South San Francisco, CA - November 14, 2005 FibroGen, Inc., today announced that advances in the development of FG-2216 for the treatment of anemia and FG-4592, a pioneering therapy for the anemia of chronic disease (ACD), were reported at the American Society of Nephrology (ASN) 38th Annual Meeting & Scientific Exposition, November 8-13, Philadelphia, Pennsylvania. FG-2216 Advances in Multiple Phase 2 Studies Data were presented from ongoing dose escalation studies of FG-2216 in anemic patients with chronic kidney disease (CKD). Previously reported results demonstrate that patients not previously treated with recombinant erythropoietin (EPO) therapy on average exhibit significantly increased levels of hemoglobin (Hb) in response to the low dose of FG-2216 (6 mg/kg) administered orally three times a week for four weeks. As part of ongoing efforts to determine optimal dosing, the study protocol was revised to reduce dosing level and frequency. Early results from the 10 mg/kg dose group demonstrate a mean increase of 2.7 g/dL Hb in patients dosed twice a week for four weeks (1). A second study is evaluating the ability of FG-2216 therapy to maintain Hb levels in patients following discontinuation of recombinant EPO therapy (1). Patients received recombinant EPO therapy for a minimum of sixty days prior to the washout period and were randomized to receive placebo or FG-2216. Patients receiving the low dose of FG-2216 (6 mg/kg, three times a week for four weeks) on average experienced less of a decline in Hb (1.3 g/dL) as compared to the placebo group (1.6 g/dL). The first patient treated with FG-2216 in the originally planned high-dose cohort (20 mg/kg FG-2216) exhibited a 1.8 g/dL increase in Hb at day fourteen after having received five doses of FG-2216 administered over nine days. (This patient was removed from the study to start dialysis for reasons unrelated to study drug.) Based on the robust Hb response of this patient, the Company amended the protocol to reduce the high dose to 15 mg/kg. ""We are very pleased the activity of FG-2216 was confirmed in the low-dose cohorts of both CKD anemia studies,"" said David Y. Liu, Ph.D., Vice President of Research at FibroGen. ""We are now focused on a larger phase 2 study of FG-2216 evaluating optimal dosing frequency and dose levels in order to maintain stable hemoglobin on a dose-titration schedule, which is a common clinical practice employed with erythropoietic therapy to account for individual responses to treatment."" Safety To date, no serious adverse events related to FG-2216 have been observed in more than 125 trial enrollees. The clinical data also show that CKD patients treated with FG-2216 experienced an increase in endogenous EPO, a key component of erythropoiesis, but not vascular endothelial growth factor (VEGF). - Tumor Progression Studies / Anemia of Cancer Models: In six different tumor models of lung, colon, and prostate cancers, FG-2216 did not increase VEGF and did not promote tumor progression (2). In addition, FG-2216 treatment resulted in increases in circulating EPO, red blood cells, Hb, and hematocrit, indicating that FG-2216 stimulated erythropoiesis by overcoming functional iron deficiency and inflammatory suppression. Similarly, FG-2216 was shown to correct anemia in a model of inflammation-induced anemia relevant to the ACD clinical setting (3).
- Endogenous EPO Levels at Active Dose; Thrombotic Action of EPO: The circulating levels of endogenous EPO induced by FG-2216 were only three to five times above baseline, which is at least one order of magnitude lower than levels reported in patients treated with recombinant EPO products. The relatively modest elevation of endogenous EPO observed with the low dose of FG-2216 is consistent with EPO levels in Chuvash people who have a congenital mutation leading to constitutive HIF stabilization and polycythemia (4). In light of an emerging body of evidence suggesting that abnormally high levels of EPO are directly prothrombotic, the Company believes that Hb levels could potentially be raised to the normal range using FG-2216 employing EPO doses far lower than current therapy and potentially with reduced risk of thrombosis that otherwise limits the amount of anemia correction permissible with current therapy.
FG-4592 Therapy for Anemia of Chronic Disease (ACD)The Company also presented data on FG-4592 (5), designed for treatment of anemia of chronic disease (ACD), which recently entered phase 1 testing. ACD, caused primarily by inflammatory suppression of erythropoiesis, is a common complication in millions of patients with cancer, rheumatoid arthritis, inflammatory bowel disease and other chronic diseases. A significant percentage of patients with ACD, as well as patients with CKD anemia and chemotherapy-induced anemia, are hyporesponsive (inadequate correction of low Hb levels) to current therapy. - Hepcidin Reduction: FG-4592 was reported to dramatically reduce abnormally high levels of hepcidin back to normal levels and restore the natural balance in iron regulation in an experimental model of inflammation-induced anemia. Hepcidin, a hormone that regulates the availability of iron for erythropoiesis, is known to be the key mediator of anemia caused by inflammation. Inflammation causes upregulation of hepcidin, leading to degradation of the iron transporter protein ferroportin. Downregulation of hepcidin by FG-4592 prevents ferroportin degradation and leads to improvement of iron mobilization and utilization. Iron availability for erythropoiesis is an important factor in treating anemia, which recombinant EPO therapy alone fails to address.
- Microcytosis Alleviation: In the same model as described above, FG-4592 alleviated microcytosis (abnormally small red blood cells) and hypochromia (lack of Hb) and corrected anemia. By comparison, a dose of darbepoetin alfa that produced robust increases in Hb in normal animals had no effect in animals with ACD. Microcytosis and hypochromia are indicative of functional iron deficiency, which is symptomatic of ACD in multiple clinical settings.
- Phase 1 Safety Study Initiated: The Company reported initiation of a phase 1, single-dose, dose-escalation study of FG-4592 in normal subjects. Early results demonstrate the potential for FG-4592 to treat anemia as evidenced by increases in endogenous EPO up to eight-fold above baseline following a single oral dose. Previous preclinical and clinical studies demonstrate that therapeutically relevant increases in Hb are observed following a two- to three-fold elevation in endogenous EPO levels resulting from repeated intermittent dosing. No serious adverse events related to FG-4592 have been reported.
""We believe the data continue to suggest that the unique ability of FG-2216 to activate and coordinate the body's natural mechanisms for correcting anemia could provide a safe and effective therapy for anemia at a competitive cost to blood transfusions, which are used to treat the majority of patients with anemia world-wide,"" said Thomas B. Neff, Chief Executive Officer of FibroGen. ""In addition, the advancement of FG-4592 into human clinical trials is an important milestone that affords us flexibility in developing novel therapies for anemia and reduces development risk inherent in any drug discovery program. We will continue to advance FG-2216 and FG-4592 through clinical testing and be data-driven in our development strategy."" References - Guenzler V, Muthukrishnan E, Neumayer HH, Sacherer K, Schmidt R, Mitzner A, Wiecek A, Piecha G, Ignacy W, and Scigalla P (2005) FG-2216 Increases Hemoglobin Concentration in Anemic Patients with Chronic Kidney Disease (Abstract SA-PO924). J Am Soc Nephrol 16:758A. (Abstract).
- Seeley TW, Langsetmo I, Stephenson R, Pacleb J, Gervasi D, Lomonsgod E, Klaus S, and Liu DY (2005) FG-2216: Tumor Progression Studies and Correction of Anemia of Chronic Disease in Xenograft Models (Abstract F-PO672). J Am Soc Nephrol 16:481A. (Abstract).
- Langsetmo I, Nichols B, Seeley T, Stephenson R, Klaus S, Lin A, and Liu DY (2005) FG-2216 Corrects Anemia and Improves Iron Utilization in a Rat Model of Anemia of Chronic Disease: Comparison to Darbepoetin (Abstract F-PO674). J Am Soc Nephrol 16:481A. (Abstract).
- Gordeuk VR, Sergueeva AI, Miasnikova GY, Okhotin D, Voloshin Y, Choyke PL, Butman JA, Jedlickova K, Prchal JT, and Polyakova LA (2004) Congenital disorder of oxygen sensing: association of the homozygous Chuvash polycythemia VHL mutation with thrombosis and vascular abnormalities but not tumors. Blood 103:3924-32. (Abstract on PubMed).
- Klaus S, Arend M, Fourney P, Flippin L, Gervasi D, Guenzler V, Kochendoerfer G, Langsetmo I, Lin A, Lomongsod E, McDaniel D, Meier-Davis S, Seeley T, Spong S, and Liu D (2005) Induction of Erythropoiesis and Iron Utilization by the HIF Prolyl Hydroxylase Inhibitor FG-4592 (Abstract F-FC050). J Am Soc Nephrol 16:49A. (Abstract).
About FibroGenFibroGen, 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 [email protected] "
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