FibroGen Announces New Research on HIF-PHI and Anti-CTGF Development Programs in Chronic Kidney Disease
FibroGen, Inc. today announced data from research on its therapeutic programs related to hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors (PHI) and anti-connective tissue growth factor (anti-CTGF) were reported at the 41st annual meeting of the American Society of Nephrology (ASN) Renal Week November 6-9, 2008, in Philadelphia, PA.
HIF-PHI Anemia Research Presented at Renal Week
There were two presentations on FibroGen’s oral HIF-PH inhibitors, FG-2216 and FG-4592, investigational drugs designed to stimulate erythropoiesis for the treatment of anemia.
-- FG-2216 treats anemia without exacerbation of hypertension in chronic kidney disease (CKD) model (Abstract #SA-PO2422)(1) In a study evaluating FG-2216 for its effects on anemia and hypertension associated with CKD, a rat remnant kidney model (5/6th nephrectomy) was used, and recombinant human erythropoietin (rHuEPO) was included for comparison. The doses of FG-2216 and rHuEPO employed induced comparable increases in hemoglobin in anemic rats that had undergone nephrectomy, but there was a differential effect of FG-2216 versus rHuEPO on exacerbation of hypertension associated with nephrectomy in this model. Treatment groups were prospectively stratified for comparable levels of hypertension prior to treatment with either FG-2216 or rHuEPO, and systolic blood pressure increased significantly in the rHuEPO group but decreased significantly in the FG-2216 group. Thus, treatment with either FG-2216 or rHuEPO alleviated the anemia associated with 5/6th nephrectomy; however, only FG-2216 was able to increase hemoglobin levels without increasing systolic blood pressure. Similar results were reported for FG-4592 at ASN Renal Week 2007(2). A large majority of hemodialysis patients and nearly half of late stage CKD nondialysis patients have underlying hypertension, which contributes to progression of kidney disease and cardiovascular events. Erythropoiesis-stimulating agents (ESAs) currently available to treat anemic CKD patients are associated with significant (25-40%) rates of new or worsening hypertension. The results presented at ASN suggest that HIF-PHI may provide clinical benefit over ESAs by improving anemia without exacerbating hypertension. An anemia therapy with neutral effect of blood pressure could provide a significant cardiovascular outcome benefit for patients. -- Beneficial and novel effects of HIF-PHI for treating anemia (Abstract #F-PO1835)(3) Preclinical data were reported demonstrating several novel and beneficial pharmacodynamic effects resulting from 'complete erythropoiesis' induced by HIF-PHI FG- 2216 and FG-4592 including coordinate regulation of genes that mediate erythropoiesis leading to production of EPO by cells in the kidney and liver; mobilization and proper utilization of iron stores; and erythropoiesis despite interference from chronic inflammation. The latter effect was demonstrated in a model of anemia of chronic disease and is consistent with previously reported data showing that HIF-PHI can suppress inflammatory pathways, such as IL-12-mediated T helper cell production of pro- inflammatory cytokines (e.g., TNF-(alpha) and IFN-(gamma)) and down-regulate hepcidin, a regulatory hormone that limits iron availability and thus suppresses erythropoiesis under conditions of inflammation. Other data from preclinical and clinical studies were also reported demonstrating that HIF-PHI are orally active. In contrast to ESAs, which are administered by injection, orally bioavailable HIF-PHIs may make anemia care more accessible to the largely underserved anemic CKD patient population not yet on dialysis. Although the benefits of anemia treatment in CKD have become better known, anemia continues to be undertreated, largely due to the fact that while dialysis patients are under the care of nephrologists, most nondialysis CKD patients are treated by primary care physicians who do not have ready access to ESAs. Infrastructure concerns, including inventory and personnel costs, make ESAs impractical for primary care physicians and thus not accessible to their nondialysis patients. According to the 2008 USRDS Annual Data Report(4), only half of incident dialysis Medicare patients had seen a nephrologist 12 months prior to their initiating dialysis and none had seen a nephrologist two years prior. Further, only 10-12% of incident dialysis patients received ESA therapy during the year prior to their initiating dialysis, and these were primarily patients who had been referred to a nephrologist to prepare to initiate dialysis. Thus, there is an opportunity to improve care for anemic CKD patients prior to their reaching the latest stages of disease. Clinical data were also reported demonstrating that HIF-PHI treatment increased blood hemoglobin concentration with induction of low circulating levels of endogenous EPO 10-40 fold lower than EPO levels associated with ESA therapy. Supraphysiologic levels of circulating EPO (hundreds of times above normal physiologic levels) observed with ESA therapy have been associated with poor patient outcomes, such as vascular access thrombosis and excess cardiovascular events, particularly in patients who do not respond well to ESAs and require large doses (so-called "ESA hypo- responders"). In contrast, the data presented at ASN suggest that circulating levels of endogenous EPO induced by HIF-PHIs are within the normal physiologic range and are only a small fraction of the levels associated with ESA therapy. ESA hyporesponders represent 20% of dialysis and 10% of nondialysis CKD patients. Inflammation or infection is seen as the cause in nearly three-quarters of these patients. HIF-PHI efficacy in the presence of inflammation, as suggested by the preclinical data, may present a significant efficacy advantage for HIF-PHI compared to ESAs in hyporesponsive patients.
CTGF Research Presented at Renal Week
In three presentations, FibroGen and collaborators reported results of nonclinical research on CTGF highlighting a new mechanism of fibrosis and new insights into CTGF signaling activity that could result in damage to the integrity of kidney filtration units and exacerbate proteinuria (abnormal presence of proteins in the urine) in diabetic kidney disease (DKD). In a fourth presentation, the association of increased levels of CTGF to peritoneal dialysis was described for the first time.
-- Decreased BMP-signaling and podocyte markers in human DKD are associated with CTGF overexpression (Abstract #F-PO1323)(5) Bone morphogenetic protein-7 (BMP-7) is an important antifibrotic and proregenerative repair factor, which has been shown to prevent and reverse structural and functional changes of DKD. New data were reported showing that decreased BMP-7 signaling activity in podocytes (specialized kidney cells that maintain the filtration barrier) is associated with overexpression of CTGF in human DKD, and BMP-7 signaling activity was retained in diabetic mice with genetically impaired CTGF expression. Podocyte loss, another hallmark of DKD, was also associated with elevated CTGF expression in the study. These results support the idea that restoration of BMP-7 signaling via CTGF blockade is a new potential mechanism through which prevention or reversal of fibrosis could occur. -- Molecular signaling activities of CTGF and implications for therapeutic intervention (Abstract #TH-PO123)(6) Although CTGF was recognized as a modular protein over a decade ago, it was only recently that studies began to unravel how the functional domains within the CTGF modules orchestrate signals and control key biological processes. This presentation provided further mechanistic insight into CTGF signaling involving CTGF-mediated activation of p42/44 MAPK, p38 MAPK, paxillin and Akt, at least partially, through the VWC domain. -- Putative role for CTGF in loss of podocyte slit diaphragm integrity and actin rearrangement (Abstract #TH-PO124)(7) Podocytes are responsible for maintaining the integrity of slit diaphragms, which are critical components of the kidney filtration barrier. Podocyte loss associated with proteinuria is an early manifestation of DKD, and overexpression of CTGF in podocytes has been associated with worsening proteinuria and renal failure in experimental models of diabetes. This presentation of in vitro data provided new molecular insights regarding the ability of CTGF to cause polarization of human podocytes through effects on the cytoskeleton including actin rearrangement and redistribution of the actin-myosin contractile apparatus. Similar polarizing effects of CTGF on podocytes in vivo would have profound consequences for the integrity of the slit diaphragm and may mediate loss of proteins crucial to maintaining the slit diaphragm, such as podocin and nephrin. -- Elevated CTGF levels in peritoneal dialysis (Abstract #F-PO1632)(8) Peritoneal fibrosis (PF) is an important complication of continuous ambulatory peritoneal dialysis therapy. PF often occurs in association with high transport rate and ultrafiltration failure, but little is known about the mechanistic relationship. This presentation described data from peritoneal dialysis patient samples and found that high peritoneal transport state was associated with high peritoneal CTGF expression. Further, in cultured mesothelial cells (specialized cells that form the lining of the abdominal cavity) that were isolated from peritoneal dialysis effluent, CTGF expression could be induced by TGF-(beta), and higher levels of CTGF induction were associated with high peritoneal transport state. Functional alteration of mesothelial cells may be involved in the progression of peritoneal fibrosis in high transport state.
About Anti-CTGF Monoclonal Antibody FG-3019
FibroGen has developed a fully-human monoclonal antibody against CTGF, FG-3019. This agent has been in phase 1 clinical trials for idiopathic pulmonary fibrosis, focal segmental glomerular sclerosis (FSGS), and DKD microalbuminuric patients and is currently in a study involving macroalbuminuric patients.
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.
1. Guo G, et al. (2008) Correction of Anemia without Exacerbation of Hypertension in a Rat Model of Chronic Kidney Disease: Comparison of FG-2216 to Recombinant Erythropoietin. Presented at the 41st Annual Meeting of the American Society of Nephrology (Abstract SA-PO2422)
2. Frohna P, et al. (2007) Preliminary Results from a Randomized, Single-Blind, Placebo-Controlled Trial of FG-4592, a Novel Hypoxia Inducible Factor Prolyl Hydroxylase Inhibitor, in Subjects with CKD Anemia. JASN 18:763A
3. Klaus S, et al. (2008) Beneficial Pharmacodynamic Effects Resulting from ‘Complete Erythropoiesis’ Induced by Novel HIF Prolyl Hydroxylase Inhibitors FG-2216 and FG-4592. Presented at the 41st Annual Meeting of the American Society of Nephrology (Abstract F-PO1835)
4. U.S. Renal Data System, USRDS 2008 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2008
5. Turk T, et al. (2008) BMP-Signaling and Podocyte Markers Are Decreased in Human Diabetic Nephropathy in Association with CTGF Overexpression. Presented at the 41st Annual Meeting of the American Society of Nephrology (Abstract F-PO1323)
6. O’Donovan H, et al. (2008) Modular Signaling Activities of the CTGF/CCN2 Domain Structure: Implications for Therapeutic Intervention. Presented at the 41st Annual Meeting of the American Society of Nephrology (Abstract TH-PO123)
7. Browne M, et al. (2008) A Putative Role for Connective Tissue Growth Factor (CTGF) in Loss of Podocyte Slit Diaphragm Integrity and Actin Rearrangement. Presented at the 41st Annual Meeting of the American Society of Nephrology. (Abstract TH-PO124)
8. Mizutani M, et al. (2008) Connective Tissue Growth Factor (CCN2/CTGF) Is Increased in High Peritoneal Solute Transport Rate in Peritoneal Dialysis Patients. Presented at the 41st Annual Meeting of the American Society of Nephrology. (Abstract F-PO1632)