Blood, Volume 104, issue 11, November 16, 2004 (abstract #174, oral session)

Upregulation of Endogenous Erythropoietin (EPO) in Healthy Subjects by Inhibition of Hypoxia Inducible Factor (HIF) Prolyl Hydroxylase. P. Urquilla, A. Fong, S. Oksanen, S. Leigh, E. Turtle, L. Flippin, M. Brenner, E. Muthukrishnan, P. Fourney, A. Lin, D. Yeowell, C. Molineaux (Intr. by Robert F. Todd). FibroGen, FibroGen, Inc., South San Francisco, CA, USA; FibroGen Europe, FibroGen Europe Corp, Helsinki, Finland.

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 results in the accumulation of HIF leading to the 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. Dose-dependent elevation in serum EPO levels was observed with a minimum effective dose of 6 mg/kg. FG-2216 was subsequently administered using a schedule of 2 or 3 times a week for three weeks at doses of 10 and 20 mg/kg or placebo. 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. An increase in reticulocytes and soluble transferrin receptor 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 and erythropoietic responses in humans by a specific HIF-PH inhibitor.

See also December 6, 2004 press release