November 12, 2005
American Society of Nephrology (ASN) Renal Week 2005, Philadelphia, Pennsylvania
Abstract SA-PO924
Session: Anemia and Bone Disease

FG-2216 Increases Hemoglobin Concentration in Anemic Patients with Chronic Kidney Disease. V. Günzler ¹, E. Muthukrishnan ¹, H.H. Neumayer ², K. Sacherer ², R. Schmidt ³, A. Mitzner ³, A. Wiecek ⁴, G. Piecha ⁴, W. Ignacy ⁴, and P. Scigalla ⁵.

1 FibroGen, Inc., SSF, CA,
2 Dept. Nephrol., Charité, Berlin,
3 Dept. of Internal Medicine, Univ. of Rostock,
4 Dept. Nephrol., Endocrinology & Metabolic Diseases, Silesian Univ. School of Medicine, Katowice, Poland
5 Int'l Clinical Research Consulting, Berlin.

Abstract: Two Phase 2a dose escalation studies are evaluating safety and efficacy of FG-2216, an oral drug that stabilizes hypoxia-inducible factor (HIF) and induces the HIF2 mediated natural erythropoietic cascade. One study includes rHuEPO naïve CKD patients and the other CKD patients pretreated with rHuEPO (8+ weeks of continuous therapy). FG-2216 is dosed TIW for 4 weeks with 2 weeks of followup. Dose escalation was modeled from chronic intermittent hypoxia studies in animal and man. The low dose (6 mg/kg) was expected to be non-efficacious, and the higher doses, 15-20 mg/kg, to produce significant Hb responses. By day 42, 6 mg/kg of FG-2216 produced a statistically significant mean increase in Hb of 1.3 g/dL in EPO-naïve patients (n=5). Placebo patients (n=3) experienced a mean decrease in Hb from baseline of 0.35 g/dL. In rHuEPO pretreated patients, 6 mg/kg FG-2216 given after rHuEPO withdrawal increased Hb by 1.5 g/dL in one patient while another maintained baseline levels. Four patients showed Hb decreases to varying degrees, but the mean decrease in the FG-2216 group (-0.9 g/dL, n=6) was less than in the placebo group (-1.5 g/dL, n=3). The first patient (GFR=8) receiving 20 mg/kg FG-2216 after rHuEPO withdrawal experienced an increase of 1.8 g/dL Hb within 14 days, resulting in a decision to lower the dose in this cohort. The results show that CKD patients can produce EPO despite fibrosis, dialysis stage patients respond, and FG-2216 provides clinical benefit in anemia of CKD. The rapid Hb response induced by FG-2216 cannot be attributed to EPO alone and is likely due to HIF mediated iron mobilization. Moreover, lower circulating EPO levels required to induce erythropoiesis following FG-2216 (<10% of rHuEPO) are expected to reduce the known thrombotic risk associated with high EPO concentrations and may permit correction of Hb to normal levels in CKD and a more rapid amelioration of anemia in cancer.