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.

References

  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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