Chronic Liver Disease
Liver fibrosis is a scarring process initiated in response to chronic liver disease (CLD) caused by continuous and repeated insults to the liver. The major causes of CLD are viral hepatitis B and C, alcoholic cirrhosis and non-alcoholic fatty liver disease (NAFLD). The symptoms of early-stage CLD differ according to the type of underlying damage and may be clinically silent, or can include acute inflammation, weakness and jaundice. Later stages of CLD are characterized by extensive remodeling of the liver architecture and chronic organ failure, regardless of the underlying disease.
- Hepatitis C: Chronic hepatitis C infection can cause cirrhosis (irreversible, advanced scarring of the liver), liver failure, and liver cancer. While the development of new vaccines and anti-viral therapies holds promise for preventing and treating chronic hepatitis C, a significant portion of infected patients (approximately 500,000 in the US) do not respond to anti-viral therapy and are therefore at risk of progression to cirrhosis.
- NAFLD and NASH: NAFLD refers to a wide range of different stages of CLD that are commonly associated with obesity, from accumulation of fat by the liver (steatosis), to nonalcoholic steatohepatitis (NASH), to cirrhosis (irreversible, advanced scarring of the liver). Recent studies suggest that NASH results in fibrosis in up to 40% of patients and cirrhosis in 5-10% and a progression rate of 20% over a decade. In light of the growing obesity epidemic worldwide, approximately 12.2 million NASH patients (estimated population that will develop cirrhosis over the next decade) could benefit from anti-fibrotic therapy.
- Primary Sclerosing Cholangitis (PSC): PSC is a rare disease with a prevalence of approximately 30,000 adults in the US. PSC is characterized by fibrosing inflammatory destruction of the bile ducts inside and outside the liver, leading to bile stasis, liver fibrosis, and ultimately to cirrhosis, and end-stage liver disease. In addition, cholangiocarcinoma develops in up to 23% of patients and can occur relatively early and before onset of cirrhosis. Currently, liver transplant is the only option available to extend life; thus, early intervention to prevent liver damage represents a significant unmet medical need.
Rationale for Anti-CTGF Therapy
The rationale for anti-CTGF therapy in CLD is based on several factors. Elevated levels of CTGF have been observed in fibrotic lesions of patients with various CLDs, including viral and alcoholic hepatitis, NASH, biliary atresia, and idiopathic portal hypertension. Plasma CTGF levels are also elevated in patients with chronic liver fibrosis. In addition, published models of hepatic fibrosis show that blocking CTGF correlates with reduced collagen deposition in the fibrotic lesions, reduced hepatic stellate cell activation, and improved tissue morphology.
Recent research has also elucidated the inhibitory effect of CTGF on bone morphogenic protein-7 (BMP-7), an important antifibrotic and proregenerative repair factor. Hence, there is some possibility that anti-CTGF therapy may eliminate CTGF and allow BMP-7 to be made locally and thus encourage reversal of the disease process. As the liver is capable of regeneration, the impact of reducing CTGF activity on overall function may be significant.