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New Kidney Disease Therapy Research (anti-fibrotic therapy)
FibroGen is a research-based biotechnology company using its expertise in connective tissue growth factor (CTGF) and hypoxia-inducible factor (HIF) biology to discover, develop, and commercialize novel therapeutics for serious unmet medical needs.
Chronic Kidney Disease
An estimated 13% of Americans have chronic kidney disease (CKD). Regardless of disease origin, fibrosis is a final common pathway in CKD that leads to disease progression and ultimately organ failure. FibroGen is developing anti-CTGF therapy to slow kidney decline by direct intervention in the fibrotic pathway, and recent research suggests additional benefits of blocking CTGF may be achieved in earlier stages of CKD, such as reduction of proteinuria.
Chronic kidney disease (CKD) is progressive, not curable, and ultimately fatal, either because of the consequences of kidney failure or due to an alarmingly high level of cardiovascular mortality in the CKD patient population.
The first formal classification system for defining stages of CKD progression was presented to the medical community in 2002 when a working group of the National Kidney Foundation (NKF) issued clinical practice guidelines based on using serum creatinine as a biochemical parameter to estimate glomerular filtration rate (GFR). GFR is an indicator of overall kidney function and declines slowly with age or potentially more rapidly as a result of disease or injury. In 2005, CKD including end-stage renal disease (ESRD), accounted for 27% of Medicare expenses ($60 billion) and 36% of care for patients dually covered by Medicare and Medicaid ($18 billion). With approximately 29 million Americans affected today, CKD is a crisis in the US healthcare system.
Blocking CTGF Activity to Treat CKD
Regardless of disease etiology, tubulointerstitial fibrosis is a final common pathway in CKD that leads to disease progression and ultimately ESRD. CTGF has been implicated in this process through its effects on promoting epithelial to mesenchymal transition (EMT), a process whereby injured tubular epithelial cells morph into mesenchymal cells that mainly produce components of scar tissue. Recent studies also implicate CTGF in multiple other pathologies associated with CKD including hyperfiltration, proteinuria, hypertrophy, and microvascular leakage. There is emerging evidence that anti-CTGF therapy may provide some degree of reversal of the disease process.
FibroGen believes that directly blocking CTGF will represent a first-in-class therapy that may provide a critical renoprotective benefit resulting in decreased proteinuria and slower decline of renal function. The results of administration of FG-3019, FibroGen's fully human monoclonal antibody against CTGF, in multiple experimental models of renal disease support its therapeutic potential in CKD. In models of renal fibrosis and DKD (using "db/db" diabetic mice and a combination of STZ-induced type 1 diabetes and renal ischemia-reperfusion injury), results demonstrated that FG-3019 significantly reduced urinary albumin or total protein excretion, improved kidney function (as measured by GFR), ameliorated renal hypertrophy and decreased fibrosis. Preliminary findings in clinical studies of FG-3019 in the settings of microalbuminura are also encouraging.
Diabetic Kidney Disease (DKD)
While there are many causes of CKD, DKD refers specifically to kidney disease related to diabetes. FibroGen has completed a phase 1 study of FG-3019 in patients with diabetes and microalbuminuria in which FG-3019 appeared to have a rapid effect on reducing proteinuria. The treatment phase has been completed in a similar phase 1 study of FG-3019 in patients with macroalbuminuria, and a phase 2 study of FG-3019 is underway in patients with type 2 diabetes and advanced kidney disease. Read more
FibroGen's research efforts in DKD are focused on addressing cardiovascular comorbidity, which accounts for over three quarters of deaths of people with DKD. Research has demonstrated that FG-3019 can partially reverse arterial stiffening in diabetic animals, suggesting the possibility of reversing fibrosis in DKD.
Cardiovascular Complications
In addition to diabetic kidney disease (DKD), FibroGen is exploring the role of CTGF in other diabetic complications where CTGF may mediate the damaging effects of hyperglycemia and hypertension, such as cardiovascular disease and retinopathy. Research also indicates a broader role for anti-CTGF therapy in the overall setting of heart failure.
Heart Failure (HF)
More than 5.5 million people in the US have heart failure (HF), defined as the inability of the heart to pump enough blood to meet the metabolic demands of the body's tissues. The body compensates for reduced cardiac output resulting from HF by a number of mechanisms, such as remodeling of heart muscle. Cardiac remodeling (alteration of structure and function of the heart) can be help to maintain pumping ability; however, sustained work overload on the heart causes active heart cells to die and further stresses surviving cells, creating a vicious cycle of remodeling with progressive fibrosis. In addition to cardiac remodeling, HF causes remodeling in micro- and macrovascular systems and in the lungs.
While various therapeutics address different aspects of cardiovascular disease, none ameliorate or halt remodeling. Left uncontrolled, remodeling leads to disorders of the heart (e.g., left ventricular hypertrophy) and disorders of the vascular system and lungs as a result of arterial stiffening.
Diabetic Cardiovascular Disease (CVD)
Patients with diabetes have a worse prognosis for survival if they develop cardiovascular disease (CVD) than non-diabetic patients. CVD accounts for 65-75% of the mortality in patients with diabetes despite current treatment guidelines, creating a substantial and critical unmet clinical need. Only 20-30% of patients with macroalbuminuria survive to the point of kidney failure and initiation of dialysis, as the majority of patients perish from cardiovascular complications prior to onset of end-stage renal disease. HF is accelerated in patients with diabetes, a condition known as diabetic cardiomyopathy. Although most cases occur in the setting of concomitant hypertension and/or atherosclerotic disease, cardiomyopathy can develop due to diabetes alone and is associated with fibrosis and enhanced collagen deposition.
Anti-CTGF Therapy for Prevention of HF and Reduction of CV Risk
There is a complex interplay between microvascular, macrovascular, pulmonary and cardiac systems as the body attempts to remodel in order to adapt to changing signals induced by hypertension, coronary artery disease, idiopathic cardiomyopathy or diabetes. CTGF contributes to cardiac, vascular, and pulmonary remodeling by acting as a recipient of signals from various systems and in turn acting as a central mediator of the remodeling effort.
Research shows that levels of CTGF in the heart1,2,3 and in circulation4,5 are correlated with CVD, and CTGF expression is reduced by therapies that provide benefit in improving cardiovascular function, such as angiotensin receptor blockers (ARBs)6,7 and angiotensin converting enzyme inhibitors (ACEi).8 In heart failure patients, a recent study found that plasma levels of CTGF correlated with the patient's New York Heart Association (NYHA) class and with levels of brain natriuretic peptide (BNP)4, an antifibrotic peptide and established marker of cardiac dysfunction. Another study using a rodent model of HF showed that CTGF increased in parallel with pulmonary remodeling, a well known consequence of HF.9
FibroGen's work has demonstrated the potential for FG-3019, a fully human monoclonal antibody that targets CTGF, to inhibit remodeling and potentially improve cardiac outcomes. In a nonclinical model of diabetes, treatment with FG-3019 alone or in combination with ACEi or ARB, was significantly better in preventing and reversing arterial stiffness than ACEi or ARB therapy alone.10 In the same study, blockade of CTGF prevented cardiovascular dysfunction and prevented and reversed edema (swelling due to leakage from microvasculature). Another study in a non-diabetic model of hypertension also showed that treatment with FG-3019 prevented vascular fibrosis suggesting the potential for FG-3019 to address CVD in non-diabetic settings.
Diabetic Retinopathy
FibroGen and collaborators are exploring the potential for anti-CTGF therapy in a microvascular complication that affects the eye, diabetic retinopathy, which is the number one cause of new blindness in most industrialized countries. The incidence of retinopathy is 25% when diabetes mellitus has been present for five to ten years, and rises to 70% to 90% in individuals who have had diabetes for more than 10 years. High levels of ocular CTGF are correlated with the degree of severity of neovascularization and fibrosis, which cause vision loss. A recently published study regarding the role of CTGF in proliferative vitreoretinopathy provides the first direct evidence that CTGF promotes the development of intraocular fibrosis.11 CTGF may play a role earlier in the disease as well, when the capillaries of the eye first become leaky.
1. Gabrielsen A, et al. Gene expression signals involved in ischemic injury, extracellular matrix composition and fibrosis defined by global mRNA profiling of the human left ventricular myocardium. J Mol Cell Cardiol 42, 870-883 (2007).
2. Barth AS, et al. Identification of a common gene expression signature in dilated cardiomyopathy across independent microarray studies. J Am Coll Cardiol 48, 1610-1617 (2006).
3. Koitabashi N, et al. Increased connective tissue growth factor relative to brain natriuretic peptide as a determinant of myocardial fibrosis. Hypertension. 2007 May;49(5):1120-7.
4. Koitabashi N, et al. Plasma connective tissue growth factor is a novel potential biomarker of cardiac dysfunction in patients with chronic heart failure. Eur J Heart Fail. 2008 Apr;10(4):373-9.
5. Jaffa AA, et al. Connective tissue growth factor and susceptibility to renal and vascular disease risk in type 1 diabetes. J Clin Endocrinol Metab. 2008 May;93(5):1893-900.
6. Ahmed MS, et al. Connective tissue growth factor-a novel mediator of angiotensin II-stimulated cardiac fibroblast activation in heart failure in rats. J Mol Cell Cardiol. 36, 393-404 (2004).
7. Guo P, et al. Contribution of reactive oxygen species to the pathogenesis of left ventricular failure in Dahl salt-sensitive hypertensive rats: effects of angiotensin II blockade. J Hypertens 24, 1097-1104 (2006).
8. Peng H, et al. Ac-SDKP reverses cardiac fibrosis in rats with renovascular hypertension. Hypertension 42, 1164-1170 (2003).
9. Ahmed MS, et al. (2007) Induction of pulmonary connective tissue growth factor in heart failure is associated with pulmonary parenchymal and vascular remodeling. Cardiovasc Res 74: (2):323-333.
10. 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.
11. He S, et al. Connective tissue growth factor as a mediator of intraocular fibrosis. Invest Ophthalmol Vis Sci. 2008 Sep;49(9):4078-88.
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