November 3, 2007
American Society of Nephrology (ASN) Renal Week 2007, San Francisco, CA
Abstract SA-PO784

The prolylhydroxylase inhibitor FG2216 stimulates EPO production in nephric and anephric dialysis patients - evidence for an underutilized production capacity in liver and kidneys. W.M. Bernhardt, MD¹, M.S. Wiesener, MD¹, R.E. Schmieder, MD¹, V. Guenzler, MD, Ph.D.² and K.-U. Eckardt, MD¹.

1 Nephrology and Hypertension, University of Erlangen-Nuremberg, Erlangen, Germany and 2 FibroGen Inc., San Francisco, CA, United States.

Abstract: Inadequate serum EPO levels are considered the main cause of renal anemia, and the reasons are poorly understood. It is assumed that the EPO-producing peritubular fibroblasts lose endocrine function during the course of kidney injury and that the liver does not sufficiently compensate. Progress in understanding the molecular control of oxygen-dependent EPO production revealed an important role of hypoxia-inducible transcription factors (HIF) in the oxygen-dependent regulation of EPO. HIF degradation occurs through oxygen-dependent hydroxylation of prolyl residues by prolyl hydroxylases (PHD). To test the ability of fibrotic kidneys to produce EPO and the ability of other organs to make EPO in anephric patients, we used FG-2216, a novel PHD inhibitor, which stabilizes HIF in an oxygen-independent fashion. A single dose Phase 1 study was performed in 12 hemodialysis (HD) patients, 6 of whom were anephric, and in 6 non-anemic volunteers. Recombinant EPO therapy was discontinued one week before dosing in all HD patients. Day 1 hemoglobin levels were 13.8 ±1.9, 14.2 ±1.2, and 15.5 ±0.6 g/dL for nephrics, anephrics and controls, respectively. FG-2216 (20mg/kg p.o.) resulted in a rise in EPO levels in all study subjects (Tmax was comparable for all groups). Median EPO levels increased from 17.4 to 240.6 (nephric), from 5.7 to 42.55 (anephric), and from 6.7 to 47.1 mU/ml in controls. Mean plasma half life of FG-2216 was similar in nephric and anephric patients, but twice as long as in controls. Dialysis clearance of FG-2216 was less than 2%, suggesting that timing of the dose of FG-2216 could be independent from HD. In conclusion, endogenous EPO production can be stimulated by pharmacological manipulation of the HIF system. The response in nephric and anephric patients demonstrates that diseased kidneys retain a significant production capacity for EPO and that liver production of EPO may also be useful in a clinical setting.

See also November 7, 2007 press release