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FibroGen Announces Preliminary Clinical Findings on the Positive Effects of FG-4592, Its Investigational HIF-PHI Therapy for Anemia, on Lowering Blood Pressure and Cholesterol in Patients with Chronic Kidney Disease
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San Francisco, CA - June 4, 2012 FibroGen, Inc., today announced preliminary clinical findings from two ongoing, open-label phase 2 studies demonstrating that FG-4592, its investigational oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor (PHI) therapy for anemia, reduced blood pressure in hypertensive patients, reduced cholesterol levels, and improved the ratio of HDL to LDL in lipid profiles, in patients with chronic kidney disease (CKD). Hypertension and dyslipidemia are two of the major risk factors associated with increasing cardiovascular risk in patients with advanced CKD Stages 3b through 5. Current anemia therapy using erythropoiesis-stimulating agents (ESAs) is known to increase hypertension in CKD patients, especially during the period of hemoglobin correction. ESA-induced elevation of blood pressure often necessitates initiation of, or increases in, antihypertensive medications in patients with CKD.1,2 “The ability to treat anemia without ESA-induced hypertension would be a major advance in care of patients with Stage 3 or Stage 4 CKD,” said George L. Bakris, MD, Department of Medicine, ASH Comprehensive Hypertension Center, The University of Chicago Medicine, Chicago, IL. “The preliminary data show that FG-4592 therapy is not associated with increased blood pressure while hemoglobin is corrected in CKD patients, and may even reduce hypertension in patients taking FG-4592 three times a week. The observed effects of FG-4592 on lowering cholesterol and improving lipid profile can potentially contribute to additional clinical benefits in treating CKD patients.” Dr. Bakris reported new data related to the effects of FG-4592 on hypertension and cholesterol in a late-breaking clinical session at the annual meeting of the American Society of Hypertension (ASH) on May 22, 2012 in New York (Abstract #LB-OR-06). FibroGen also gave a related presentation at the annual meeting of the European Renal Association- European Dialysis and Transplant Association (ERA-EDTA) on May 25, 2012 in Paris, France (Abstract # FP-215). Data described were from two ongoing, randomized, open-label studies of FG-4592 in patients with Stages 3-4 CKD not receiving dialysis (Study 041) and in patients with ESRD receiving dialysis (Study 040). · In Study 041, a total of 145 patients with Stages 3-4 CKD and anemia (hemoglobin ≤ 10.5 g/dL) were randomized to receive FG-4592 for 16 or 24 weeks using a range of starting doses, dose frequencies, and dose adjustment guidelines. · In Study 040, a total of 159 ESRD patients previously taking epoetin alfa (an ESA) were randomized to take FG-4592 thrice weekly or continue on epoetin alfa for 6 or 19 weeks. There were no protocol-specified restrictions on number of blood pressure and lipid medications used or thresholds for changing medications in either study. Effect of FG-4592 on Blood Pressure in CKD Patients Not on Dialysis · No Increase in Blood Pressures Overall Exploratory analyses on the effect of FG-4592 on blood pressure were reported for Study 041. Ninety percent (90%) of patients were taking antihypertensive medications upon study entry. For those who completed treatment and took FG-4592 twice or thrice weekly (n=94), a slight decrease in blood pressure from baseline compared with the end of treatment was observed, although statistical significance was not reached. · High Blood Pressures Reduced Significantly In a subgroup analysis of those who took FG-4592 thrice weekly (TIW) and did not have any changes in blood pressure medication (n=39), there was a significant mean reduction from baseline to the end of treatment in systolic (-5.3±2.4 mmHg, p=0.03) and diastolic (-2.5±1.1 mmHg, p<0.03) blood pressure, and a significant mean increase in systolic blood pressure from the end of treatment compared to the follow-up period (3.3±1.5 mmHg, p<0.04). Mean baseline blood pressure levels were 132.5±2.3 (systolic) and 68.6±1.2 (diastolic). · Adverse Event Rates Similar to Historical Placebo Controls Seven percent (7%) of patients reported an adverse event of hypertension. This rate is markedly lower than that reported in the medical literature for ESA studies3,4 and resembles rates found in placebo treated groups in prior FibroGen studies of similar patients for similar lengths of treatment duration.5,6 Effect of FG-4592 on Cholesterol in CKD Patients Not on Dialysis · Independent of Statins and Fibrates In Study 041, approximately two-thirds of the patients were taking lipid-lowering agents (primarily statins and fibrates). Mean decreases from baseline in total cholesterol were observed in all FG-4592 treatment groups; levels rebounded after FG-4592 treatment was completed. Mean decreases in total cholesterol after 16 weeks of treatment with FG-4592 were similar for those taking concomitant lipid lowering agents (-16.5±4.2 mg/dL) and those who were not (-16.2±1.5 mg/dL). · LDL, VLDL, and Triglycerides Lowered More than Total Cholesterol Preliminary lipid panel testing from frozen samples in a subset of patients (n=28) showed mean reductions from baseline at week 9 in LDL (18%±4%, p<0.0001), VLDL (14%±8%, p=0.014), triglycerides (13%±8%, p=0.015), and HDL (8%±3%, p=0.002). For patients already taking statins but whose LDL at baseline remained above normal (>100 mg/dL, n=4), FG-4592 treatment was associated with LDL reductions ranging from 7.0% to 33%. · HDL/LDL Ratio Improved The HDL/LDL ratio increased from a mean of 0.56 at baseline to 0.67 at week 9 (p=0.013). Maintenance Therapy with FG-4592 in Dialysis Patients · FG-4592 Lowered Cholesterol While ESA Raised Cholesterol In Study 040, interim data show that ESRD patients on dialysis taking FG-4592 to maintain hemoglobin levels (n=91) achieved a mean reduction in total cholesterol from baseline of 20%±15% at week 6 compared with an increase in total cholesterol of 4% ±16% for patients taking epoetin alfa (n=32), p< 0.0001. The durability of the FG-4592 effect on lowering cholesterol was demonstrated as a mean reduction in total cholesterol from baseline of 17%±15% at week 19 in patients treated with FG-4592 (n=41) compared with a mean increase in total cholesterol of 6%±18% in patients treated with epoetin alfa (n=14), p<.0001. · FG-4592 More Effective in Patients with Higher Total Cholesterol Patients with elevated baseline total cholesterol levels (>200 mg/dL) underwent a greater mean reduction in total cholesterol at week 6 in response to FG-4592 treatment, compared with patients with normal baseline total cholesterol (≤ 200 mg/dL) (25% versus 19%, p=0.0005). “These new, preliminary clinical observations suggest that FG-4592 may offer additional therapeutic benefits beyond treating anemia in CKD patients,” said Thomas B. Neff, Chief Executive Officer of FibroGen. “The possibility that FG-4592 can lower blood pressure and cholesterol levels, and improve the lipid profile, is consistent with preclinical observations using FibroGen’s HIF-PHI technology. We believe that FG-4592 as a first-in-class oral HIF-PHI for treating anemia has the potential to overcome the common and serious side effects of ESAs such as hypertension, thrombosis, and functional iron deficiency and iron depletion. These new data suggest the potential for lowering the overall cardiovascular and cerebrovascular risks in longer term use of FG-4592, consistent with the current understanding of lipid lowering and hypertension control in CKD patients. We are looking forward to testing this in phase 3 studies planned to begin by the end of the year.” 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 1.5% of CKD patients receive treatment with ESAs prior to referral to a nephrologist in the U.S. Undertreatment 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 22% are treated with ESAs prior to initiation of dialysis. 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 dialysis7 and in patients with end-stage renal disease receiving dialysis8 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 are progressing toward commencement of parallel phase 3 studies in the U.S. and Europe at 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 trials have been completed in China, and phase 2 studies are ongoing. 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. was founded to discover and develop anti-fibrotic therapeutics. Using its expertise in the field of tissue fibrosis, in particular with matricellular proteins, such as connective tissue growth factor (CTGF), and matrix assembly enzymes, such as prolyl hydroxylases, FibroGen is now engaged in clinical development of anti-CTGF therapy and prolyl hydroxylase inhibitors for serious unmet medical needs. A placebo-controlled phase 2 clinical trial of FG-3019 in Hong Kong addresses reversing advanced liver fibrosis and cirrhosis, the major consequences of chronic hepatitis B and C infections. Another phase 2 pilot study addresses the ability of FG-3019 to prevent disease progression and reverse the consequences of tissue damage in idiopathic pulmonary fibrosis. Early results from an ongoing dose-escalation study in pancreatic cancer showed bioactivity of FG-3019, which is consistent with preclinical data implicating CTGF mechanistically in pancreatic cancer. From its large proprietary library of prolyl hydroxylase inhibitors, FibroGen is developing clinical and preclinical candidates designed to selectively activate HIF biology for the treatment of anemia and elicit a rapid, multifactorial, cytoprotective response for treating or preventing conditions resulting from acute ischemic injury and/or inflammation, including cardioprotection and inflammatory bowel disease. FibroGen also develops and produces recombinant human collagens and gelatins using proprietary production technology that permits making collagen essentially identical to the native protein. Development of medical devices, such as corneal implants fabricated with recombinant human collagen type III, is ongoing. For more information about FibroGen, Inc., please visit www.fibrogen.com. Contact: Laura Hansen, Ph.D., Director, Corporate Communications, 415-978-1433 or lhansen@fibrogen.com References 1. Amgen Inc. (2011) Epogen (epoetin alfa) Prescribing Information, Thousand Oaks, CA 2. Amgen Inc. (2011) Aranesp (darbepoetin alfa) Prescribing Information, Thousand Oaks, CA 3. Locatelli F, et al (2001) Kidney International 60:741–747 4. Roger S et al (2011) Nephrol Dial Transplant 26(12):3980-6 5. Provenzano R., et al. (2008) Am. J. Kidney Dis Vol. 51 4:B80 6. Besarab A., et al (2010) J Am Soc Nephrol 21:201:95A 7. Besarab A, et al (2011) J Am Soc Nephrol 22:196A 8. Provenzano R, et al. (2011) Am. J. Kidney Dis Vol. 57 4:B80
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