Use of F-652 in Patients With Alcoholic Hepatitis

Study Overview
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Brief Summary
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Alcoholic hepatitis is a syndrome of progressive inflammatory liver injury associated with long-term heavy intake of ethanol. The pathogenesis is not completely understood. Patients who are severely affected present with subacute onset of fever, hepatomegaly, leukocytosis, marked impairment of liver function (e.g., jaundice, coagulopathy), and manifestations of portal hypertension (e.g., ascites, hepatic encephalopathy, variceal hemorrhage). However, milder forms of alcoholic hepatitis often do not cause any symptoms. Alcoholic hepatitis usually persists and progresses to cirrhosis if heavy alcohol use continues. If alcohol use ceases, alcoholic hepatitis resolves slowly over weeks to months, sometimes without permanent sequelae but often with residual cirrhosis. F-652 is a recombinant fusion protein containing human interleukin 22 (IL-22) and human Immunoglobulin G2 (IgG2)-Fc produced in CHO cells in serum-free culture. F-652 under development is intended to treat patients with graft vs host disease (GvHD) after bone marrow transplantation, and acute alcoholic hepatitis (AAH), a severe form of alcoholic liver disease (ALD). Both GvHD and AAH are diseases with unmet medical need. The current investigational new drug (IND) application is to conduct a phase Ia clinical study in GvHD patients to evaluate the safety and pharmacokinetic profile, and biomarkers of F-652 treatment by intravenous infusion (IV). IL-22 is a member of the IL-10 family of cytokines which control bacterial infection, homeostasis, and tissue repair. IL-22 may be used to treat patients with ALD because of its antioxidant, anti-apoptotic, anti-steatotic, anti-microbial, and proliferative effect that have been demonstrated in various experimental systems.

Detailed Description
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IL-22 is a member of the IL-10 family of cytokines which control bacterial infection, homeostasis, and tissue repair. IL-22 may be used to treat patients with ALD because of its antioxidant, anti-apoptotic, anti-steatotic, anti-microbial, and proliferative effect that have been demonstrated in various experimental systems. The sponsor has developed F-652, a recombinant human IL-22 IgG2 Fc fusion protein produced in serum-free culture of Chinese Hamster Ovary (CHO) cells. F-652 is able to protect tissue from damage and enhance tissue repair during the inflammation process and infection by activation of STAT3 mediated by the interleukin-22 receptor subunit 1 (IL-22R1) expressed on epithelial cells such as hepatocytes.

Official Title
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An Open-Label, Cohort Dose Escalation Study to Assess the Safety and Efficacy of F-652 in Patients With Alcoholic Hepatitis

Conditions
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Alcoholic Hepatitis

Intervention / Treatment
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* Drug: F-652


Participation Criteria
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Eligibility Criteria
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3.1 Inclusion Criteria To participate in this study, patients must meet all of the following criteria: Able to provide written informed consent (either from patient or patient's legally acceptable representative) Male or female patients 21 years of age or older Patients with alcoholic hepatitis defined as: History of heavy alcohol abuse use: >40 g/day in females and >60 g/day in males for a minimum period of 6 months Consumed alcohol within 6 weeks of entry into the study Serum bilirubin > 3mg/dL AND AST >ALT, but less than 500 U/L MELD score between 11-28 Liver biopsy will be carried out to confirm diagnosis in all patients except those who meet criteria a-c and in whom other causes of liver disease have been excluded (viral, drug, autoimmune etc). Women of child-bearing potential must utilize appropriate birth control. *Patients on steroids and/or pentoxifylline will not be excluded from the study. Exclusion Criteria Other or concomitant cause of liver disease as a result of: Autoimmune liver disease Wilson disease Vascular liver disease Drug induced liver disease Note: Concurrent viral hepatitis is not excluded. Co-infection with human immunodeficiency virus (HIV) Any active malignancies other than curatively treated skin cancer (basal cell or squamous cell carcinomas) or any other malignancy diagnosed within the last five years. Active tuberculosis on chest x-ray at study entry Significant systemic or major illness other than liver disease, including coronary artery disease, cerebrovascular disease, pulmonary disease, renal failure, serious psychiatric disease, that, in the opinion of the Investigator would preclude the patient from participating in and completing the study Patients requiring the use of vasopressors or inotropic support Liver biopsy, if carried out, showing findings not compatible with alcoholic hepatitis Any patient that has received any investigational drug or device within 30 days of dosing or who is scheduled to receive another investigational drug or device in the course of the study Note: Investigational drug includes any drug that is used off-label. If female, known pregnancy, or has a positive urine or serum pregnancy test, or lactating/breastfeeding Serum creatinine >2.5 mg/dL

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: A phase 2 dose escalating study was carried out. F-652 (10, 30 or 45 μg/kg) administered on day 1 and 7 was tested in 3 patients each with moderate (MELD scores: 11-20) and severe AH (MELD scores: 21-28).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: F-652<br>Participants will receive 10 μg/kg, 30 μg/kg or 45 μg/kg of F-652 on Day 1 and Day 7 via slow intravenous infusion. Three patients with MELD 11-20 will receive 10 μg/kg of F-652. Pharmacokinetic testing will be completed on these subjects. If evaluations demonstrate safety and efficacy signals, the next 3 patients will receive 30 μg/kg. If pharmacokinetic testing demonstrates safety and efficacy signals, the next 3 patients will receive 45 μg/kg. After demonstrating absence of side effects in this group, patients in MELD 21-28 will follow the same dose escalation regiment as the MELD 11-20 group. | Drug: F-652<br>* Participants will receive 10 μg/kg, 30 μg/kg or 45 μg/kg of F-652 on Day 1 and Day 7 via slow intravenous infusion. Three patients will receive 10 μg/kg of F-652. Pharmacokinetic testing will be completed on these subjects. If evaluations demonstrate safety and efficacy signals, the next 3 patients will receive 30 μg/kg. If pharmacokinetic testing demonstrates safety and efficacy signals, the next 3 patients will receive 45 μg/kg.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Subjects With Unexpected Serious Adverse Events. | The count of subjects who experience serious adverse events | From day 1 up to 42 days following administration of last dose of study drug |