South San Francisco, Calif. - August 22, 2006 - FibroGen, Inc. today announced that the Company has received a Phase II Small Business Innovation Research (SBIR) grant from the National Heart, Lung, and Blood Institute (NHLBI), part of National Institutes of Health (NIH), which provides continued support for the development of FibroGen hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors as therapeutic agents to treat sickle cell disease (SCD).

SCD is an inherited blood disorder that affects millions of people worldwide, and is caused by a genetic mutation in the adult form of hemoglobin (the oxygen-carrying molecule in red blood cells). This mutation causes the formation of sickle-shaped red blood cells, which are less deformable, more fragile and susceptible to hemolysis, leading to anemia and episodic vaso-occlusive crises and pain when sickling occurs and tissues are deprived of oxygen.

FibroGen is already conducting multiple phase 2 clinical studies of HIF-PH inhibitors that stimulate erythropoiesis for the treatment of anemia, including the Company's lead candidate, FG-2216, in the settings of chronic kidney disease and cancer. Erythropoietic HIF-PH inhibitors increase the body's endogenous production of erythropoietin, a hormone that stimulates the production of red blood cells, normalize iron regulation, and reduce the adverse effects of inflammatory cytokines that otherwise suppress the formation of healthy red blood cells.

The SCD research program at FibroGen seeks to combine the erythropoietic effects of HIF-PH inhibitors with the additional capacity to elevate fetal hemoglobin (HbF). The replacement of mutant adult hemoglobin with HbF has long been recognized as a means to mitigate the pathophysiology of SCD. Hydroxyurea, a chemotherapeutic agent, is the only approved therapy and the standard of care for SCD, and is thought to work in part by this mechanism. Its use is limited, however, by myelosuppression and bone marrow toxicity which exacerbates anemia and increases risk of serious infection and bleeding. FibroGen's Phase I SBIR research showed that HIF-PH inhibitors with demonstrable erythropoietic effects can also act alone or in synergy with hydroxyurea to raise levels of HbF in human erythroid progenitor cells.

Work conducted under the Phase II SBIR grant will focus on the identification of HIF-PH inhibitors that are effective in raising HbF either alone or in combination with hydroxyurea in a model of chronic anemia. From these studies, a HIF-PH inhibitor will be selected as a therapeutic candidate for clinical testing in patients with SCD.

"Our research indicates that using novel HIF-PH inhibitors designed to stimulate HbF may address the common and debilitating symptom of anemia affecting individuals with SCD to improve clinical outcomes," said David Y. Liu, Ph.D., Vice President of Research at FibroGen. "We appreciate NHLBI's continued support and recognition of the value of our work."

HIF-PH inhibitors as novel inducers of fetal hemoglobin (HbF) for treating SCD

A putative therapeutic approach to treat SCD was recognized more than fifty years ago when it was observed that infants with SCD do not manifest pathophysiological symptoms during the first six months after birth, at a time when expression of HbF and the fetal gamma-chain remain high. The benefits of elevated HbF expression also are evident in patients who harbor the sickle cell mutation and an additional mutation for hereditary persistence of fetal hemoglobin (HPFH). Populations with HPFH exhibit elevated HbF expression, which persists throughout adulthood, and do not manifest the clinical pathologies of SCD despite having the beta-chain mutation. The decrease in the pathophysiological consequences of SCD that are associated with elevated HbF expression ostensibly occur as a result of substituting the absent or mutated beta-chain with a functional gamma-chain.

The rationale underlying FibroGen's HIF-PH inhibitor therapeutic program for SCD is guided by published reports demonstrating that the expression of HbF can be induced in primates, including humans, by exposure to hypoxic conditions^1,2. In nature, HbF expression is most pronounced during fetal development at a time when intrauterine oxygen levels are low³, and research indicates that HIF is a critical mediator of gene expression in this hypoxic environment.

Other studies show that HbF levels are higher in hypoxemic children², and infants born at high altitude have elevated levels of HbF as compared to infants born at sea level⁴. In addition, cultures of erythroid progenitor cells (immature red blood cells) derived from SCD patients can be induced to increase expression of HbF when subjected to experimental hypoxic conditions^5,6.

FibroGen's research demonstrates that through the stabilization of HIF, certain HIF-PH inhibitors elevate HbF alone and in synergy with hydroxyurea in primary human CD34+ bone marrow cells that were induced to undergo erythroid differentiation ex vivo. In addition, certain HIF-PH inhibitors have been found to upregulate heme oxygenase-1, which catabolizes free heme that would otherwise limit nitric oxide bioavailability and contribute to vaso-occlusive ischemic crises in SCD patients. Further studies of HIF-PH inhibitors' effects on increasing erythropoiesis and elevating levels of HbF will be conducted in primate models of chronic anemia to evaluate the potential of using select HIF-PH inhibitors in the clinical setting of SCD.

References

1. DeSimone J, Biel SI, and Heller P. Stimulation of fetal hemoglobin synthesis in baboons by hemolysis and hypoxia. Proc. Natl. Acad. Sci. USA 1978; 75:2937-2940.

2. Bard H, Fouron JC, Gagnon C and Gagnon J. Hypoxemia and increased fetal hemoglobin synthesis. The Journal of Pediatrics 1994; 124:941-3.

3. Atweh GF and Schechter AN. Pharmacologic induction of fetal hemoglobin: raising the therapeutic bar in sickle cell disease. Current Opinion in Hematology 2001; 8:123-130.

4. Ballew C and Hass JD. Hematologic evidence of fetal hypoxia among newborn infants at high altitude in Bolivia. American Journal of Obstetrics and Gynecology 1986; 155:166-169.

5. Fibach E, Burke LP, Schechter AN, Noguchi CT, and Rodgers GP. Hydroxyurea increases fetal hemoglobin in cultured erythroid cells derived from normal individuals and patients with sickle cell anemia or beta-thalassemia. Blood 1993; 81:1630-1635.

6. Weinberg RS, Acosta R, Knobloch ME, Garber M, and Alter BP. Low oxygen enhances sickle and normal erythropoiesis and fetal hemoglobin synthesis in vitro. Hemoglobin 1995; 19:263-275.

FibroGen, Inc., is a biotechnology-based drug discovery company using its expertise in the fields of tissue fibrosis, connective tissue growth factor (CTGF), and hypoxia-inducible factor (HIF) biology to discover, develop, and commercialize novel therapeutics for fibrotic disorders, diabetic complications, 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.

Contact:
Laura Hansen 650-866-7828 or lhansen@fibrogen.com