Press Releases
FibroGen Announces New Research in HIF and CTGF Therapeutic Programs Presented at the Annual Meeting of the American Society of Nephrology
San Francisco, CA - November 7, 2007
FibroGen, Inc. today announced data from research on its therapeutic programs targeting hypoxia-inducible factor prolyl hydroxylase (HIF-PH) and connective tissue growth factor (CTGF) reported at the 40th annual meeting of the American Society of Nephrology (ASN) Renal Week November 2-5, 2007, in San Francisco, CA.
Renal Cytoprotection
FibroGen collaborators reported results of nonclinical research
demonstrating the ability of HIF-PH inhibitor, FG-4497, to activate HIF
and protect kidneys from acute and chronic injury.
Allogeneic Kidney Transplant Model (Abstract # SA-FC135; Abstract)(1): Professor Kai-Uwe Eckardt, Director of the Nephrology Section, University Clinic of Erlangen, Germany, reported results from a rat allogeneic renal transplant model examining the renoprotective effects of a single dose of FG-4497 (40 mg/kg) in independent acute and chronic studies. Donor animals were treated 6 hours prior to organ harvest with either vehicle or FG-4497. Kidneys were harvested 24 hours prior to allogeneic transplantation into bilaterally nephrectomized rats of a different genetic strain. In the acute study, pretreatment of donors with FG-4497 resulted in reduced perioperative mortality versus placebo (53% versus 23% survival, respectively), and significantly improved renal function (p<0.05) as early as one day after transplant. In a chronic model lasting 24 weeks, survival was also significantly higher (p<0.05) for recipients transplanted with kidneys from FG-4497-treated donors versus vehicle control (54% versus 19%, respectively). Finding ways to reduce organ dysfunction is an important goal in kidney transplantation, and these data suggest that renoprotection with HIF-PH inhibitors is a promising approach to achieve this therapeutic goal.
Prevention of Hypoxic Distal Tubular Injury in Isolated Perfused Kidney Model (Abstract # SU-PO279; Abstract)(2): Professor Samuel Heyman of Hebrew University and Hadassah Hospital, Mt. Scopus, Jerusalem reported on the ability of FG-4497 to stabilize HIF and prevent hypoxic distal tubular injury in a rat isolated perfused kidney (IPK) model, which is characterized by hypoxic injury to medullary thick ascending limb (mTAL). Distal tubular damage is an important factor in various forms of hypoxic acute kidney injury. In the IPK model, rats were administered a single dose of FG-4497 (50 mg/kg i.p.) prior to surgical removal of kidneys and subsequent perfusion ex vivo in oxygen-poor perfusate. Using immunohistochemistry, HIF was detected in all renal zones of the perfused kidneys treated with FG-4497, including proximal tubules, interstitial fibroblasts and vascular endothelial cells. Importantly, HIF stabilization in kidneys and mTAL from FG-4497 treated rats correlated with improved renal perfusate flow and less hypoxic injury to mTAL possibly due to cytoprotection of the distal tubules and improved epithelial and endothelial cell function.
Erythropoiesis
There were three presentations on FibroGen's oral HIF-PH inhibitors,
FG-2216 and FG-4592, designed to stimulate erythropoiesis (the production
of oxygen-carrying red blood cells) for the treatment of anemia.
Phase 1 study of FG-2216 in patients receiving hemodialysis (Abstract # SA-PO784; Abstract)(3): Results were presented on a phase 1 clinical study of FG-2216 in hemodialysis patients completed at the University Clinic of Erlangen, Germany, by Professor Eckardt and colleagues. After a single oral dose of FG-2216 was administered to 12 hemodialysis patients, 6 of whom were anephric (without kidneys), and to 6 healthy volunteers, median erythropoietin (EPO) levels increased from 7.8 to 240.6 mIU/mL (nephric), from 4.4 to 57.8 mIU/mL (anephric), and from 6.4 to 81.2 mIU/ml in healthy controls. EPO, a hormone produced mainly by the kidneys in response to hypoxia (low oxygen levels), stimulates erythropoiesis in the bone marrow. Inadequate levels of EPO are considered the main cause of renal anemia; however, the reasons underlying this inadequacy have been poorly understood. It has been thought that diseased kidneys lose the ability to make EPO and that other sources of EPO, such as the liver, do not adequately compensate. Others have proposed that loss of kidney function leads to decreased oxygen consumption and a state of local hyperoxia (high oxygen levels) in the EPO-producing peritubular area of the kidneys despite systemic hypoxia. The phase 1 data suggest that renal anemia appears to be due to disturbed oxygen sensing in the kidney rather than destruction of EPO-producing cells of the kidney. Taken together with the ability of extra-renal sources (liver) to make EPO, these findings suggest an underutilized EPO production capacity that could potentially be harnessed for therapeutic benefit.
Preliminary results from phase 2 study of FG-4592 in patients with chronic kidney disease (CKD) (Abstract # SU-PO806; Abstract)(4): Data were presented by FibroGen scientists from the first dose group (1 mg/kg) of a randomized, single-blind, placebo-controlled, dose-escalation study of FG-4592 administered orally 2 or 3 times weekly for 4 weeks. The objectives of this study were to characterize the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of FG-4592 in subjects with CKD anemia. All subjects were monitored for safety, including vital signs, clinical labs, and adverse events during the 4 weeks of treatment and for 4 weeks thereafter. Data from the 1 mg/kg cohort (21 active- and 8 placebo-treated) demonstrate that FG-4592 doses up to 120 mg were generally well-tolerated, with treatment emergent adverse events reported for 2 subjects (1 active and 1 placebo). No clinically significant changes in serum chemistry or vital signs were observed in any subjects. In efficacy evaluable subjects, 5 of 8 subjects (62%) treated with doses of FG-4592 ranging from 40 to 120 mg had increases in hemoglobin ≥1 g/dL during the 4-week treatment period, and maintained that increase for 2-4 wks after stopping treatment. None of 4 placebo subjects had a similar hemoglobin increase.
FG-4592 treats anemia and reverses hypertension in uremia model (Abstract # F-PO228; Abstract)(5): FibroGen scientists also reported on the effects of FG-4592 on anemia and hypertension associated with CKD using a rat model in which one whole kidney and 2/3 of the other were surgically removed (5/6th nephrectomy). The results demonstrate that FG-4592 was effective in stimulating red blood cell production and corrected anemia in a dose-dependent fashion, without significant effects on body weight or uremia. The data also suggest that FG-4592 reversed pre-existing hypertension in this model. Post-surgery baseline measurements of systolic blood pressure (SBP) indicated that hypertension had developed to the same degree (approximately a 42% increase in SBP on average) in all nephrectomized groups compared to sham-operated control groups. At the end of the study, SBP was significantly reduced (p<0.05) in nephrectomized rats treated with 20 mg/kg FG-4592 (164.7 ± 26.7 mmHg) and with 40 mg/kg FG-4592 (155.4 ± 42.9 mmHg) compared to vehicle-treated nephrectomized controls (195.7 ± 24.4). A trend towards decreased SBP from baseline was also observed in both nephrectomized groups treated with FG-4592; however, SBP was not significantly different between sham-operated animals (123.6 ± 17.5) and sham-operated animals treated with 20 mg/kg FG-4592 (123.7 ± 15.9) indicating that drug treatment does not appear to have a direct hypotensive effect.
CTGF and Biology of Diabetic Nephropathy (DN)
FibroGen collaborators reported results of nonclinical research related to
FibroGen's anti-CTGF program for the treatment of DN. The renal expression
of CTGF mRNA and protein is upregulated in human and experimental DN, and
inhibition of CTGF was shown to affect cellular processes associated with
disease progression, consistent with the view that CTGF is an important
factor in the pathogenesis of this disease.
Plasma CTGF predicts end-stage renal disease and mortality in type 1 DN (Abstract # F-PO1013; Abstract)(6): Roel Goldschmeding, MD, Ph.D., of the University Hospital Utrecht, Department of Pathology, Utrecht, Netherlands, presented data on the predictive value of baseline plasma CTGF for outcome and disease progression in a prospective study of 198 type 1 diabetic patients with overt DN and 188 type 1 diabetic patients with persistent normoalbuminuria. Follow-up time was 12.8 years. Baseline plasma CTGF correlated with baseline urinary albumin excretion (UAE), glomerular filtration rate (GFR), and rate of decline in GFR. Baseline plasma CTGF contributed to the association of UAE with rate of decline in GFR (cumulative R=0.46) and contributed to the prediction of progression to ESRD, overall mortality, and cardiovascular mortality. In contrast, 188 matched type 1 diabetic patients with persistent normoalbuminuria, baseline plasma CTGF did not correlate with severity of disease and did not predict outcome. The data show that addition of plasma CTGF to conventional risk factor analysis improves prediction of outcome in type 1 DN.
FG-3019 modulates CTGF-mediated mesangial cell adhesion and cytoskeletal signaling in vitro (Abstract # SA-PO325; Abstract)(7): John Crean, Ph.D., of the University College Dublin, School of Biomolecular and Biomedical Science, Conway Institute, Belfield, Dublin 4, Ireland reported results of in vitro studies examining the ability of FG-3019, FibroGen's fully human monoclonal antibody against CTGF, to modulate CTGF-dependent cell adhesion and adhesive responses. Hyperglycemia-induced increases in glomerular mesangial extracellular matrix production and actin cytoskeleton rearrangement are key pathological hallmarks of DN. Elevated expression of glomerular CTGF plays an important role in the development and progression of DN, at least in part through dysregulation of these processes. FG-3019 was shown to abrogate CTGF-mediated mesangial cell adhesion by interference with MAP kinase signaling and paxillin phosphorylation. These findings provide important mechanistic insights regarding the role of CTGF in progression of DN.
A targeted cDNA microarray identifies cytoskeletal regulatory proteins as transcriptional targets of CTGF (Abstract # SU-PO191; Abstract)(8): Dr. Crean also reported results from studies examining the role of CTGF in human glomerular mesangial cell (HMC) dysfunction at the level of gene expression. Microarrays were constructed that contained genes differentially expressed in HMCs under conditions of either normal or high physiological glucose. Stimulation of these arrays with CTGF revealed induction of 10 distinct transcripts. CTGF was observed to induce the expression of the actin/myosin-binding protein caldesmon, the myosin regulatory chain and T-plastin alongside Arp-3 and fibronectin. In addition, CTGF caused a down-regulation of tubulin alpha-3 and the F-actin capping protein. These data suggest that CTGF activates an actin binding and regulatory protein cluster, representing a previously undescribed genetic program, which likely contributes to mesangial cell dysfunction in DN. When HMCs were stimulated with CTGF and stained for tubulin and F-actin, widespread microtubular and actin rearrangement was apparent. This was accompanied by a polarized redistribution of myosin, suggesting activation of the machinery of cell migration. Increased expression of Arp-3 in response to CTGF was associated with cdc42 dependent PAK-1 phosphorylation. These data indicate that CTGF-mediated actin rearrangement likely contributes to the pathophysiology of the glomerular mesangium in DN.
About FibroGen
FibroGen, Inc. is a biotechnology 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.
Contact:
Laura Hansen 650-866-7828 or lhansen@fibrogen.com
References
1. Bernhardt W.M., Gottmann U., Doyon F., Buchholz B., Campean V., Klaus S., Flippin L. A., Arend M., Willam C., Yard B. A., Warnecke C., Eckardt K.-U., Donor Pre-Treatment with an HIF-Prolylhydroxylase-Inhibitor Improves Function and Increases Long-Term Graft Survival in an Allogenic Rat Transplant Model. American Society of Nephrology Renal Week 2007: Abstract SA-FC135. (Abstract)
2. Heyman S.N., Shina A., Flippin L.A., Arend M., Klaus S.J., Eckardt K.-U., Rosen S., Rosenberger C., Activation of Hypoxia Inducible Factors (HIF) Ameliorates Hypoxic Distal Tubular Injury in the Isolated Perfused Rat Kidney (IPK). American Society of Nephrology Renal Week 2007: Abstract SU-PO279. (Abstract)
3. Bernhardt W. M., Wiesener M. S., Schmieder R. E., Gunzler V., Eckardt K.-U., The Prolyl Hydroxylase Inhibitor FG-2216 Stimulates EPO Production in Nephric and Anephric Dialysis Patients - Evidence for an Underutilized Production Capacity in Liver and Kidneys. American Society of Nephrology Renal Week 2007: Abstract SA-PO784. (Abstract)
4. Frohna P. A., Milwee S., Pinkett J., Lee T., Moore-Perry K., Chou J., Ellison R. H., Results from a Randomized, Single-Blind, Placebo-Controlled Trial of FG-4592, a Novel Hypoxia Inducible Factor Prolyl Hydroxylase Inhibitor, in CKD Anemia. American Society of Nephrology Renal Week 2007: Abstract SU-PO806. (Abstract)
5. Guo G., Winmill R., Arend M., Flippin L., Lin A., Klaus S, Liu D., Langsetmo I., Wang Q., HIF-PH Inhibitor, FG-4592, Treats Anemia and Prevents Elevation of SBP in Uremic Rats. American Society of Nephrology Renal Week 2007: Abstract F-PO228. (Abstract)
6. Nguyen T. Q., Tarnow L., Jorsa A., Oliver N., Roestenberg P., Ito Y., van Nieuwenhoven F. A., Parving H. H., Goldschmeding R., Plasma Connective Tissue Growth Factor (CTGF; CCN-2) Predicts End-Stage Renal Disease and Mortality in Type 1 Diabetic Nephropathy. American Society of Nephrology Renal Week 2007: Abstract F-PO1013. (Abstract)
7. Crean J. K., Gaffney A., Oliver N., Godson C., FG-3019 Modulates CTGF-Mediated Mesangial Cell Adhesion and Cytoskeletal Signaling: Implications for Anti-CTGF Directed Therapeutic Intervention. American Society of Nephrology Renal Week 2007: Abstract SA-PO325. (Abstract)
8. Browne M., Gaffney A., Godson C., Martin F., Crean J., A Targeted cDNA Microarray Identifies Cytoskeletal Regulatory Proteins as Transcriptional Targets of Connective Tissue Growth Factor (CTGF)/CCN2: Implications for Diabetic Nephropathy. American Society of Nephrology Renal Week 2007: Abstract SU-PO191. (Abstract)
