SAN FRANCISCO
FibroGen, Inc., today announced preliminary clinical findings from an ongoing open-label Phase 2 study demonstrating the safety and efficacy of FG-4592, investigational oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor (PHI), in the correction of anemia in patients with end-stage renal disease who recently started dialysis with no iron, with oral iron, or with intravenous (IV) iron supplementation.
For the majority of dialysis patients worldwide, the treatment of chronic kidney disease (CKD) anemia with erythropoiesis-stimulating agents (ESAs) is initiated together with dialysis. Accordingly, the inclusion of newly initiated dialysis patients in the evaluation of FG-4592 is significant as this segment of the CKD population represents the majority of patients who initiate anemia therapy. These patients generally have no prior experience with ESAs, particularly those who have not seen a nephrologist prior to starting ESRD therapy. Newly initiated dialysis patients are also at high risk of mortality prior to stabilization on dialysis therapy.1 It is during the first 3-4 months of dialysis (incident dialysis) therapy that the highest ESA dose consumption, high cardiovascular (CV) event rates, and highest mortality rate are observed. Anemia correction with ESAs in end-stage renal disease (ESRD) patients has been associated with frequent hypertensive adverse events (19% to 45%) and with iron depletion. Further, ESRD patients often require intravenous (IV) iron supplementation because oral iron supplementation may be ineffective in this population.
The randomized, open-label Phase 2 study of FG-4592 in incident dialysis patients (Study 053) is being conducted at clinical sites in the U.S., Hong Kong, and Russia, and includes patients on hemodialysis for two weeks to four months, with baseline hemoglobin ≤ 10.0 g/dL, who are randomized to three arms (N=12/arm) to receive FG-4592 thrice weekly for 12 weeks without iron, with oral iron, or with intravenous iron. Another arm evaluated FG-4592 with oral iron in peritoneal dialysis patients (N=12). A confirmatory arm further assessed FG-4592 without iron in hemodialysis patients (N=12). Initial FG-4592 doses were tiered by weight; dose adjustments are allowed every four weeks. The study population was chosen as the group of patients who typically require the highest ESA doses and the most substantial need for iron supplementation associated with ESA therapy.
Preliminary data indicate that treatment with oral FG-4592 thrice weekly increased mean hemoglobin in incident dialysis patients in the first 8 weeks, regardless of supplementation with IV iron or oral iron, or with no iron supplementation. Clinical data up to 12 weeks suggest that oral iron supplementation to FG-4592 therapy is as effective as IV iron, likely associated with HIF-induced modulation of iron availability for coordinated erythropoiesis, as differentiated from ESA therapy, in which IV iron supplementation is required for effective anemia treatment.
These findings were presented by Anatole Besarab, MD, of Henry Ford Hospital in Detroit, Michigan, in an oral presentation on Thursday, November 1st, at American Society of Nephrology (ASN) Kidney Week 2012 in San Diego, California. (Besarab et al., Oral Program # TH-OR096, “FG-4592, an Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor, Corrects Anemia Without Iron Supplementation in Incident Dialysis Patients.”)
“FG-4592 is the first agent which allows integration of red blood cell production and efficient iron incorporation, simultaneously,” said Dr. Besarab. “Other approaches to treatment of anemia in chronic kidney disease patients require the separate management of ESA and of iron dosing.”
Data show FG-4592 to be as effective when used with oral iron as when used with IV iron, even in patients with elevated C-reactive protein (CRP), which is associated with inflammation and known to dampen hemoglobin responsiveness in ESA therapy. This is in contrast to the IV iron supplementation required for optimal epoetin α-driven erythropoiesis in incident dialysis patients, in which oral iron was found to be ineffective when administered with recombinant EPO.2 Accordingly, FG-4592 therapy can potentially avoid the documented safety liabilities associated with the use of IV iron.3
FG-4592 was found to be well tolerated in the study population, with no evidence of hepatotoxicity and no study drug-related serious adverse events.
“These encouraging preliminary clinical findings suggest that FG-4592 may be able to overcome common and deleterious effects of ESA therapy,” said Thomas B. Neff, Chief Executive Officer of FibroGen. “We continue to see signs of potential therapeutic advantages, including the ability of FG-4592 to effectively treat anemia and to do so safely, by modest increases in erythropoietin levels to within physiologic range, while promoting iron bioavailability.”
About Anemia of Chronic Kidney Disease (CKD)
CKD is a worldwide critical healthcare problem that affects millions of people and drives significant healthcare cost. In the U.S., prevalence of CKD has increased dramatically in the past 20 years, from 10% of the U.S. adult population (or approximately 20 million U.S. adults) per the National Health and Nutrition Evaluation Survey (NHANES) 1988-1994, to 15% (or approximately 30 million adults) in NHANES 2003-2006. In 2009, total Medicare costs for CKD patients were $34 billion.
Anemia is the condition of having fewer red blood cells and/or lower hemoglobin levels than is normal. The prevalence of anemia increases with the progression of CKD and is a demonstrated risk multiplier in patients with preexisting cardiovascular disease. Anemia has been associated with adverse outcomes in CKD patients, increased hospitalization rates, increased mortality, and reduced quality of life, but the condition tends to be undertreated due in part to the cost and complexity of treatment with injectable erythropoiesis-stimulating agents (ESAs) and intravenous iron supplements. Whereas nearly all patients on hemodialysis have easy access to ESA therapy, only 2% of CKD patients receive treatment with ESAs prior to referral to a nephrologist in the U.S.1 Under-treatment of anemia in the primary care setting can be attributed in part to lack of convenience and reimbursement rules, requiring physicians to buy ESA inventory and bill after procedures. This deters physicians in the primary care setting where anemic patients are a minority of total patients. The company estimates there are 1 million late-stage CKD patients (CKD Stages 3-5) with anemia in the U.S., and less than 20% are treated with ESAs prior to initiation of dialysis.1
About FG-4592
FibroGen is developing FG-4592, a novel oral HIF-PHI, for the treatment of anemia in patients with CKD. FG-4592 has been shown to correct and maintain hemoglobin levels in patients with CKD not receiving dialysis4 and in patients with end-stage renal disease receiving dialysis5 without the need for supplementation with intravenous iron. An Independent Data Monitoring Committee has found no signals or trends to date to suggest that treatment with FG-4592 is associated with increased risk of cardiovascular events, thrombosis, or increases in blood pressure requiring initiation or intensification of antihypertensive medications.
Global Development of FG-4592
FG-4592 is in clinical development in the U.S., Europe, Japan, and the People’s Republic of China. Multiple clinical trials in the U.S. have progressed toward commencement of Phase 3 clinical development in the U.S. and Europe by the end of 2012. In Japan, Astellas has completed Phase 1 studies and plans to begin Phase 2 studies soon. On September 20, 2010, FibroGen announced that the Chinese State Food and Drug Administration had granted FibroGen a clinical trial application approval to commence Phase 1 and Phase 2 clinical development for FG-4592 for the treatment of anemia associated with CKD in the People’s Republic of China. Phase 1 in China is completed, and FibroGen has completed dosing in all patients in two Phase 2 studies in CKD anemia, in patients on dialysis and in patients not on dialysis. Phase 3 clinical development in China is expected to commence in 2013.
Astellas has licensed certain rights from FibroGen to FG-4592 (Astellas designation ASP1517) in Japan, Europe, the Commonwealth of Independent States, the Middle East, and South Africa. As part of these agreements, Astellas pays 50% of development costs for FG-4592 in the U.S. and Europe, and makes milestone payments for clinical advancement and approvals in Europe and in Japan, as well as other subsequent events. FibroGen retains rights to its anemia therapies in North America and South America, remaining parts of Africa, and all of Asia Pacific ex-Japan.
About FibroGen, Inc.
FibroGen, Inc. is a biotechnology company focused on the discovery, development, and commercialization of therapeutics for fibrosis, anemia, cancer, and other serious unmet medical needs. FibroGen’s research into the role of CTGF in various proliferative diseases has led to the development of therapies for the treatment of idiopathic pulmonary fibrosis and cancers, including pancreatic cancer, and other life-threatening disorders. FibroGen’s expertise in the area of prolyl hydroxylase inhibition has led the development of an extensive library of small molecule inhibitors of hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors, including FG-4592 and FG-6874, currently in clinical development for the treatment of anemia. FibroGen also develops and produces recombinant biomaterials, such as human collagens and gelatins, for various purposes, and is currently pursuing the use of recombinant human type III collagen in synthetic corneas for treatment of corneal blindness. FibroGen was founded in 1993 and is based in San Francisco, California.
For more information about FibroGen, Inc., please visit www.fibrogen.com.
- U.S. Renal Data System, USRDS 2012 Annual Data Report: Atlas of Chronic Kidney and End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2012
- MacDougall et al (1996) Kidney Int., 50:1694-1699.
- Kalantar-Zadeh et al (2005) J Am Soc Nephrol 16:3070
- Besarab A, et al (2011) J Am Soc Nephrol 22:196A
- Provenzano R, et al. (2011) Am. J. Kidney Dis Vol. 57 4:B80
CONTACT
FibroGen, Inc.
Meichiel Keenan, 415-978-1431
mkeenan@fibrogen.com
