011	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	8/12/2021	COMPETING CONTINUATION	$992,469
														Subtotal = $992,469

Grand Total All Awards = $6,758,500

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Subcutaneous Drug Development for Portal Hypertension Ascites

Award Number: R44DK103553

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/22/2014

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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