FibroGen, Inc. today announced initiation of a phase 2 study to compare the efficacy of FG-3019, a human monoclonal antibody against connective tissue growth factor (CTGF), with placebo in reversing liver fibrosis (scarring of the liver) due to chronic infection with hepatitis B virus (HBV). FG-3019 will be studied on a background of the antiviral therapy entecavir. The study is being conducted in Hong Kong where approximately 10% of the population has chronic HBV and is consequently at increased risk of progression to liver failure and hepatocellular carcinoma (HCC).
“By directly removing the fibrotic insult to the liver driven by CTGF, FG-3019 may accelerate the regression of liver fibrosis and improve outcomes for chronically infected HBV patients, particularly those who have advanced liver fibrosis and cirrhosis.”
CTGF has been demonstrated to be a central mediator of fibrosis. In this study, the ability of FG-3019 to reverse liver fibrosis will be evaluated by comparing change in Ishak fibrosis scores (as assessed by liver biopsy) from baseline to the end of the 48-week treatment period with FG-3019 or placebo. In HBV-infected patients, severe fibrosis is associated with decline in liver function, progression to cirrhosis and development of HCC.Cirrhosis is associated with HCC in 60-80% of all cases, and the incidence rates of HCC are higher in HBV-infected patients with underlying condition of cirrhosis compared to those without underlying cirrhosis.
The study is a randomized, double-blind, placebo-controlled study. Up to 144 patients with chronic HBV infection and moderate to severe liver fibrosis (Ishak score 2-5) who have not previously received antiviral therapy will be enrolled in the first part of the study. Two-thirds of all patients will receive FG-3019, and one-third will receive placebo as an intravenous infusion every 3 weeks for a total of 48 weeks of treatment. Following the first 48 weeks of the study, patients who had been assigned to placebo will be eligible to receive FG-3019 for 48 weeks in an open-label format. Based on interim analyses of data, the study may also be expanded to include up to a total of 228 patients. FibroGen will provide entecavir antiviral therapy to all patients for the entire 2-year duration of the study.
Antiviral therapy aims at sustained suppression of viral replication and remission of liver disease, and development of new antiviral therapies has allowed improved control of the virus and greater patient responder rates. The HBV DNA polymerase inhibitor entecavir has recently evolved as first line treatment predominantly because the development of virus strains resistant to entecavir is low compared to other antiviral agents. Despite these advances in antiviral therapy, improvement of liver architecture and reversal of fibrosis are slow, and only approximately 35%-40% of entecavir patients show at least a 1-point improvement in Ishak fibrosis score after 48 weeks of therapy.
"While liver regeneration is possible with long-term antiviral therapy, additional therapeutic options that directly address fibrosis and allow more rapid normal regeneration to reduce the risk of developing life-threatening liver complications are needed," said Ching-Lung Lai, MD, Principal Investigator of the study and Professor of Medicine & Hepatology in the University Department of Medicine at Queen Mary Hospital in Hong Kong. "By directly removing the fibrotic insult to the liver driven by CTGF, FG-3019 may accelerate the regression of liver fibrosis and improve outcomes for chronically infected HBV patients, particularly those who have advanced liver fibrosis and cirrhosis."
Anti-CTGF and Reversal of Liver Fibrosis
CTGF is expressed only at low levels in healthy adult liver; however, elevated levels of CTGF have been observed in fibrotic lesions of patients with various chronic liver diseases, and plasma CTGF levels are also elevated in patients with chronic liver fibrosis. Nonclinical studies have shown that genetic blockade of CTGF can prevent and reverse liver fibrosis, and FG-3019 reversed the fibrotic process in a model of radiation-induced lung fibrosis.
"There is a significant unmet medical need among patients who are non-responsive to antiviral therapy or who, despite receiving antiviral therapy, still have advanced liver fibrosis," said Frank Valone, MD, Chief Medical Officer of FibroGen. "We believe the potential benefit of anti-fibrotic therapy in these patients would be to prevent liver disease from progressing to the point of liver failure and to reduce the risk of developing liver cancer."