November 11, 2005
American Society of Nephrology (ASN) Renal Week 2005, Philadelphia, Pennsylvania
Abstract F-FC050
Session: Complications of ESRD: Bone Disease, Malnutrition, and Anemia

Induction of Erythropoiesis and Iron Utilization by the HIF Prolyl Hydroxylase Inhibitor FG-4592. S. Klaus, M. Arend, P. Fourney, L. Flippin, D. Gervasi, V. Guenzler, G. Kochendoerfer, I. Langsetmo, A. Lin, E. Lomongsod, D. McDaniel, S. Meier-Davis, T. Seeley, S. Spong, and D. Liu.
FibroGen, Inc. 225 Gateway Blvd., SSF, CA 94080

Abstract: FibroGen is developing HIF prolyl hydroxylase inhibitors (PHI) that selectively induce the expression of genes that mediate erythropoiesis, including erythropoietin (EPO) and genes that increase iron utilization by erythroid progenitors, and also overcome the suppression of erythropoiesis by chronic inflammation. FG-2216 is the first therapeutic PHI that has been shown to elevate circulating endogenous EPO (eEPO) and to increase hemoglobin (Hb) in healthy subjects and anemic patients with chronic kidney disease (CKD). FG-4592 represents one of several next generation PHI that has been optimized for multiple pharmacokinetic and pharmacodynamic parameters related to erythropoiesis, including selective inhibition of HIF prolyl and asparaginyl hydroxylases, potency, iron utilization, and ADME. FG-4592 stabilizes HIF-2 and induces EPO production in Hep3B cells, and increases circulating eEPO after a single i.v. or oral dose in rodents. FG-4592 elevates Hb in rodents when administered on an intermittent or daily dosing regimen, leading to significant dose-dependent elevation in Hb in less than 7 days. The erythropoietic potency of FG-4592 in rodents translates to efficacy in non-human primates with no adverse effects, with dose-dependent increases in circulating eEPO that exceed 1000 mIU/mL. Repeated daily dosing with FG-4592 in non-human primates for up to 28 days led to dramatic increases in circulating reticulocytes and RBC, with associated elevation of Hb of greater than 5 g/dl and no dose-limiting toxicities or adverse effects. The dose dependent increase in Hb was accompanied by increases in mean cell volume and mean cell hemoglobin, demonstrating that FG-4592 induces complete erythropoiesis by coordinately elevating eEPO and increasing iron utilization for newly emerging erythrocytes. Other hematopoietic lineages were not affected by repeated oral dosing with FG-4592. Together the data show that FG-4592 is a selective and potent oral erythropoietic agent that should be efficacious for treating anemia associated with CKD and chronic inflammation, with clinical studies scheduled to begin in 2005.