October 31, 2004
American Society of Nephrology (ASN) Renal Week 2004, St. Louis, Missouri
Abstract SU-PO062
Poster: Anemia in Chronic Kidney Disease

J Am Soc Nephrol 15: 546A

Upregulation of Endogenous EPO in Healthy Subjects by Inhibition of HIF-PH. P. Urquilla, A. Fong, S. Oksanen, S. Leigh, E. Turtle, L. Flippin, M. Brenner, E. Muthukrishnan, P. Fourney, A. Lin, D. Yeowell, C. Molineaux. FibroGen, FibroGen,Inc., South San Francisco, CA.

High-altitude hypoxia stimulates erythropoiesis in anemic hemodialysis patients. Similarly, intermittent exposure to hypobaric hypoxia elevates EPO and stimulates erythropoiesis in normal subjects. HIF is a transcription factor that mediates the body's response to hypoxia. The stability and activity of HIF are regulated by HIF Prolyl Hydroxylase (HIF-PH). Inhibition of HIF-PH leads to rapid HIF stabilization and upregulation of erythropoietic genes. A FibroGen HIF-PH inhibitor, FG-2216, is an orally active small molecule with appropriate pharmacokinetic and pharmacodynamic activity for testing in humans. In animal studies, inhibitors of HIF-PH induce erythropoietic changes qualitatively similar to the effects of intermittent exposure to high altitude.

Phase 1 studies were initiated in healthy male subjects to determine the safety, tolerability, pharmacokinetics, and biologic activity of FG-2216 dosed orally (0.3 to 20 mg/kg). Serum levels of FG-2216 increased in a dose-dependent fashion; its elimination was characterized by a half-life of ~14 hr. Doses of 6 mg/kg and higher were associated with dose-dependent elevation in serum EPO levels. FG-2216 was subsequently administered using a repeated intermittent schedule, 2 or 3 times weekly. Doses of 10 and 20 mg/kg or placebo were given up to three weeks. Increased EPO was observed after each dose of FG-2216. There was no decrement in EPO response to subsequent doses, indicating a resetting of the EPO response during the dosing interval. Elevation in reticulocytes and soluble transferrin receptors was accompanied by a modest increase in hematocrit and hemoglobin above normal values at baseline. A total of 54 subjects received FG-2216, which was well tolerated. There were no serious adverse events or dose-limiting toxicities. Adverse events possibly related to FG-2216 were mild and subsided with continued administration. The data provide first proof of concept for upregulation of endogenous EPO by a specific HIF-PH inhibitor resulting in erythropoietic responses in humans.

Scientific Advisor: FibroGen,Inc.

See also November 1, 2004 press release