November 12, 2005
American Society of Nephrology (ASN) Renal Week 2005, Philadelphia, Pennsylvania
Abstract SA-PO935
Session: Anemia and Bone Disease

Novel and Beneficial Pharmacodynamic Properties of Endogenous EPO and 'Complete Erythropoiesis' Induced by Selective HIF Prolyl Hydroxylase Inhibitors. David Y. Liu, T.B. Neff, V. Guenzler, I. Langsetmo, P. Fourney, B. Nichols, E. Muthukrishnan, A. Lin, S. Klaus. FibroGen, Inc. 225 Gateway Blvd., SSF, CA 94080

Abstract: FibroGen is developing hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors (PHI) that stabilize HIF and stimulate 'complete erythropoiesis', as shown in preclinical studies where PHI induce endogenous EPO (eEPO), improve iron absorption and utilization, overcome the inflammatory suppression of erythropoiesis, and potently drive RBC maturation. Recent human data show that oral doses of the PHI FG-2216 are erythropoietic in patients with chronic kidney disease, at doses that induce only modest increases of eEPO in healthy subjects. The small increases in eEPO induced by erythropoietic doses of FG-2216 are consistent with preclinical studies in rodents and monkeys, where PHI elevate Hb at doses that increase eEPO by only 2-fold, and previous published studies in humans showing that repeated intermittent hypoxia, high altitude conditioning or standard phlebotomy are erythropoietic but lead to only modest increases in eEPO. Thus, stimulation of HIF-dependent erythropoiesis by physiological stimuli or PHI in several species requires only small increases in eEPO, which are 30 to 300-fold less than peak or sustained levels of rHuEPO associated with therapeutic doses of current recombinant therapeutics. The enhanced potency of PHI-induced erythropoiesis as compared to rHuEPO entails several novel and beneficial mechanisms, including coordinate regulation of eEPO and genes that improve iron utilization, eEPO signaling and responsiveness, and potential autocrine and paracrine EPO production within the marrow. Erythropoietic doses of PHI that modestly elevate eEPO could reduce the thrombotic risk caused by therapeutic doses of rHuEPO where supra-physiologic levels of rHuEPO lead to direct activation of the pro-thrombotic activities of platelets and the endothelium. PHI therapy may ultimately lead to anemia correction to target Hb levels that exceed current clinical practice guidelines and are closer to normal levels.