November 11, 2005
American Society of Nephrology (ASN) Renal Week 2005, Philadelphia, Pennsylvania
Abstract F-PO672
Session: ESRD: Associated Anemia

FG-2216: Tumor Progression Studies and Correction of Anemia of Chronic Disease in Xenograft Models. T. W. Seeley, I. Langsetmo, R. Stephenson, J. Pacleb, D. Gervasi, E. Lomonsgod, S. Klaus and D. Y. Liu. Therapeutics R&D, FibroGen, Inc., South San Francisco, CA.

Abstract: Anemia is a frequent complication of cancer in patients experiencing anemia of chronic disease (also, Anemia of Cancer, AoC) and anemia associated with cancer chemotherapy (Chemotherapy Induced Anemia, CIA). Patient response rates to rHuEpo therapy have been reported in the 50% range in AoC and the 60% range in CIA. Factors adversely affecting erythropoietic response in AoC are common to anemia of chronic disease (ACD) and include inflammatory suppression of endogenous EPO production and erythroid progenitors, increased iron retention, decreased iron absorption, and decreased iron bioavailability in the bone marrow. FG-2216, a novel orally active inhibitor of HIF prolyl hydroxylases designed to activate HIF2, up-regulates EPO and iron mobilization genes, down-regulates hepcidin, and overcomes inflammatory suppression of erythropoiesis. FG-2216 has also been shown to be efficacious in treating anemic CKD patients. Here, FG-2216 was administered to animals for periods of 14 to 70 days in xenograft models of NSCLC. Key hematology parameters (Hct, RBC, Hb) were suppressed in vehicle treated tumor-bearing animals vs. controls, indicating the induction of ACD by xenograft tumors. In tumor-bearing animals, FG-2216 treatment resulted in increases in circulating EPO, RBC, Hb, and Hct, indicating that FG-2216 stimulated erythropoiesis by overcoming functional iron deficiency and inflammatory suppression. As measured by final excised tumor weights, no stimulation of tumor progression by FG-2216 treatment was observed. Similar conclusions were obtained by caliper measurement of tumor volumes in subcutaneous tumor studies. In these studies, FG-2216 treatment was associated with a small to moderate inhibition of tumor development. In an orthotopic model of lung tumor metastasis, FG-2216 treatment groups had lowered incidence of tumor-induced morbidity and metastasis. FG-2216 treatment was well tolerated, with no reduction in mean body weights or increase in frequency of animal deaths. Together, this data supports use of FG-2216 in AoC, CIA, and various other forms of EPO-hyporesponsive ACD, such as uremic CKD patients.