Lung & Other Fibrosis

FibroGen is evaluating potential development of FG-3019, a fully human monoclonal antibody against CTGF, for treatment of the following rare diseases for which there are currently no effective therapies.

Idiopathic pulmonary fibrosis (IPF)

IPF is a debilitating and life-threatening lung disease characterized by a progressive scarring of the lungs that hinders oxygen uptake. The cause of IPF is not known. As scarring progresses, patients with IPF experience shortness of breath and difficulty with performing routine functions, such as walking and talking. The prevalence of IPF has been estimated to be over 100,000 cases in the U.S. There are no FDA-approved treatments for IPF, and approximately two-thirds of patients die within five years after diagnosis. Patients are typically treated with anti-inflammatory agents; however, none have been clinically proven to improve survival or quality of life for patients with IPF.

In IPF, CTGF has been implicated in all levels of the disease from increased CTGF gene expression to elevated levels of CTGF protein in the cells thought to play an active role in the disease. Researchers have reported increased expression of the CTGF gene in transbronchial-biopsy specimens and bronchoalveolar lavage cells.¹ Further, the presence of CTGF protein in lung tissue of IPF patients appears to be confined predominantly to those cell types believed to play a critical role in pulmonary fibrosis (proliferating type II alveolar cells and activated fibroblasts). CTGF has been shown to be necessary to cause pulmonary fibrosis in experimental models of bleomycin-induced lung fibrosis, suggesting that CTGF is crucial to the pathogenesis of IPF.²

Results from a phase 1 study of FG-3019 in patients with IPF suggest that a single 2-hour infusion of FG-3019 was safe and well tolerated.

Systemic Sclerosis

Systemic sclerosis is a degenerative disorder in which excessive fibrosis occurs in multiple organ systems, including the skin, blood vessels, heart, lungs, and kidneys. There are no effective therapies for this life-threatening disease that affects more women than men (female to male ratio, 3:1). The annual incidence of systemic sclerosis is estimated to be 19 cases per million population.

Early work on CTGF revealed a significant correlation between CTGF gene expression and skin sclerosis in tissue samples from patients with systemic sclerosis.^3-8 More recent research has shown a genetic association between CTGF and systemic sclerosis and identified a risk genotype.⁹ Evidence of an antifibrotic effect of blocking CTGF has been demonstrated in cultured skin fibroblasts obtained from scleroderma patients in which experimental prevention of CTGF expression resulted in reduced expression of collagen (a major protein component of scar tissue).¹⁰ CTGF is also implicated in several forms of fibrotic diseases that cause death in scleroderma patients, including pulmonary fibrosis, congestive heart failure, renal fibrosis each of which occurs in about half of systemic sclerosis patients. FG-3019 represents a potential therapy that addresses fibrosis in multiple tissues and organ systems that are affected by systemic sclerosis.

Organ Transplant Fibrosis

In 2005, over 50,000 solid organ transplants were conducted in the US, Japan and five major European markets. The total number of transplant procedures is expected to increase to more than 67,000 by 2015. The number of patients living with functional grafts in the US alone at year-end 2005 was nearly 164,000. While remarkable progress has been made in the ability to transplant various organs, long term preservation (greater than one year) of organ function and patient survival suffers primarily because of chronic rejection.

The precise manifestations of chronic rejection vary according to the transplanted organ, but all exhibit proliferation of myofibroblasts, or related cells, ultimately resulting in fibrosis that leads to loss of function. At this time, no drugs are available for treatment of the fibroproliferative lesions of progressive chronic allograft rejection. Organ transplants represent an opportunity for FG-3019 in the area of both transplant rejection and disease treatment for some organs, notably the liver and kidney, where there is recurrence of disease.

References

Pan LH, et al. Type II alveolar epithelial cells and interstitial fibroblasts express connective tissue growth factor in IPF. European Respiratory Journal 2001 17:1220-1227.
Bonniaud P, et.al. CTGF is crucial to induce a profibrotic environment in “fibrosis resistant” Balb/c mouse lungs. Am J Respir Cell Mol Biol. 2004 Nov;31(5):510-6.
Shi-wen,X. et al. Autocrine overexpression of CTGF maintains fibrosis: RDA analysis of fibrosis genes in systemic sclerosis. Exp Cell Res 259, 213-224 (2000).
Leask,A. Transcriptional profiling of the scleroderma fibroblast reveals a potential role for connective tissue growth factor (CTGF) in pathological fibrosis. Keio J Med 53, 74-77 (2004).
Igarashi,A. et al. Significant correlation between connective tissue growth factor gene expression and skin sclerosis in tissue sections from patients with systemic sclerosis. J Invest Dermatol. 105, 280-4 (1995).
Igarashi,A. et al. Connective tissue growth factor gene expression in tissue sections from localized scleroderma, keloid, and other fibrotic skin disorders. J Invest Dermatol. 106, 729-33 (1996).
Sato,S. et al. Serum levels of connective tissue growth factor are elevated in patients with systemic sclerosis: Association with extent of skin sclerosis and severity of pulmoary fibrosis. J Rheumatol 27, 149-154 (2000).
Dziadzio,M. et al. N-terminal connective tissue growth factor is a marker of the fibrotic phenotype in scleroderma. QJM. (2005).
Fonseca,C. et al. A polymorphism in the CTGF promoter region associated with systemic sclerosis. N Engl J Med 357, 1210-1220 (2007).
Xiao,R. et al. Effect of small interfering RNA on the expression of connective tissue growth factor and type I and III collagen in skin fibroblasts of patients with systemic sclerosis. Br J Dermatol 155, 1145-1153 (2006).