Patient Recruitment Resumes in FibroGen Phase 2 Study of Investigational Oral HIF-PH Inhibitor, FG-4592/ASP1517, for the Treatment of Anemia Associated with Chronic Kidney Disease

Patient Recruitment Resumes in FibroGen Phase 2 Study of Investigational Oral HIF-PH Inhibitor, FG-4592/ASP1517, for the Treatment of Anemia Associated with Chronic Kidney Disease

FibroGen, Inc. today announced that patient recruitment has resumed in a phase 2 study of FG-4592/ASP1517, an investigational oral hypoxia-inducible factor (HIF) prolyl hydroxylase (PH) inhibitor in development for the treatment of anemia associated with chronic kidney disease (CKD).

The phase 2 study is a single-blind, placebo-controlled, dose-escalation trial expected to enroll a total of 130 patients with anemia of CKD who are not receiving dialysis (predialysis). The objectives of the study are to characterize safety, pharmacokinetics and pharmacodynamics, of FG-4592/ASP1517 and to obtain exploratory efficacy data.

FibroGen previously reported interim results from patients randomized to the first dose group of this trial. These results demonstrated that intermittent oral administration of FG-4592/ASP1517 for 4 weeks led to clinically relevant increases in hemoglobin concentration with induction of endogenous levels of erythropoietin (EPO) that were within the normal physiologic range.¹ FG-4592/ASP1517 has been found to be generally safe and well tolerated in clinical studies conducted to date.

“Anemia of CKD is under-recognized and undertreated despite the severity of associated risks including increased rate of progression to end-stage renal disease, cardiovascular complications and death,” said Frank Valone, MD, Chief Medical Officer of FibroGen. “Treatment of anemia using orally bioavailable HIF-PH inhibitors represents a promising investigational therapeutic approach with the potential to meet a large unmet need for anemia therapy in the nondialysis patient population.”

Anemia is Undertreated Among Predialysis CKD Patients

Currently, more than one million predialysis CKD patients in the US are anemic (hemoglobin concentration <11 g/dL), but most do not receive anemia therapy. In fact, only 5% of incident dialysis patients have received therapy with Erythropoiesis-Stimulating Agents (ESAs), the primary treatment for anemia of CKD, for more than one year.²

Primary care physicians and specialists in cardiology, endocrinology and diabetology who treat CKD patients rarely use ESA products. Before referral to nephrologists, less than 5% of CKD patients have ever had any exposure to ESA products.² Although some data suggest that early treatment of anemia can help to delay progression to ESRD,³ infrastructure concerns including inventory and personnel required to administer costly ESA infusions or injections, and concerns with affordability for patients, limit access to ESAs for patients treated outside of the nephrology setting.

Undertreatment of CKD anemia in the predialysis patient population is also due in part to the phenomenon of delayed referral to nephrologists. Primary care physicians and other specialists typically refer CKD patients to nephrologists too late in the patients’ disease, when they are close to end-stage renal disease (ESRD) requiring dialysis. In the US, only 10% of patients with CKD that go on to dialysis see a nephrologist for more than one year prior to initiation of dialysis, and only half of these patients see a nephrologist even immediately prior to dialysis initiation.² Nephrologists have access to therapeutic options such as ESAs to treat anemia.

Potential Advantages of HIF-PH Inhibitors Compared to ESAs

Less expensive and more easily accessible oral therapy using HIF-PH inhibitors has the potential to increase access to anemia therapy for predialysis CKD patients. In addition, preclinical and clinical studies to date have suggested several potential clinical benefits of HIF-PH inhibitors compared with ESAs:

• Treat anemia with erythropoietin (EPO) levels in the normal physiologic range. ESA therapy involves administration of large (pharmacologic) doses of a recombinant protein leading to circulating levels of EPO hundreds of times higher than normal.⁴ Such supraphysiologic levels of circulating EPO observed with ESA therapy have been associated with poor patient outcomes, particularly in patients who do not respond well to ESAs and require large doses.⁵ In contrast, HIF-PH inhibitors harness the body’s natural response to hypoxia and generate a coordinated biological response to promote erythropoiesis. Studies to date show this can be achieved by induction of circulating levels of endogenous EPO within the normal physiologic range.^1,6
• Minimize risk of worsening hypertension. Eighty percent of hemodialysis patients and nearly half of late stage 3-5 CKD nondialysis patients have underlying hypertension,⁵ a factor that contributes to progression of CKD and increases risk of cardiovascular events. Consequently, hypertensive CKD patients are highly vulnerable to increases in blood pressure levels. Each increase in blood pressure of 20/10 mmHg is associated with a doubling of cardiovascular mortality risk. As a result, the blood pressure treatment goal is <130/80 mmHg for CKD patients, lower than the goals for the general population.⁷
  
  ESAs are recognized to increase blood pressure in significant numbers of patients and in some instances cause significant exacerbation of hypertension. Package inserts reveal that blood pressure increases from ESA products are significant enough to require initiation of, or intensification of, antihypertensive medication in 25-40% of patients.^8,9 Despite administration of antihypertensive medication, the reported incidence of hypertension adverse events in clinical studies of ESAs ranges from 10-30%. An analysis of patients in Framingham, MA, showed that among hypertensive patients, more than 30% of their risk of stroke remained even after these patients were treated to normal blood pressure.¹⁰ A review of the literature indicates that ESA use increases blood pressure directly and notably independently of its erythropoietic effect and its effect on blood rheology.¹¹
  
  In contrast, HIF-PH inhibitors have been shown to be blood pressure neutral or hypertension-reducing at erythropoietic doses in clinical and preclinical studies to date.^1,6,12,13 As blood pressure neutrality compared with ESAs could translate into a significant cardiovascular and renal failure progression outcome benefit for patients, FibroGen will evaluate the effect of HIF-PH inhibitors on blood pressure in the phase 2 study of FG-4592/ASP1517 and other upcoming clinical studies.

• Treat the cohort of high-risk ESA-hyporesponsive patients. Analyses by the Food and Drug Administration (FDA) and others of the large-scale morbidity and mortality clinical trials of ESAs (e.g., The Normal Hematocrit Study, Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta Trial (CREATE) and the Correction of Hemoglobin and Outcomes in Renal Insufficiency Trial (CHOIR)) have shown an association between high ESA doses and patient mortality, prompting one FDA reviewer to comment on the possibility that epoetin alfa is directly deleterious to the cardiovascular system.^14,15 This effect has been shown to be greatest among the patients who require the highest ESA doses, so-called “hyporesponders”, a group that represents 20% of dialysis² and 10% of nondialysis patients.¹⁶ Hyporesponsiveness is attributed to inflammation or infection in approximately 70% of these hyporesponsive patients. In preclinical studies, HIF-PH inhibitors have demonstrated efficacy in the presence of inflammation¹⁷ and may therefore present a significant efficacy advantage for HIF-PH inhibitors compared to ESAs in hyporesponsive patients.
• Provide efficacy in the presence of inflammation. Inflammation, identified by an elevated C-reactive protein level, is common in dialysis patients (~50% of patients) and in nondialysis CKD patients (~15-33%).¹⁸ HIF-PH inhibitors have been shown in preclinical models to be effective in the presence of inflammation where the ESA darbepoetin alfa was not, indicating a potential efficacy benefit for a significant number of CKD patients and ultimately for patients with anemia associated with other inflammatory diseases such as rheumatoid arthritis.¹⁷
• Reduce or potentially eliminate the need for supplemental iron. Currently, intravenous administration of iron is given in combination with ESAs to improve erythropoiesis in many patients. Preclincial studies suggest that HIF-PH inhibitors may themselves be able to improve iron metabolism and promote erythropoiesis in anemic patients thereby decreasing or in some cases eliminating iron supplementation.¹⁷

About FG-4592/ASP1517

FG-4592/ASP1517 is an investigational HIF-PH inhibitor for the treatment of anemia in development by FibroGen and Astellas Pharma Inc., the company’s partner in Europe and Japan. The phase 2 study of FG-4592/ASP1517 in nondialysis patients is resuming after a clinical hold placed on the investigational agent by the FDA following an adverse event in a clinical trial with another HIF-PH inhibitor, FG-2216/YM311. The FDA has stated that clinical studies of both HIF-PH inhibitors may continue. To date, 139 subjects have been treated with FG-4592/ASP1517, and no serious adverse events have been reported.

ASP1517 and YM311 are Astellas designations for FG-4592 and FG-2216, respectively.

About FibroGen

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, conditions associated with tissue damage or injury, 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 .

References

1. Frohna P, et al. (2007) Preliminary Results from a Randomized, Single-Blind, Placebo-Controlled Trial of FG-4592, a Novel Hypoxia Inducible Factor Prolyl Hydroxylase Inhibitor, in Subjects with CKD Anemia (abstract). JASN 18:763A.

2. United States Renal Data System, USRDS 2007 Annual Data Reports: Atlas of End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and digestive and Kidney Diseases, Bethesda, MD, 2006. Available at: http://www.usrds.org/ .

3. Gouva C, et al. (2004) Treating anemia early in renal failure patients slows the decline of renal function: a randomized controlled trial. Kidney Int 66: (2):753-760.

4. Fishbane S, Besarab A (2007) Mechanism of increased mortality risk with erythropoietin treatment to higher hemoglobin targets. Clinical Journal of the American Society of Nephrology 2: (6):1274-1282.

5. Zhang Y, et al. (2004) Epoetin requirements predict mortality in hemodialysis patients. Am J Kidney Dis 44: (5):866-876.

6. Provenzano R, et al. (2008) FG-2216, A Novel Oral HIF-PHI, Stimulates Erythropoiesis and Increases Hemoglobin Concentration in Patients with Non-Dialysis CKD. Presented at National Kidney Foundation Spring Clinical Meetings 08: Abstract 120.

7. Chobanian AV, et al. (2003) Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 42:1206-1252.

8. EPOGEN [package insert]. Thousand Oaks, CA: Amgen Inc.; August 2008.

9. Aranesp [package insert]. Thousand Oaks, CA: Amgen Inc.; August 2008.

10. D'Agostino RB, et al. (1994) Stroke risk profile: adjustment for antihypertensive medication. The Framingham Study. Stroke 25: (1):40-43.

11. Krapf R, Hulter HN (2009) Arterial Hypertension Induced by Erythropoietin and Erythropoiesis-Stimulating Agents (ESA). Clin J Am Soc Nephrol 4: (2): [in press].

12. Guo, G. et al. (2007) HIF-PH Inhibitor, FG-4592, Treats Anemia and Prevents Elevation of Systolic Blood Pressure in Uremic Rats (abstract). JASN 18:154A.

13. Guo G, et al. (2008) Correction of Anemia without Exacerbation of Hypertension in a Rat Model of Chronic Kidney Disease: Comparison of FG-2216 to Recombinant Erythropoietin (abstract). Annual Meeting of the American Society of Nephrology JASN 19:654A.

14. Unger E (September 11, 2007) FDA Perspectives on ESAs for Anemia of Chronic Renal Failure: Hemoglobin Target and Dose Optimization, FDA Department of Health and Human Services; Available at: http://www.fda.gov/OHRMS/DOCKETS/AC/07/slides/2007-4315s1-10-FDA-Unger_files/frame.htm .

15. Szczech LA, et al. (2008) Secondary analysis of the CHOIR trial epoetin-alpha dose and achieved hemoglobin outcomes. Kidney Int 74: (6):791-8.

16. Johnson DW, et al. (2007) Erythropoiesis-stimulating agent hyporesponsiveness. Nephrology (Carlton) 12: (4):321-330.

17. Langsetmo I, et al. (2005) FG-2216 Corrects Anemia and Improves Iron Utilization in a Rat Model of Anemia of Chronic Disease: Comparison to Darbepoetin (abstract). JASN 16:481A.

18. Kharagjitsingh AV, et al. (2005) Incidence of recombinant erythropoietin (EPO) hyporesponse, EPO-associated antibodies, and pure red cell aplasia in dialysis patients. Kidney Int 68: (3):1215-1222.

Contact:

FibroGen, Inc.
Laura Hansen, Ph.D., 415-978-1433
Director, Corporate Communications
lhansen@fibrogen.com