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FibroGen Reports Proof-of-Principle for Oral Anemia Therapy FG-4592 in Hemodialysis Patients Switched from Intravenous rhEPO in an Active-Controlled Randomized Phase 2 Study
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-Interim results of ongoing study presented at the National Kidney Foundation Spring Clinical Meetings-San Francisco, CA - May 3, 2011 FibroGen, Inc., today announced proof-of-principle for oral anemia therapy FG-4592, a hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor (PHI), in end-stage renal disease (ESRD) patients receiving hemodialysis. In this first clinical study of a HIF-PHI to include a recombinant human erythropoietin (rhEPO) control arm, FG-4592 was directly compared with rhEPO on numerous parameters in this controlled study. Six weeks of dosing with FG-4592 maintained correction of hemoglobin in the absence of intravenous (IV) iron supplementation and led to marked, dose-dependent decreases in hepcidin (an iron regulatory hormone) compared with levels achieved with rhEPO. An interim analysis of results from this ongoing phase 2 study were reported at the 2011 National Kidney Foundation Spring Clinical Meetings in Las Vegas, Nevada, April 26–30 (Abstract #188).1 Patients were required to have stable hemoglobin maintained by stable steady-state doses of IV rhEPO prior to randomization to either 6 weeks of study treatment with FG-4592 (1.0, 1.5, or 2.0 mg/kg three times a week) or to IV rhEPO (dosed according to community standard of care). As per protocol, IV iron supplementation was not allowed beginning 2 weeks prior to randomization and extending throughout the dosing period. The dosing period was followed by an 8-week safety assessment period, during which all patients received IV rhEPO and were allowed to receive IV and oral iron. Key findings reported from the interim analysis were as follows:
“These results represent the first proof-of-principle that FG-4592 can maintain or increase hemoglobin levels in patients with ESRD on hemodialysis using doses that have been shown to be effective in studies of nondialysis patients with chronic kidney disease,” said Peony Yu, MD, Vice President of Clinical Development. “These data, which are the first to be generated on a HIF-PHI in the hemodialysis setting where there is a high background rate of adverse events, suggest a favorable safety profile for FG-4592.” “The observation that FG-4592 therapy led to statistically significant reduction in serum hepcidin levels beyond what was observed with rhEPO suggests that HIF-PHIs may be effective at treating anemia in patients who are unable to achieve adequate increases in hemoglobin levels due to the presence of significant inflammation,” said Thomas B. Neff, Chief Executive Officer. “The increases observed in MCV raise the possibility that HIF-PHIs may also have a clinically beneficial effect on iron deficiency anemia. We plan to explore the impact of increased MCV in treatment of anemia in newly initiated dialysis ESRD. Potential therapeutic effects of HIF-PHIs outside of chronic kidney disease settings, such as iron deficiency anemia, are worthy of additional investigation.” In another study presented at NKF, the pharmacokinetics (PK) and pharmacodynamics (PD) of FG-4592 in hemodialysis were reported. Results demonstrated that hemodialysis does not have a clinically significant impact on the PK/PD of orally administered FG-4592.4 This finding is supportive of a flexible dosing schedule of FG-4592 for patient convenience, not limited by hemodialysis schedule. Levels of EPO in plasma were measured in this study. Peak concentrations of circulating plasma endogenous erythropoietin (eEPO) nearly tripled with a doubling of dose of FG-4592, but the Cmax values remained significantly less than the peak circulating plasma rhEPO levels (eEPO Cmax was less than 10% of rhEPO Cmax levels expected for dialysis patients receiving the U.S. mean dose [approximately 8000 U] of synthetic source rhEPO9). About the Phase 2 Study The phase 2 study is a randomized, open-label, active-controlled clinical trial of patients with ESRD undergoing hemodialysis three times a week (TIW). Patients are grouped into three levels of rhEPO therapy responsiveness: A. patients with rhEPO dosing requirements of median of 35 to 45 U/kg/dose with a range restriction for any single dose limited to 20 and 80 U/kg/dose (hyperresponders); B. patients requiring the greatest amount of rhEPO dosing to maintain stable correction (above >120 U/kg/dose) as the poorest responders (hyporesponders); and C. patients falling in between those rhEPO dose ranges as the normal responders (normoresponders). Patients randomized into the phase 2a portion of study were hyperresponders and demonstrated stable hemoglobin levels for 3 months prior to randomization with a median 39 U/kg/dose (a value in the lowest quartile of IV rhEPO doses in the U.S. hemodialysis population).5 Hyperresponders have been shown to have the lowest mortality and best clinical outcomes relative to normo- or hyporesponders.6 The interim study results reported at NKF involved a total of 52 patients, including 36 patients who received FG-4592 (1.0, 1.5, or 2.0 mg/kg) for 6 weeks after switching over from IV rhEPO and IV iron standard of care, followed by an 8-week safety assessment period during which patients returned to rhEPO therapy; 16 patients who received IV rhEPO throughout this study served as active control. Patients entered the study with corrected anemia and had maintained hemoglobin between 10.5–13.0 g/dL with stable doses of rhEPO IV for at least 4 weeks before being randomized to receive FG-4592 or rhEPO IV. At baseline, mean transferrin saturation (TSAT) and ferritin ranged from 25–35% and 804–1069 ng/mL, respectively, values which indicate iron repletion in ESRD patient populations. IV iron supplementation and red blood cell transfusion were prohibited by protocol during the 6-week comparative dosing period. Following this dosing period, patients in the FG-4592 cohort crossed back over to resume IV rhEPO therapy, and the rhEPO cohort continued IV rhEPO therapy during the 8-week safety assessment period. In a review of the interim data from the phase 2 study, the DMC judged no discernable safety signals, including no trends suggesting that events of special interest commonly associated with erythropoiesis-stimulating agents (ESAs) (e.g., cardiovascular events, hypertension, seizure, thrombosis or functional iron deficiency) were attributable to treatment with FG-4592, and no evidence of hepatotoxicity. In recognition of proof-of-principle achieved for the treatment of anemia associated with chronic renal failure in both ESRD patients receiving hemodialysis in this study, and in nondialysis chronic kidney disease (CKD) patients in a previously reported study and in an ongoing phase 2b study, and in consideration of the collective safety findings with the FG-4592 program, the DMC further endorsed expansion of FG-4592 dosing to 19 weeks and encouraged acceleration of FG-4592 development. The decision to expand this study was jointly made with FibroGen’s partner Astellas Pharma Inc. Having completed initial assessment of FG-4592 in the best responders to IV rhEPO therapy, this ongoing phase 2 study has expanded to include Group C patients who require median range rhEPO doses to maintain hemoglobin correction. Separate cohorts are included in this study to evaluate patients who are less responsive to ESA therapy, who typically have chronic inflammation and may not be able to maintain adequate hemoglobin levels with chronic IV rhEPO dosing. Need for Novel Mechanisms in Anemia Therapy ESAs are recombinantly produced biologics intended to have the same biological effect as endogenous EPO, a protein that stimulates erythropoiesis in the bone marrow. The need for novel mechanisms in anemia therapy has been underscored by growing concern over ESA safety, as discussed at CardioRenal Advisory Committee meetings held by the U.S. Food and Drug Administration (FDA) in September 2007 and October 2010. Clinical trials using rhEPO in chronic renal failure patients, including the Normal Hematocrit Study in hemodialysis patients and the CHOIR and CREATE trials in nondialysis patients, have suggested that increased frequency of thrombotic events results in higher mortality and morbidity in patients treated to higher hemoglobin targets with ESAs, particularly in ESA hyporesponders who require a median dose of ESA that is 1.5–4 times higher than that required for normoresponders to achieve target hemoglobin levels. The TREAT trial in non-dialysis patients with type 2 diabetes showed no imbalance in total cardiovascular events or overall outcome, but showed excess risk for stroke as well as deep vein and arterial thrombosis in the patients treated with the ESA darbepoetin alfa. Post-hoc analyses of larger ESA studies, such as those performed by Szczech et al.7 on the results of the CHOIR study, correlate adverse patient outcomes with higher ESA doses and lower hemoglobin responsiveness to ESAs. Safety signals with ESAs have been observed as early as the original registration trials conducted in the late 1980s for the first marketed ESA, epoetin alfa (Epogen® or Procrit®). In a phase 3 trial in dialysis patients (n=333, all treated with epoetin alfa), Eschbach et al.8 outlined several significant adverse events. Among the 251 patients with sufficient data to evaluate changes in blood pressure and antihypertensive medications after 3 months of epoetin alfa therapy, 35% developed an increase of ≥10 mm Hg diastolic blood pressure or required additional hypertension medication. Of the 180 patients who were hypertensive before therapy, 32% experienced exacerbations of hypertension; and among the 71 patients who were not hypertensive before the trial, 44% had an increase in blood pressure of ≥10 mmHg in systolic blood pressure. Eschbach et al. also reported the following adverse events in the trial: seizures (5.4%), absolute or functional iron deficiency (defined as ferritin <30 mcg/mL and TSAT<20%) (43%); and thrombotic events of various types (12%). Since this time, the FDA has maintained warnings of these events as well as other cardiovascular and thrombotic events in the ESA prescribing information. Multiple potential mechanisms for these safety findings have been hypothesized, including issues related to high ESA dose leading to high circulating EPO levels, which could trigger off-target effects such as endothelial activation and cardiovascular risk in association with rapid rate of hemoglobin rise (greater than 1 g/dL over 2 weeks) associated with ESA therapy (while this has not been a concern with blood transfusion), iron depletion, and blunted efficacy of ESAs in the presence of inflammation or functional iron deficiency.9 To date, data from 540 subjects dosed with FG-4592 suggest the potential for a safety profile different from that of ESAs used in current anemia therapy, as there have been no trends suggesting that events of special interest associated with ESA products (e.g., cardiovascular events, hypertension, seizure, thrombosis, or functional iron deficiency) are attributable to treatment with FG-4592. Background Information on the FG-4592 Program EPO Levels Normal levels of circulating EPO at sea level are in the 5-20 mIU/mL range (Normal EPO Range). The natural physiologic response to hypoxic stress, such as that elicited by rapid ascent to high altitude or blood loss, is mediated through HIF stabilization and leads to modest induction of eEPO and other biologic signals for complete erythropoiesis.10-16 Maximum observed physiological plasma eEPO (Maximum Physiologic EPO Levels) is approximately 200 mIU/mL for brief periods of time, generally resulting in hemoglobin increase to meet the body’s demand for oxygen. The HIF-stabilizing mechanism of FG-4592 resembles this physiological response to hypoxic stress. Based on clinical experience with FG-4592 to date, median peak circulating plasma eEPO levels in CKD patients (on dialysis and not on dialysis) treated with FG-4592 at 1 mg/kg are approximately 100 mIU/mL or lower.4,17 In these patients, eEPO begins to increase around 4–6 hours postingestion of FG-4592 and rises to a peak level measured at 8–12 hours post-ingestion, followed by a gradual decline to nearly baseline (pre-dose) levels by approximately 18–24 hours. In 2007, Fishbane and Besarab reported that a median dose of epoetin alfa in the hemodialysis population would result in peak rhEPO levels of 3000 mIU/mL.9 Period of Supraphysiologic Exposure to EPO per Treatment Cycle in Dialysis In addition to the maximum concentration of EPO, the period of time to which patients are exposed to above-normal EPO levels is a key question. In the U.S. hemodialysis population, over 90% of patients receive epoetin alfa (an rhEPO) IV, three times weekly. The half-life of epoetin alfa in typical CKD patients has been reported to be in the range of 6-9 hours.18 This suggests that, during the standard TIW dosing schedule using the mean U.S. dialysis epoetin alfa dose (8000 U/dose), circulating synthetic rhEPO levels after the first of the three weekly doses are well above the highest levels seen in normal physiology. For the second 24 hours before the next dose, rhEPO concentrations may decline to the range below Maximum Physiologic EPO Levels (dependent on the dose level), but remain above Normal EPO Range. This means that circulating rhEPO levels are frequently far above Maximum Physiologic EPO Levels for the average patient receiving thrice weekly therapy in the U.S. dialysis population. By comparison, with FG-4592, median natural eEPO levels remain in the Normal EPO Range until about 4 hours postdose, then transiently rise to a maximum within the range of Maximum Physiologic EPO Levels between 8–12 hours postdose, and return to normal between by 18–24 hours after dosing. At the 1 mg/kg dose of FG-4592 in dialysis patients,4 the peak median level of 96.2 mIU/mL transiently exceeds the Normal EPO Range but remains at approximately half of the Maximum Physiologic EPO Levels or below at all times. The data collected to date suggest circulating eEPO levels at this dose would exceed the Normal EPO Range for less than 12 hours per treatment cycle thus minimizing exposure to unnecessary EPO and allowing patients to maintain stable corrected hemoglobin with circulating eEPO in the Normal EPO Range 75% of the time during any treatment cycle. Iron/Hepcidin In a phase 2a nondialysis CKD study of FG-4592 in which a dose-dependent response for anemia correction was demonstrated using 0.7, 1.0, 1.5, and 2.0 mg/kg doses,17 serum iron was measured at baseline through end of treatment. Despite the robust hemoglobin response (80–100% response rate, mean maximum change in hemoglobin from baseline of 2.2 g/dL), no change in serum iron compared with placebo was observed in either the 1.5 mg/kg or 2.0 mg/kg dose arms. FibroGen researchers have shown that iron levels can be modulated via stabilization of the HIF system, induced by HIF-PHIs, and that bioavailable iron can be increased by at least an order of magnitude from baseline by HIF-PHIs. These data were contrasted with the finding from Schwartz et al.19 that despite 100% of patients taking oral iron and having similar baseline serum iron (72 ng/mL±8.7 ng/mL compared with 71.1-73.0±4.0 ng/mL in the placebo, 1.5 mg/kg and 2.0 mg/kg arms of the FG-4592 study), serum iron decreased significantly during a similar hemoglobin rise and 4-week treatment period. In addition, FibroGen has demonstrated significant differences in the quality of red blood cell formation achievable with HIF-PHIs vs. ESAs, enhancing the company’s proprietary position.20 In human clinical studies of FibroGen HIF-PHIs, CKD patients were allowed to enter trials without previous iron therapy or demonstration of sufficient iron in the body.21,22 In the phase 2b study of FibroGen’s first-generation HIF-PHI, FG-2216, more than 150 anemic CKD patients who had a wide range of iron parameter values at baseline (TSAT levels from 4–75% and ferritin levels from 23–1,444 ng/mL) were treated for up to 15 weeks. Patients who were not iron replete at study entry (i.e., TSAT <20% and ferritin <100 ng/mL) achieved treatment success equally as patients who were iron replete at baseline, even in the absence of iron supplementation.21 Similarly, in the phase 2a study of FG-4592, a subset of nondialysis CKD patients who had a range of subnormal iron parameters (TSAT and ferritin as low as 8% and 25 ng/mL, respectively) were successfully treated with FG-4592 at 1.0 and 2.0 mg/kg (as per protocol, no IV iron or red blood cell transfusion was allowed). In an iron load substudy from the phase 2b trial of FG-2216, plasma iron levels were measured following oral iron intake. Anemic CKD patients dosed with FG-2216 adequately to achieve hemoglobin correction had statistically significant increases in absorption of oral iron in the gut. Use of IV iron supplementation was not permitted per study protocol. The increases in serum iron levels were observed both immediately after initiation of FG-2216 therapy and after 15 weeks of therapy with maintenance of hemoglobin to levels above 11 g/dL. 21 Subsequent to FibroGen’s findings, independent research groups have demonstrated that the HIF system is an iron sensor that activates rapid absorption of iron from the gut into the blood stream at up to 10 times basal levels.22 Proof-of-Concept Regarding Hepcidin and Treatment In Presence of Inflammation The combination of data reported at NKF 2011 in dialysis patients and data from the non-dialysis CKD study of FG-4592 reported in November 2010 showing significant suppression of hepcidin levels with FG-4592 doses from 0.7–2.0 mg/kg supports the company’s proprietary position relating to key aspects of iron metabolism.1,17 These data support earlier work and the discovery by FibroGen that HIF-PHIs downregulate hepcidin in conditions of inflammation.20 Hepcidin is a regulatory hormone that limits iron availability and thus suppresses erythropoiesis under conditions of inflammation. Lowering of serum hepcidin levels prevents ferroportin degradation and leads to improved iron mobilization and utilization. Iron availability for erythropoiesis is an important factor in treating anemia, which ESA therapy alone fails to address. It is estimated that approximately 75% of hyporesponsiveness to ESA therapy is caused by inflammation or infection.24 FibroGen has demonstrated in animal models that FG-4592 is effective in the presence of inflammation when darbepoetin alfa (Aranesp®), even with the addition of IV iron, is not.25 This effect may be attributable to a decline in levels of hepcidin achieved with FG-4592. Emerging Science on HIF Stabilization In addition to these promising clinical data with FibroGen HIF-PHI molecules, emerging epidemiology and basic research findings support pharmacologic HIF stabilization as a promising therapeutic mechanism. Effects of Altitude of Residence: Recently, researchers have observed positive effects of residing at high altitudes on outcomes in a normal population and in hemodialysis patients. The effects of hypoxia experienced at altitude are similar to what is achieved by pharmacologic stabilization of HIF. If these associations are validated, the results below suggest incremental benefits for dialysis patients may be achievable by treatment with FG-4592.
PHD-1 and PHD-2 Targets of FG-4592 are Shown to be Antitumor when Inhibited: Studies have shown that inhibition of PHD1 and PHD2 (HIF prolyl hydroxylases and targets of FibroGen HIF-PHIs) can have antitumor effects. Dr. William Kaelin, a principal collaborator on FibroGen HIF programs at the Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, and his colleagues have demonstrated that genetic inhibition of PHD1 led to decreased cyclin D1 protein levels and suppressed tumorigenic proliferation in estrogen-dependent human breast cancer cells.29 Inhibition of PHD1 with a FibroGen HIF-PHI showed similar results. In a separate study, genetic reduction of PHD2 resulted in antitumor phenotypes.30,31 ESA therapy has also been used to treat anemia in the cancer setting. Generally, ESA therapy in oncologic anemia requires initial doses 5-15 times higher than those in CKD, sharply increasing the level of circulating EPO compared with that seen in CKD. A number of clinical trials in oncologic anemia have shown that the thrombotic effects associated with ESA therapy are amplified in the oncology setting and drive mortality.32,33 In addition, studies have shown other off-target effects of ESA therapy at those dose levels, particularly in pegylated EPO forms that increase ESA exposure, are associated with worse outcomes for treated patients, including tumor progression. As a result, the FDA has restricted use of ESA products to indications for which acceptable risk:benefit ratios have been determined. By avoiding the supraphysiologic circulating EPO levels exhibited by ESA therapies, and possibly triggering antitumor responses in the HIF-PH enzymes that are inhibited, HIF-PHI therapy has the potential to be a superior approach to treating anemia in oncology settings, and further clinical research may be warranted. 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 in the second half of 2011. 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 will commence soon. Astellas has licensed certain rights to FG-4592 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 Anemia in CKD and ESRD Patients on Hemodialysis CKD is a medical problem of progressive epidemic proportions 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 in the 1988-1994 National Health and Nutrition Evaluation Survey (NHANES) to 15% in 2003-2006 NHANES, or approximately 30 million adults.3, 34 In 2008, 31% of all Medicare expenditures were incurred by patients with a diagnosis of kidney disease.3 Anemia is the condition of having fewer red blood cells and/or lower-than-normal (≤11 g/dL) hemoglobin levels. As CKD progresses, prevalence rates of anemia increase. Anemia has been associated with adverse outcomes in CKD patients, including increased mortality, higher hospitalization rates, and reduced quality of life, and the condition tends to be undertreated due to the cost and complexity of treatment with injectable ESAs and IV iron supplements. Whereas it is estimated that only ~15% of late-stage (i.e., stages 3–5) CKD patients with anemia are treated with ESAs, nearly all ESRD patients on hemodialysis in the U.S. receive ESAs to treat their anemia, and ~76% of these are supplemented with IV iron.32 The approval of epoetin alfa, the first ESA more than 20 years ago significantly reduced the need for red blood cell transfusion; nevertheless, red blood cell transfusion is still needed in anemia treatment and remains the only approved alternative to ESAs. On the other hand, in China there is widespread undertreatment of anemia. For example, the average corrected hemoglobin level achieved in the dialysis patient population in Shanghai was 10.2 g/dL in 2009.35 A therapeutic agent with multiprong mechanisms for treating ESRD anemia, such as one which could eliminate the cost and inconvenience of IV iron supplementation while enhancing efficacy safely, will be an asset in the clinical management of ESRD patients. 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. Current and planned clinical trials of FG-3019 will study the potential of anti-CTGF therapy to reverse liver and lung fibrosis, and improve clinical outcomes in pancreatic cancer. From its large proprietary library of prolyl hydroxylase inhibitors, FibroGen is developing multiple prolyl hydroxylase inhibitors 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
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