Benefits of Anti-CTGF

An ideal renoprotective agent would address the multifactorial pathology of diabetic kidney disease (DKD), provide clinical benefit across the course of the disease and address the cardiovascular complications associated with the disease.

These benefits would include normalization of hyperfiltration, inhibition of tubular and glomerular hypertrophy, reduction in synthesis of matrix components, maintenance of low urinary protein or amelioration of proteinuria, reduction in the rate of decline of glomerular filtration rate, and inhibition of glomerulosclerosis and tubulointerstitial fibrosis. Because CTGF is a necessary mediator of chronic fibrosis, and is strongly implicated as a central mediator of the multiple pathogenic processes underlying early- and late-stage DKD, molecules that inhibit CTGF could provide the renoprotection necessary to halt disease progression, prevent renal failure, and increase life expectancy.

Nonclinical research demonstrating the renoprotective capacity of blocking CTGF activity in treating early- and late-stage DKD underscores the potential for FibroGen’s FG-3019, a fully human monoclonal antibody that targets CTGF, to be a first-in-class therapy to reduce proteinuria and prevent or slow renal function decline thus extending the time to, or preventing the development of, end-stage renal disease. FibroGen has also shown vascular benefits of FG-3019 in a nonclinical model of type 1 diabetes.

EARLY STAGE DKD	DKD Pathology Reduced by Anti-CTGF	Representative Supporting Studies
EARLY STAGE DKD	Renal Hypertrophy Hyperfiltration Microalbuminuria	CTGF antisense blocked angiotensin II (Ang II)-stimulated fibronectin expression¹ and anti-CTGF antibody blocked advanced glycation endproducts (AGE) -stimulated fibronectin and collagen in mesangial cell cultures² FG-3019 reduced urinary albumin excretion, glomerular basement membrane (GBM) thickening and normalized hyperfiltration in a nonclinical model of type 2 diabetes³ FG-3019 reduced proteinuria in a nonclinical model resembling late-stage DKD⁴ Renal expression of CTGF and CTGF protein were significantly reduced in diabetic CTGF +/- transgenic mice, which correlated with attenuated albuminuria and GBM thickness⁵ FG-3019 reduced microalbuminuria in patients with diabetes⁶
LATE STAGE DKD	Epithelial to Mesenchymal Transition (EMT) Tubulointerstitial Fibrosis Declining Kidney Function	CTGF antisense inhibited EMT (creation of myofibroblastic cells that drive scarring) of tubular eptithelial cells⁷ CTGF antisense blocked interstitial fibrosis and biomarkers (e.g., fibronectin, collagen) in various kidney disease models including UUO⁸, db/db obese type 2 diabetes⁹, and STZ-induced diabetes¹⁰ CTGF antisense blocked the rise in serum creatinine associated with renal function decline in nonclinical models on DKD⁵ FG-3019 treatment improved kidney function and histopathology in a nonclinical DKD model, which was attributed, in part, to reduction of fibrosis⁴
CV RISK	Arterial Stiffness Microvascular leakage Edema	FG-3019 prevented arterial stiffening, reversed vascular stiffness and microvascular leakage, improved cardiac function, and normalized hypertension in a nonclinical model of type 1 diabetes¹⁰

References

Rupérez, M., et al. (2003) Connective tissue growth factor is a mediator of angiotensin II-induced fibrosis. Circulation. 2003 Sep 23;108(12):1499-505
Zhou, G., et al. (2004) Advanced glycation end-products induce connective tissue growth factor-mediated renal fibrosis predominantly through transforming growth factor beta-independent pathway. Am J Pathol. 2004 Dec;165(6):2033-43
Flyvbjerg A., et al. (2004) Long-Term Renal Effects of a Neutralizing Connective Tissue Growth Factor (CTGF) - Antibody in Obese Type 2 Diabetic Mice JASN;15:261A
Wang,Q.J., et al. (2004) Amelioration of Diabetic Nephropathy (DN) incused by Renal Ischemia-Reperfusion (IR) in rats with diabetes mellitus (DM) by treatment with FG-3019, a monoclonal antibody against connective tissue growth factor (CTGF). JASN;15:731A
Nguyen, T.Q., et al. (2008) CTGF inhibits BMP-7 signaling in diabetic nephropathy. J Am Soc Nephrol. 2008 Jul 16. [Epub ahead of print]
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.
Burns WC et al., (2006) Connective tissue growth factor plays an important role in advanced glycation end product-induced tubular epithelial-to-mesenchymal transition: implications for diabetic renal disease. J Am Soc Nephrol 17: 2484-2494.
Yokoi, H., et al. (2004) Reduction in CTGF by antisense treatment ameliorates renal tubulointerstitial fibrosis JASN 15, 1430-1440.
Guha, M., et al. (2007) Specific downregulation of CTGF attenuates progression of DN in mouse models of type 1 and type 2 diabetes. FASEB J. 2007 Oct;21(12):3355-68.
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.