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.