FibroGen Reports Results of a Phase 1b Study of FG-3019, Therapeutic Antibody Against CTGF, in Diabetic Patients with Microalbuminuria.

SAN DIEGO -- FibroGen, Inc. today announced results of a phase 1b study of FG-3019, a fully human monoclonal antibody against connective tissue growth factor (CTGF), in people with type 1 or type 2 diabetes and microalbuminuria (the earliest clinical sign of diabetic nephropathy). The data (Abstract TH-PO239) were presented at Renal Week 2006, the annual meeting of the American Society of Nephrology (ASN), by Sharon G. Adler, MD, Associate Chief, Division of Nephrology and Hypertension, Harvard UCLA Medical Center, and Professor of Medicine, UCLA School of Medicine.

The primary objectives of this open-label, multiple dose, sequential-group, dose-escalation, multi-center study were to characterize the safety, tolerability, and pharmacokinetics of FG-3019. Results demonstrated that FG-3019 was well tolerated. Only one serious adverse event was reported, which was considered unrelated to study drug. No dose-limiting toxicities were observed. Clearance of FG-3019 was saturable, and accumulation of FG-3019 in the bloodstream was limited during the dosing interval.

In addition, it was observed that urinary albumin to creatinine ratio (ACR), an early marker of kidney disease, significantly decreased from baseline as compared to Day 56 (two weeks after the last dose of FG-3019). The mean change in ACR was a reduction of 27 mg/g (p=0.027) from a baseline average of 61 mg/g. Urinary ACR decreased by 50% or more in 7 of 19 subjects (6 of 13 patients who enrolled with microalbuminuria). Mean arterial pressure (MAP) declined 2.6 (10) mm Hg on average, but this was not a statistically significant finding.

"The finding that ACR significantly declined in microalbuminuric patients after only two months of treatment with FG-3019 exceeded our expectations," said Dr. Adler. "These data support longer-term studies of FG-3019 in diabetic patients with more advanced kidney disease where the development of a safe and effective therapy that significantly delays or halts progression to renal failure is greatly needed. These studies will be performed to further examine the role of anti-CTGF therapy in attenuating albuminuria and assess its anti-fibrotic impact on renal function and patient mortality."

"We are encouraged by these results, which are consistent with previous research suggesting an important role of CTGF in diabetic kidney disease," said Thomas B. Neff, Chief Executive Officer at FibroGen. "We believe FG-3019 will have the greatest therapeutic impact as an anti-fibrotic agent in patients with more advanced disease. We look forward to initiating longer-term, controlled studies in patients with diabetic nephropathy where higher CTGF levels have been strongly associated with progression of renal and cardiovascular disease."

Additional Background on Study Design

Study subjects were adults greater than or equal to 21 years of age with type 1 or type 2 diabetes and microalbuminuria. They received 3 or 10 mg/kg of FG-3019 administered as 2-hour intravenous infusions once every 2 weeks (Days 0, 14, 28 and 42) for a total of 4 doses over 2 months. At conclusion of the study, 14 patients received doses of 3 mg/kg, and 10 patients received doses of 10 mg/kg. The patients will receive long-term follow-up for 10 months.

The study required concomitant therapy with angiotensin-converting-enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), and anti-hypertensive agents to be stable for at least 4 weeks prior to study entry. Of 19 evaluable patients, 18 were taking either an ACEi or ARB at study entry, and 10 of these 18 patients were additionally taking anti-hypertensive agents. Eleven (11) patients taking ACEi or ARB therapy and 6 patients taking anti-hypertensive agents were using these medications for over 6 months prior to study entry, and 5 of these patients were taking the combination of ACEi or ARB in addition to antihypertensive agents. Four (4) patients were taking the combination of an ACEi, ARB, and anti-hypertensive medications at study entry, and 3 of these patients were using these medications for over 6 months.

About the Role of CTGF in Complications of Diabetes

CTGF stimulates cell adhesion and migration, production and deposition of extracellular matrix proteins, and angiogenesis. With these actions, CTGF has been shown to be a necessary factor in all forms of fibrotic disease. Particularly, CTGF has also been implicated as a central factor in the pathogenesis of micro- and macrovascular complications of diabetes1-3:

* Increasing CTGF levels correlate with disease progression: An analysis of the landmark Diabetes Complications and Control Trial (DCCT) / Epidemiology of Diabetes Interventions and Complications (EDIC) study showed that significantly higher levels of plasma CTGF are apparent in advanced kidney disease as measured by albumin excretion rate (AER).4 In addition, increased levels of plasma CTGF were significantly correlated with increased systolic blood pressure (SBP), and increased levels of plasma CTGF were significantly correlated with increased carotid intima media thickness (IMT). Ito and colleagues showed in a separate study that urine levels of CTGF increased exponentially as renal disease progresses from normalbuminuria, to micro- and macroalbuminuria and ultimately to ESRD.5

* CTGF is up-regulated by key drivers of diabetic nephropathy: CTGF has been shown to be profoundly up-regulated by components of key pathways driving the progression of diabetic nephropathy including: hyperglycemia6-10, hypertension11-13, and the renin-angiotensin-aldosterone system (RAAS) (angiotensin-II, endothelin-I, aldosterone)14-17; stimulators of blood vessel growth and function (thrombin, VEGF, TGF-[eth])18-21; stimulators of cell growth (EGF, bFGF)22; and the kallikrein-kinin system (KKS).23

* Blocking CTGF attenuates key pathologies induced by drivers of diabetic nephropathy: Studies have demonstrated that blocking CTGF attenuates AGE- and RAAS-induced renal pathologies including: tubular cell hypertrophy10,16,24, epithelial mesenchymal transition25, and fibronectin synthesis.14,26 Other studies show that PKC-induced pathologies may be mediated by CTGF, including mesangial cell migration27 and fibrosis.28 PKC has also been shown to mediate angiotensin-II-induced expression of CTGF in diabetic states.17 CTGF and collagen expression were associated with KKS-induced pathology in a study examining mechanisms through which bradykinin promotes glomerular injury in diabetes.23

* Blocking CTGF attenuates proteinuria: VEGF and AGE have been implicated as key factors in promoting early pathologies associated with diabetic nephropathy, such as hyperfiltration and the onset of proteinuria29,30, and recent similar studies suggest a role for CTGF in mediating these same effects. In a model of early-stage diabetic nephropathy, anti-CTGF therapy normalized kidney hyperfiltration and reduced kidney hypertrophy, excess urine production, proteinuria, and glomerular membrane thickening.31 Other studies have shown that CTGF is highly expressed in cell types involved in the development of proteinuria including vascular endothelial cells32 and podocytes.33

* Blocking CTGF prevents renal fibrosis in vitro and in animal models: The prominent role that CTGF plays in renal fibrosis has been clearly demonstrated by multiple studies in which blocking the synthesis of, or directly inhibiting CTGF prevented key steps of renal fibrosis including transdifferentiation of normal human renal tubular epithelial cells to scar-producing myofibroblasts34-35, production of key proteins that compose scar 3, 6, 13, 33, and development of kidney fibrosis.11, 36, 37

* FG-3019 reversed arterial stiffening and preserved cardiovascular function: In preclinical models of diabetes, administration of 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. In addition, FG-3019 prevented cardiovascular dysfunction and prevented and reversed edema (swelling due to leakage from microvasculature) in this model.38,39

About Diabetic Nephropathy

The American Diabetes Association reports there are currently 20.8 million people with diabetes mellitus in the U.S. (7.0% of the population) and approximately 1.5 million new cases are diagnosed each year. Recent estimates indicate the number of newly diagnosed diabetics has been growing at a compounded annual rate of 8-9%, and the prevalent population is growing between 4 and 5%. Approximately half of the diabetic patient population has some degree of proteinuria40; approximately 5.4 million and 1.4 million diabetics in the U.S. are microalbuminuric and macroalbuminuric, respectively. Macroalbuminuria ("overt nephropathy") is an extremely serious condition where most patients need for long-term dialysis or kidney transplantation. Diabetes is the leading cause of End-Stage Renal Disease. However, approximately three-quarters of patients with macroalbuminuria die of cardiovascular disease before, or soon after progressing to dialysis or transplantation.

About FibroGen

FibroGen, Inc. is a biotechnology-based drug discovery company using its expertise in the fields of tissue fibrosis, connective tissue growth factor (CTGF), and hypoxia-inducible factor (HIF) biology to discover, develop, and commercialize novel therapeutics for fibrotic disorders, diabetic complications, anemia, conditions associated with tissue damage or injury, cancer, and other areas of unmet medical need. FibroGen also develops and produces recombinant human collagens and gelatins using unique production technology that provides the basis for FibroGen's proprietary cosmetic dermal filler and biomaterials supply business.

For more information about FibroGen, Inc., please visit www.fibrogen.com.

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