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FibroGen starts liver fibrosis study
  San Francisco Business Times - by Ron Leuty
Date: Thursday, October 14, 2010
FibroGen Inc. started a mid-stage study of a treatment aimed at reversing scarring of the liver from the hepatitis B virus.
The San Francisco biotech company said the study of its human monoclonal antibody, FT-3019, will be conducted in Hong Kong, where about 10 percent of the population has chronic hepatitis B.
Chronic hepatitis B, which is more prevalent in Asian populations, puts patients more at risk of liver failure and liver cancer.
FibroGen has been excited about the drug, as CEO Tom Neff told me last month, because it could reverse fibrosis that leads to scarring of the liver, lungs and arteries. That means it could turn hard-as-stone liver, for example, back into regular tissue.
The connective tissue growth factor protein at the core of the tissue scarring was discovered by FibroGen and an academic partner. CTGF also may be a factor in pancreatic cancer.
FibroGen's Hong Kong study will compare change in fibrosis through the end of 48 weeks of treatment with FG-3019 versus placebo. It will include up to 144 patients who have not previously received antiviral therapy, with two-thirds of the patients receiving FG-3019 every three weeks.
Anti-CTGF Therapy
Development of Anti-CTGF Monoclonal Antibodies

FibroGen is developing fully human monoclonal antibodies to block the pathological activity of CTGF for the treatment of chronic kidney disease (CKD), fibrotic diseases, and certain metastatic cancers. FG-3019 is FibroGen's lead clinical candidate.
Anticipated clinical benefits of directly blocking CTGF activity include:
* Slowing the decline of kidney function in chronic kidney diseases: FibroGen believes that blocking CTGF, a final common pathway factor for progression of kidney disease, will represent a first-in-class therapy that may provide a critical renoprotective benefit resulting in decreased proteinuria and slower decline of renal function. Research demonstrates that an anti-CTGF therapeutic approach has the potential to address multiple pathogenic processes involved in chronic kidney disease: fibrosis,1-3 proteinuria,4-6 hyperfiltration and hypertrophy,6 myofibroblast differentiation and microvascular leakage.7 Available clinical data also suggests that FG-3019 may have a rapid effect on treating nephrotic diseases (kidney fibrotic diseases characterized by a very high level of proteinuria), such as FSGS and IgA nephropathy.8
* Reducing cardiovascular risk and slowing progression of chronic heart failure (CHF): FibroGen's nonclinical research has demonstrated the potential for FG-3019 to inhibit vascular remodeling and potentially improve cardiac outcomes in diabetic and non-diabetic settings. In a model of type 1 diabetes, treatment with FG-3019 prevented arterial stiffening, reversed vascular stiffness and microvascular leakage, improved cardiac function, and normalized hypertension.7 Decreased arterial stiffness can reduce the workload on the heart and may delay or prevent progression of CHF, a progressive condition associated with tissue remodeling. In a model of hypertension, FG-3019 prevented vascular fibrosis, suggesting the potential for FG-3019 to decrease cardiovascular risk in non-diabetic settings.
* Preserving organ function in fibrotic diseases including liver and lung fibrosis: Liver and lung fibrosis are life-threatening diseases for which there are no current therapies. Nonclincal research suggests that blocking CTGF activity reduces liver fibrosis and preserves liver function.9 FibroGen has also shown that FG-3019 reduces collagen deposition in nonclinical models of liver, lung and kidney fibrosis and neonatal systemic scleroderma. FibroGen believes that reducing fibrosis using FG-3019 will delay and/or prevent disease progression and organ failure.
* Reducing tumor growth and metastases in certain cancers, such as pancreatic cancer: FG-3019 represents a unique approach to the treatment of pancreatic cancer by preventing the metastatic spread of tumor cells through the disruption of multiple pro-tumor pathways. Results from nonclinical models of pancreatic cancer have shown that treatment with FG-3019 reduces tumor growth and metastasis.10,11 FG-3019 may prove to have similar effectiveness in other cancers in which CTGF is implicated, such as glioblastoma and acute lymphoblastic leukemia (ALL).
Clinical Development
FibroGen has completed a phase 1 study of FG-3019 in patients with diabetes and microalbuminuria8 and has completed the treatment phase of a similar phase 1 study of FG-3019 in patients with diabetes and more severe macroalbuminuria. A phase 2 study of FG-3019 in patients with type 2 diabetes and advanced kidney disease is underway. Another phase 1 study is evaluating FG-3019 in patients with pancreatic cancer. A phase 1 study in patients with idiopathic pulmonary fibrosis was also completed. To date, FG-3019 has been found well tolerated in these studies.
Read more about FibroGen's anti-CTGF development programs for Chronic Kidney Disease, Fibrotic Disease and Cancer.
1. Yokoi, H. et al 2004. Reduction in connective tissue growth factor by antisense treatment ameliorates renal tubulointerstitial fibrosis. J. Am. Soc. Nephrol. 15:1430-1440.
2. Okada, H. et al 2005. Connective tissue growth factor expressed in tubular epithelium plays a pivotal role in renal fibrogenesis. J. Am. Soc. Nephrol. 16:133-143.
3. Okada, H. et al. 2006. Dexamethasone induces connective tissue growth factor expression in renal tubular epithelial cells in a mouse strain-specific manner. Am. J. Pathol. 168:737-747.
4. Guha M, et al. (2007) Specific down-regulation of connective tissue growth factor attenuates progression of nephropathy in mouse models of type 1 and type 2 diabetes. FASEB J. 21:3355-3368.
5. Yokoi H, et al. (2008) Overexpression of connective tissue growth factor in podocytes worsens diabetic nephropathy in mice. Kidney International 73:446-455.
6. Flyvbjerg A, et al. (2004) Long-term effects of a neutralizing connective tissue growth factor (CTGF)-antibody in obese type 2 diabetic mice. J Am Soc Nephrol 15:261A.
7. Langsetmo I, et al. Anti-CTGF human antibody FG-3019 prevents and reverses diabetes-induced cardiovascular complications in streptozotocin (STZ) treated rats. Diabetes¨:, Vol. 55, Suppl.1, 2006; A122.
8. Schwartz S, et al. Phase 1 study of FG-3019, an anti-CTGF monoclonal antibody, in type 1/2 diabetes mellitus with microalbuminuria. Diabetes¨:, Vol. 56, Suppl.1, 2007; A151.
9. Li G, et al. (2006) Inhibition of connective tissue growth factor by siRNA prevents liver fibrosis in rats. J Gene Med 8(7):889-900.
10. Dornhofer N, et al. (2006) Connective tissue growth factor-specific monoclonal antibody therapy inhibits pancreatic tumor growth and metastasis. Cancer Res 66: (11):5816-5827.
11. Aikawa T, et al. (2006) Connective tissue growth factor-specific antibody attenuates tumor growth, metastasis, and angiogenesis in an orthotopic mouse model of pancreatic cancer. Molecular Cancer Therapeutics 5: (5):1108-1116.
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