FibroGen Investigational Small Molecule Anemia Therapy, FG-2216, Increased Endogenous EPO Production in Humans.

ST. LOUIS -- Results of FG-2216 Safety Study Reported at American Society of Nephrology Annual Meeting

FibroGen, Inc., today announced that oral administration of FG-2216, the Company's investigational therapy for anemia, was safe and well tolerated and significantly increased production of endogenous erythropoietin (EPO) in healthy human subjects. FG-2216 given orally two or three times weekly also increased the number of circulating reticulocytes (young red blood cells) compared with placebo over the course of administration.

These data were part of multiple abstracts evaluating the effect of FG-2216, an inhibitor of hypoxia-inducible factor-prolyl hydroxylase (HIF-PH), and other FibroGen HIF-PH inhibitors in stimulation of erythropoiesis (the production of red blood cells) and the treatment of anemia and of iron processing deficiency in experimental models, which were presented at Renal Week 2004, the annual meeting of the American Society of Nephrology (ASN) being held in St. Louis, Missouri, October 27th - November 1st.

"The clinical results regarding FG-2216 provide the first demonstration in humans of an erythropoietic response to an entirely novel class of HIF-PH inhibitors," said Pedro Urquilla, M.D., Vice President of Medical Affairs at FibroGen. "FibroGen is now conducting clinical studies evaluating various dosing regimens of FG-2216 in patients with anemia of chronic kidney disease."

In addition to the clinical study results of FG-2216 regarding induction of endogenous EPO and of reticulocytes, the Company presented preclinical data demonstrating the ability of FG-2216 and other erythropoiesis-stimulating FibroGen HIF-PH inhibitors to overcome inflammatory cytokine-mediated suppression of EPO secretion, to improve iron status and microcytosis and reverse anemia in a model of anemia of chronic disease, and to correct anemia in preclinical models of end-stage renal disease and cisplatin-induced anemia.

"The human proof of concept demonstrated with FG-2216 is a major milestone in our development of a first-in-class small molecule therapy for anemia," said Thomas B. Neff, Chief Executive Officer of FibroGen. "With a unique mechanism of action, the convenience of oral administration, and the cost effectiveness of a small molecule therapy, FG-2216 offers the potential to expand existing markets for anemia therapy, to open new markets where recombinant EPO is not approved or used, and to offer a better therapeutic approach in markets where intravenous iron and anti-inflammatory agents are required in addition to recombinant EPO."

Upregulation of Endogenous EPO in Healthy Subjects by Inhibition of HIF-PH (Abstract SU-PO062)(1)

This Phase 1 study was conducted in 68 healthy male subjects (54 treated, 14 placebo) to determine the safety, tolerability, pharmacokinetics, and biologic activity of FG-2216 dosed orally. Doses of FG-2216 ranging from 0.3 to 20 mg/kg were well tolerated, and no dose-limiting toxicities or serious adverse events were observed. Adverse events possibly related to FG-2216 included nausea and headache but were mild and subsided with continued administration.

Oral dosing of FG-2216 indicated excellent absorption, and serum levels of FG-2216 increased in a dose-dependent fashion; its elimination was characterized by a half-life of approximately 14 hours.

Doses of 6 mg/kg and higher were associated with a marked dose-dependent elevation in serum EPO levels. Repeated dosing (twice or three times weekly) for two to three weeks was associated with a consistent increase in EPO production with no evidence of desensitization. The increases in mean endogenous EPO observed were as high as 500% above baseline levels and were well in excess of those associated with effective erythropoiesis reported in a study of intermittent hypoxia in normal subjects(2). In addition, reticulocyte responses observed in response to repeated dosing with FG-2216 were consistent with intermittent hypoxia-induced reticulocyte responses in normal subjects. Taken together, the data suggest that effective red blood cell production can be achieved by oral administration of FG-2216.

Novel Prolyl Hydroxylase Inhibitors Overcome Inflammatory Cytokine-Mediated Suppression of EPO Secretion (Abstract SA-PO672)(3)

This in vitro study examined the therapeutic potential of FibroGen HIF-PH inhibitors in treating patients with anemia of chronic disease (ACD), which occurs as a result of the inflammation associated with chronic inflammatory diseases such as rheumatoid arthritis, ulcerative colitis and cancer, or uremia caused by chronic kidney disease (CKD).

The pathology of ACD is partly mediated through the suppression of EPO gene expression by inflammatory cytokines such as TNF-alpha and IL-1beta. IL-6 expression is often elevated in ACD; however, IL-6 has both pro- and anti-inflammatory effects and has been found to upregulate EPO expression during hypoxia.

FibroGen scientists demonstrated that HIF-PH inhibitors overcome the suppression of EPO production in the presence of inflammatory cytokines and synergize with IL-6 to further elevate EPO secretion thereby supporting the potential of using FibroGen HIF-PH inhibitors to treat ACD.

Effect of FG-2216 on Anemia and Iron Transport in a Rat Model of Anemia of Chronic Disease (Abstract SU-PO072)(4)

This in vivo study examined the effect of FG-2216 on gene expression and on hematologic outcomes in a rat model of ACD in which systemic inflammation induces a severe, acute anemia, which is followed by a protracted, mild to moderate microcytic anemia.

The results demonstrated that FG-2216 normalized expression of hepcidin (a factor that decreases dietary iron absorption) in challenged animals, and increased expression of duodenal cytochrome b reductase and Slc11a2 (Nramp2) (factors that facilitate intestinal iron absorption), leading to improved iron status in the FG-2216 treated group. FG-2216 also increased iron and transferrin saturation and hematocrit, hemoglobin, red cell count, reticulocyte count, mean cell volume and mean cell hemoglobin and restored those parameters to levels not different from unchallenged controls.

Recombinant EPO is currently not approved for ACD, and uremic CKD patients are often non-responsive or refractory to recombinant EPO due to deficient iron utilization and inflammation. The results from the rat model of ACD and the in vitro results regarding cytokine-mediated inflammatory suppression of EPO secretion (see Abstract SAPO672) support the potential of using FG-2216 or another FibroGen HIF-PH inhibitor to treat anemias that have been shown to be resistant to recombinant EPO therapy, such ACD, iron processing deficiency, and uremic CKD.

Stimulation of Erythropoiesis and Treatment of Anemia in Rodents by Oral Administration of FG-2216, a Novel HIF-Prolyl Hydroxylase Inhibitor (Abstract PUB052)(5)

This abstract summarized the results of several studies suggesting a number of important clinical applications of using FibroGen HIF-PH inhibitors to treat anemic conditions ranging from kidney failure to anemia of chronic disease to cancer chemotherapy to surgical blood loss.

In normal mice and rats, FG-2216 was reported to elevate serum concentration of endogenous EPO, increase reticulocyte counts, and raise hematocrit and hemoglobin in a dose-dependent and schedule-related fashion.

Studies were also described demonstrating that FG-2216 prevents anemia associated with acute renal failure in a rat model of renal ischemia-reperfusion injury; corrects anemia associated with end-stage renal failure in a rat remnant kidney model; improves anemia induced in rats by the chemotherapeutic agent cisplatin; and accelerates recovery from phlebotomy-induced anemia in mice.

About HIF and Erythropoiesis

Virtually all tissues depend on a supply of oxygen in sufficient amounts for survival. As a consequence, hypoxia (lack of oxygen) triggers a series of emergency responses. These responses comprise a highly evolved system of protective physiology that is conserved across aerobic organisms. HIF is a key protein that coordinates the several compensatory changes comprising the hypoxic response. When blood delivered to the kidney does not contain enough oxygen, for example, HIF activates the EPO gene and other genes involved in iron metabolism and hemoglobin synthesis. By coordinating the entire erythropoietic process, HIF promotes the production of properly formed mature red blood cells, helping to restore delivery of sufficient oxygen to the body.

About FG-2216

FG-2216 is an orally active, small molecule inhibitor of HIF-PH, an enzyme that regulates the stability and activity of HIF. FG-2216 is designed to stabilize HIF and selectively activate the body's natural process of HIF-mediated erythropoiesis, including the induction of endogenous EPO and the mobilization and utilization of iron stores, essential to the formation of new oxygen-carrying red blood cells.

In 2004, FibroGen entered an agreement to license FG-2216 to Yamanouchi Pharmaceutical Co., Ltd., for development and sale in Japan for the treatment of anemia. FibroGen retains rights to FG-2216 for the rest of the world.

References

1. Urquilla P, Fong A, Oksanen S, Leigh S, Turtle E, Flippin L, Brenner M, Muthukrishnan E, Fourney P, Lin A, Yeowell D, Molineaux C (2004) Upregulation of Endogenous EPO in Healthy Subjects by Inhibition of HIF-PH (abstract SU-PO062). J Am Soc Nephrol 15: 546A

2. Rodriguez FA, Ventura JL, Casas M, Casas H, Pages T, Rama R, Ricart A, Palacios L, Viscor G (2000) Erythropoietin Acute Reaction and Haematological Adaptations to Short, Intermittent Hypobaric Hypoxia. Eur J Appl Physiol 82: 170-177

3. Klaus S, Gervasi D, Spong S, Lomongsod E, Arend M, Flippin L, Liu D, Guenzler V (2004) Novel Prolyl Hydroxylase Inhibitors Overcome Inflammatory Cytokine-Mediated Suppression of EPO Secretion (abstract SA-PO672). J Am Soc Nephrol 15: 449A - 450A

4. Langsetmo I, Young B, Zhang W, Guenzler V, Seeley T, Stephenson R, Molineaux C, Liu D, Lin A (2004) Effect of FG-2216 on Anemia and Iron Transport in a Rat Model of Anemia of Chronic Disease (abstract SU-PO072). J Am Soc Nephrol 15: 548A

5. Wang Q, Guo G, Guenzler V, Neff T, Klaus S, Turtle E, Molineaux C, Yeowell D, Lin A (2004) Stimulation of Erythropoiesis and Treatment of Anemia in Rodents by Oral Administration of FG-2216, a Novel HIF Prolyl Hydroxylase Inhibitor (abstract PUB052). J Am Soc Nephrol 15: 773A

About FibroGen

FibroGen, Inc., is a biotechnology-based drug discovery company using its expertise in the fields of tissue fibrosis and hypoxia-inducible factor (HIF) biology to discover, develop, and commercialize novel therapeutics for fibrotic disorders, anemia, ischemic disease, cancer, and other areas of unmet medical need. FibroGen also develops and produces recombinant human collagens and gelatins using unique production technology that provides the basis for FibroGen's proprietary cosmetic dermal filler and biomaterials supply business.

For more information about FibroGen, Inc., please visit www.fibrogen.com.