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FibroGen Reports Combinations of FG-3019 Plus ACEi and FG-3019 Plus ARB Prevented and Reversed Arterial Stiffness Significantly Better Than ACEi or ARB Alone in Preclinical Models of Diabetes
Washington--FibroGen, Inc. today announced that administration of FG-3019 alone, or in combination with angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB), was significantly better in preventing and reversing arterial stiffness than ACEi or ARB therapy alone in preclinical models of diabetes. In addition, FG-3019 prevented cardiovascular dysfunction and prevented and reversed edema (swelling due to leakage from microvasculature). The data were presented at the 66th Annual Scientific Sessions of the American Diabetes Association (Abstract #513-P). FG-3019, the Company's investigational therapeutic antibody against connective tissue growth factor (CTGF), is currently the subject of a phase 1b study in diabetic patients with microalbuminuria (early-stage kidney disease).
Cardiovascular disease is the leading cause of death among individuals with diabetes, accounting for at least two-thirds of diabetes-related deaths. Risk of death from heart disease or stroke among diabetics is two to four times greater than for those without diabetes.
"These studies suggest that FG-3019 protects blood vessels of the heart and periphery from damage caused by diabetes," said David Y. Liu, Ph.D., Vice President of Research at FibroGen. "Importantly, FG-3019 appears to address pathways not affected by ACEi or ARB therapy, suggesting that combining anti-CTGF therapy with anti-hypertension medications may improve cardiovascular outcomes in patients with diabetes."
FibroGen presented data from multiple studies designed to examine the effects of FG-3019 alone and in combination with current therapeutics, captopril (ACEi) and losartan (ARB), on diabetic vascular and cardiac complications including arterial passive stiffness, cardiac dysfunction, and vascular permeability. Type 1 diabetes was induced in rats by injection of streptozotocin (STZ), which destroys the insulin-producing islet cells of the pancreas.
After six weeks of treatment with IgG (control antibody) or captopril, diabetic rats showed increases in arterial stiffness as measured by circumferential stiffening of the carotid artery (the ability of the artery to expand in response to increases in pressure) compared to non-diabetic control mice. In contrast, diabetic rats treated with FG-3019 did not show significant increases in arterial stiffness and remained similar to healthy control animals.
In a subsequent study, when STZ-injected rats were left untreated for six weeks, allowing diabetes and associated vascular pathologies to first be established, and then treated for six more weeks, results demonstrated that FG-3019 was significantly better than either captopril (p less than 0.01) or losartan (p less than 0.05) in preventing arterial stiffening. In addition, combinations of FG-3019 with captopril or losartan were better than captopril (p less than 0.01) or losartan therapy (p less than 0.01) alone, and significantly reversed arterial stiffening (p less than 0.05) to levels not different from healthy controls. Measurements of ejection fraction and end diastolic pressure indicated that FG-3019 therapy prevented cardiac dysfunction. FG-3019 also prevented diabetes-induced leakage from blood vessels in the skin and associated edema whereas captopril did not. In the follow-up study, neither captopril nor losartan prevented diabetes-induced vascular leakage.
"Previous research in preclinical models has demonstrated the benefit of using FG-3019 to treat diabetic kidney disease, and these new findings extend the potential therapeutic utility of FG-3019 to diabetic cardiovascular disease," said Thomas B. Neff, Chief Executive Officer at FibroGen. "These results are particularly relevant as we continue to develop FG-3019 in the setting of diabetic nephropathy where the vast majority of patients die of cardiovascular disease before reaching renal failure. FG-3019 shows potential to be a novel therapeutic for diabetic nephropathy that may provide additional benefit in improving cardiovascular outcomes beyond current therapies. In addition, FG-3019 uniquely addresses other complications, such as vascular leakage, which are non-responsive to current therapies."