Diabetes is a disease of insulin deficiency associated with hyperglycemia (high blood glucose). Hypertension (high blood pressure) is a common coexisting factor. Both factors place people with diabetes at high risk for developing long-term complications including diabetic nephropathy, which causes a progressive decline over many years in the ability of the kidneys to filter blood and produce urine. Diabetic nephropathy is the leading cause of end-stage renal disease (ESRD), which requires dialysis or transplant.

Unmet medical need
In the United States, the Center for Disease Control estimates (as of the end of calendar year 2002) that there are 13 million diagnosed diabetics, and another 5.2 million undiagnosed patients. The sum total of 18.2 million diabetics represents 6.3% of the total population. The number of new cases of diabetes continues to accelerate, increasing from 847,000 in 1997 to 1.3 million in 2002, an increase of 47% (or an 8% compound annual growth rate) over the most recently reported five-year period. Total U.S. diabetic patients are projected to exceed 30 million by 2030.

The American Diabetes Association estimates that 20-30% of people with type 1 and type 2 diabetes will develop evidence of overt nephropathy, an advanced stage of the disease marked by proteinuria (the presence of proteins in the urine). After the onset of proteinuria, over 75% of type 1 diabetics and 20% of type 2 diabetics progress to ESRD within 20 years. The discrepancy may be explained by the fact that patients with type 2 diabetes have a greater risk of dying from coronary artery disease than from kidney failure and therefore do not progress to ESRD. Nonetheless, because type 2 diabetes accounts for up to 95% of all diabetes cases, over half of the diabetic patients starting dialysis are type 2. After the start of dialysis, the mortality rate for people with diabetic nephropathy is approximately 38% within two years, and nearly 73% die within 5-years.

Current management of diabetic nephropathy aims at controlling hyperglycemia and hypertension. Strict control of the former is difficult to achieve in practice, and anti-hypertensive drugs, such as angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) have been shown to delay progression to ESRD by only approximately one to two years in clinical studies conducted in type 2 diabetic patients. These factors dictate a significant need for novel approaches to treat diabetic nephropathy and to prevent ESRD.

Natural course of diabetic nephropathy
During the initial stages of diabetic nephropathy, hyperglycemia and hypertension damage the main structures of the kidney causing hyperfiltration, hypertrophy (increased kidney weight) and microalbuminuria, or the presence of low but abnormal levels of proteins (mainly albumin) in the urine. As kidney disease progresses, proteinuria (macroalbuminuria or overt nephropathy) develops as a result of increased permeability of the glomeruli (filtering units), and the excessive production and build up of extracellular matrix components leads to pathological scarring or chronic fibrosis. Fibrosis is a major factor in the late-stage progression of diabetic nephropathy, and, without specific interventions, causes a decline in glomerular filtration rate and ultimately leads to end-stage renal disease ESRD.

CTGF mediates early- and late-stage damage in diabetic nephropathy
Connective tissue growth factor (CTGF) is barely detectable in normal kidneys but increases in kidney disease. Levels of CTGF track the progression of kidney disease in type 1 and type 2 diabetes, increasing in magnitude as proteinuria worsens. A growing body of scientific evidence further suggests an active role of CTGF in early- and late-stage pathological aspects of diabetic nephropathy including the mediation of damage resulting from hyperglycemia and hypertension, and leading to proteinuria and fibrosis.

In early stage kidney disease, CTGF is directly upregulated by pathogenic conditions such as high glucose and static pressure. CTGF is also upregulated by factors induced by hyperglycemia and hypertension including advanced glycation end products (AGE), vascular endothelial growth factor (VEGF), and angiotensin II. Insulin-like growth factor-1, also stimulated by hyperglycemia, interacts with CTGF to induce scarring. CTGF also causes mesangial cell expansion, which leads to kidney hypertrophy. CTGF continues to play a key role in mediating the structural damage caused by proteinuria and in accelerating progression to ESRD by acting as a downstream mediator of the chronic fibrotic effects of transforming growth factor-beta (TGF-beta).

Anti-CTGF therapy: new approach to treating diabetic nephropathy
FibroGen believes that effective blockade of CTGF will be essential in preventing ESRD or further delaying time to progression. FibroGen expects the therapeutic benefit of anti-CTGF therapy in diabetic nephropathy would be to extend life and the time to dialysis by reducing early-stage pathologies related to hyperglycemia and hypertension, including hyperfiltration and kidney hypertrophy, and by preventing the development of proteinuria and chronic fibrosis. In addition, administration of anti-CTGF therapy during the early stages of diabetic nephropathy may help prevent the onset of, or reduce the severity of, cardiovascular diseases and retinopathy, which frequently accompany progression to ESRD. The Company has initiated a Phase 1b study of FG-3019, FibroGen's lead anti-CTGF therapeutic antibody, in patients with diabetic nephropathy.

More information about FG-3019 can be found on the Products in Development section of this Web site.