Overview
This single and multiple ascending dose (SAD and MAD) study evaluates PHIN-214, being studied to determine the safety, tolerability, and pharmacokinetics, and establish the maximum tolerated dose of this compound in patients with Child Pugh A and B Cirrhosis.
Description
Terlipressin has been shown to reduce portal hypertension, improve renal function, and induce natriuresis in cirrhotic patients with ascites without hepatorenal syndrome (HRS). It is approved in Europe for the treatment of bleeding esophageal varices and HRS type 1 and is usually administered as an IV bolus.
This study is an open label, First in Human study of PHIN-214. PHIN-214 is a terlipressin derivative administered subcutaneously. It is a partial V1a agonist which is designed to reduce splanchnic blood pooling and portal hypertension. A resultant increase in systemic pressure and renal arterial pressure may increase kidney perfusion and creatinine clearance. As a partial V1a agonist that traffics into the bloodstream from a subcutaneous depot, this derivative is designed to be gentler than terlipressin and has been well tolerated at the injection site, to date.
This study will evaluate the use of PHIN-214 administered at various dosing levels to establish the maximum tolerated dose in patients with Child Pugh A and B Cirrhosis.
Eligibility
Inclusion Criteria:
- Body mass index within the range 18 to 40 kg/m2 (inclusive) at screening.
- Females must be non-pregnant, non-lactating or of non-childbearing potential or using highly efficient contraception for the full duration of the study.
- Cirrhosis based on histology or a combination of clinical, radiological, or biochemical and classified as Child-Pugh A or B.
Exclusion Criteria:
- Significant abnormalities in medical history or on physical examination, including: respiratory disease requiring therapy or history of respiratory failure, cardiovascular disease or hypertension, electrocardiogram abnormalities or history of significant EKG abnormalities.
- History of diabetes insipidus, syndrome of inappropriate antidiuretic hormone secretion, or any other disorder associated with fluid or sodium imbalance.
- Significant kidney disease
- Estimated glomerular filtration rate (eGFR by CKD-Epi) <60 ml/min/1.73 m2 or Cr >2.0 mg/dL.
- Hepatic encephalopathy > grade 2 in the previous 3 months. Stable drug treatment for HE is not exclusionary.
- Recipient of a transjugular intrahepatic portosystemic shunt (TIPS).
- Known positive HIV serology confirmed by HIV viral load.
- Subjects with acute infections, including acute viral hepatitis are to be excluded. Subjects with chronic hepatitis B are eligible if treatment regimen is stable ≥ 3 months prior to study inclusion.