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FibroGen Reports Dose-finding Data from Phase 2b Study of FG-4592 for Anemia Correction and Maintenance in Chronic Kidney Disease Patients


—Overall, Hb increases > 1g/dL were observed in 96% of patients; 93% also reached Hb target—
—A significant reduction in mean arterial pressure was observed at the end of treatment—

San Francisco, CA - November 15, 2011

FibroGen, Inc., today announced data from an ongoing phase 2b dose-finding study of FG-4592, an investigational hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor (PHI), for anemia correction and hemoglobin (Hb) maintenance in patients with stage 3 or 4 chronic kidney disease (CKD) not on dialysis.  The study is designed to evaluate several different starting doses, dose frequencies, and dose adjustment schemes of FG-4592 as well as efficacy and safety of FG-4592 over 16- and 24 week-treatment periods.  A total of 96 patients were enrolled in the first four treatment arms (n=24 each).  Treatment with FG-4592 was designed to increase Hb by at least 1 g/dL and maintain Hb concentration in the target range of 11-13 g/dL for the first two arms (arms A and B) treated for 16 weeks, and 10.5-12.0 g/dL in the second two arms (arms C and D) treated for 24 weeks.

Results showed that during the treatment period, 96% of all patients had an increase in Hb of at least 1 g/dL, and 93% had a Hb response [defined as an increase in Hb of at least 1 g/dL and achieving an absolute Hb concentration of at least 11 g/dL (for arms A and B) and 10.5 g/dL (for arms C and D)].  Across all four arms, the maximum mean Hb increase from baseline was 2.09 g/dL at week 17.  Treatment with FG-4592 was well tolerated and led to increases in Hb that were maintained over the course of the study.  Notably:

  • The response rate was 100% in arm B, which used weight-adjusted initial doses of FG-4592 administered three times weekly during the Hb correction phase, followed by twice weekly dosing during the Hb maintenance phase.
  • The response rate was 96% in arm D, which used a fixed (regardless of body weight) starting dose of 100 mg for 4 weeks after which dose evaluation/adjustments were made every 4 weeks.
  • Arm A tested three times weekly dosing throughout the study, with dose-adjustment decisions made monthly, and achieved an 83% response rate.  A majority of patients who did not meet the dual response criteria (3 of 4 nonresponders) had low baseline Hb values of 7-8.5 g/dL at entry.  During treatment, their Hb values increased by 1.4-3 g/dL from baseline, but, despite the response, these more anemic patients may have required a longer treatment time than 16 weeks for dose titration and full Hb correction to target of  >  11 g/dL.
  • Arm C evaluated a fixed starting dose of 50 mg thrice weekly, a dose so low that only 22% patients responded in the first 4 weeks, but subsequent dose adjustments led to further Hb rise, and gradually resulted in fuller anemia correction, with a 91% response rate achieved by week 24.

                                                                                                                                                                                                                                   Results were recently presented at the American Society of Nephrology Kidney Week 2011, which took place November 8-13 in Philadelphia, PA (Abstract # THPO364).1

Treatment success was not dependent on a patient’s iron status at study entry; 46% of patients were not iron replete (ferritin levels < 100 ng/mL and/or transferrin saturation < 20%) at baseline, but responded as well as those who were iron replete.  A minority (n=25) of patients started the study already taking iron supplements and continued taking them; of the other patients enrolled (not previously taking iron), 2 started taking oral iron supplements, and 2 stopped taking iron during the study.  Intravenous iron was prohibited per protocol, and with the exception of one inadvertently administered dose, it was not used during the study.
 
“HIF stabilizers offer a new and improved means for managing CKD anemia,” said Dr. Anatole Besarab, MD, Director of Clinical Research at Henry Ford Hospital and principal investigator of the phase 2b study.  “Benefits that may be achieved through this novel mechanism of action include avoiding risks of parenteral iron therapy.”

Safety assessments were made by an independent data safety monitoring committee (DMC).  There was consensus with the DMC and the company that no serious adverse events were attributable to treatment with FG-4592, and event frequencies were consistent with what would be expected in CKD population.

Three measures related to safety suggest potential benefits with FG-4592 that have not been reported previously for treatment of CKD anemia:

  • CKD patients are prone to hypertension; 90% of the phase 2b CKD patients required antihypertensives prior to study start.  Treatment with FG-4592 resulted in significant reduction in mean arterial pressure (calculated as [(2 x diastolic)+systolic] / 3) at end of treatment as compared to baseline (mean decrease of 2.6±9.6 mmHg, p=0.03). 
  • Adverse events of hypertension were reported in 7% of FG-4592-treated patients, and none of those events were judged to be related to FG-4592 treatment.  This rate is well below what has been reported for similar patient populations treated with erythropoiesis-stimulating agents (ESAs) and the control arms of such studies.  For example, rates of 32% and 24% hypertension adverse events have been reported in studies of similar patient populations treated with darbepoetin alfa.2,3
  • Platelet counts were reduced from baseline (p<0.01) and maintained within the normal range.  Elevated platelet counts are known to be associated with ESA therapy for CKD anemia,4 which may be contributory to frequency and severity of thrombotic events. 

“Data to date suggest that FG-4592 has a favorable safety profile and lacks the common and serious side-effects associated with ESAs,” said Richard Lafayette, MD, Clinical Chief of Nephrology at Stanford University and chairman of the independent DMC for the FG-4592 development program.  “To date, there have been no signals or trends 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 anti-hypertensive medications.  In addition, the data to date have not shown any hepatotoxicity signals related to FG-4592 therapy.” 

“This study demonstrates that target hemoglobin can be achieved and maintained in nondialysis CKD patients using a wide range of starting doses of FG-4592, whether adjusted for weight or not, combined with different dose-adjustment and dose-frequency algorithms,” said Peony Yu, MD, Vice President of Clinical Development at FibroGen.  “We are now evaluating once weekly dosing with FG-4592, and continue to refine dosing strategy to optimize therapeutic benefits and patient convenience in the management of CKD anemia.”

“We see the opportunity with HIF-PHI to change the treatment paradigm for CKD patients with anemia,” said Thomas B. Neff, CEO of FibroGen.  “The observed effect of FG-4592 in lowering blood pressure in this study is consistent with previous clinical and preclinical findings.  Our results suggest that anemia management can be accomplished with lower average blood pressures, potentially reducing cardiovascular and hypertensive risks, and avoiding risks inherent in red blood cell transfusion or injections of iron, otherwise faced by CKD patients.”

About Hypoxia-inducible Factor (HIF) and FG-4592
The hypoxia-inducible factor (HIF) system has been shown to act as an iron sensor and a regulator of erythropoiesis.  Stabilization of HIF with small molecule HIF-prolyl hydroxylase (PH) inhibitors (HIF-PHIs) induces activation of many erythropoietic genes and proteins that promote iron absorption and recycling.  FG-4592, a small molecule HIF-PHI optimized from thousands of compounds, has been shown in clinical studies5-7 to induce erythropoiesis and increase Hb levels, with modest increases in endogenous erythropoietin; statistically significant reductions in hepcidin; and increased mean corpuscular volume.  These effects of FG-4592 treatment occurred without supplemental intravenous iron.  FG-4592 treatment did not increase blood pressure, nor was it associated with increased rates of cardiovascular or thrombotic events. 

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 2008, patients with CKD represented 14% of general Medicare costs, or $29 billion.

Anemia is the condition of having fewer red blood cells and/or lower hemoglobin levels than is normal.  As CKD progresses, prevalence rates of anemia (hemoglobin ≤11 g/dL) increase.  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 to the cost and complexity of treatment with injectable erythropoiesis-stimulating agents (ESAs) and intravenous iron supplements. Whereas nearly all patients on hemodialysis receive ESA therapy, only 2% of CKD patients receive treatment with ESAs prior to referral to a nephrologist in the U.S.8 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.

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 underway.

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 for various 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 antifibrotic 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 cancer9 showed bioactivity of FG-3019, which is consistent with preclinical data implicating CTGF mechanistically in pancreatic cancer.10-12  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. Besarab A et al. FG-4592 oral hypoxia-inducible factor prolyl hydroxylase inhibitor corrects anemia in nondialysis CKD patients without IV iron. Presentation at the American Society of Nephrology Kidney Week 2011 (Abstract # THPO364).
  2. Locatelli F et al. Novel erythropoiesis stimulating protein for treatment of anemia in chronic renal insufficiency. Kidney Int. 2001; 60:741−747.
  3. Pfeffer MA et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. NEJM  2009; 361:2019-2032. 
  4. Kaupke CJ et al. Effect of recombinant human erythropoietin on platelet production in dialysis patients.  J. Am. Soc. Nephrol. 1993; 3:1672-79.
  5. Provenzano R, et al. Evaluation of FG-4592, a novel oral hypoxia-inducible factor prolyl hydroxylase inhibitor, to treat anemia in hemodialysis patients. National Kidney Foundation Conference 2011 (Abstract #188).
  6. Provenzano R, et al. Pharmacokinetics of oral FG-4592 to treat anemia in hemodialysis patients. National Kidney Foundation Conference 2011 (Abstract #189).
  7. Besarab A, et al. FG-4592, a novel oral HIF prolyl hydroxylase inhibitor, elevates hemoglobin in anemic stage 3–4 CKD patients. J Am Soc Nephrol. 2010; 21:201:95A.
  8. U.S. Renal Data System, USRDS 2011 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, 2011.
  9. A phase I trial of the monoclonal antibody FG-3019 to connective tissue growth factor (CTGF) in locally advanced or metastatic pancreatic cancer.  Presentation at the 2011 Gastrointestinal Cancers Symposium (Abstract #269).
  10. Dornhöfer N, et al. Connective tissue growth factor specific mAb therapy inhibits pancreatic tumor growth and metastasis. Cancer Res. 2006; 66:5817-27.
  11. Aikawa T, et al. Connective tissue growth factor specific antibody attenuates tumor growth, metastasis and angiogenesis in an orthotopic mouse model of pancreatic cancer. Mol. Cancer Ther. 2006 May;5(5):1108-16.
  12. Bennewith K, et al. The role of tumor-derived connective tissue growth factor (CTGF/CCN2) in pancreatic tumor growth. Cancer Res. 2009; 69:775-784.

   

 
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