FibroGen, Inc., announced that FibroGen and partner Astellas Pharma Inc. advanced FG-4592 (Astellas designation ASP1517), an investigational anaemia therapy, to phase II b development for treatment of anaemia in Chronic Kidney Disease (CKD) patients on dialysis and not on dialysis. The advancement decision resulted in a payment of $40 million from Astellas to FibroGen in the fourth quarter of 2010 under Astellas’ license to rights for the European Union and certain other territories. FG-4592 is a novel, first-in-class Hypoxia-Inducible Factor (HIF) Prolyl Hydroxylase Inhibitor (PHI) that works through stabilization of HIF, a mechanism distinct from that of current anaemia therapy using Erythropoiesis-Stimulating Agents (ESAs).
“We are pleased to report progress in the clinical development program for FG-4592 for the treatment of anaemia in CKD patients on dialysis and not on dialysis,” said Thomas B Neff, FibroGen’s chief executive officer. “We continue to see signs of potential therapeutic advantages of FG-4592 compared to ESAs, such as clinical evidence that FG-4592 is potentially superior by certain efficacy measures such as median time to achieve hemoglobin correction.”
FibroGen enrolled anaemic stage 5 CKD patients [End-Stage Renal Disease (ESRD)] on haemodialysis therapy in a phase II a dose-escalation study to evaluate the ability of these patients to maintain and/or to correct haemoglobin levels when converted from stable dosing of intravenous (IV) therapy with the ESA epoetin alfa to 6 weeks of oral therapy with FG-4592. Patients in the study were classified according to their responsiveness to ESA therapy: “normoresponsive” patients required typical stable doses of epoetin alfa (= 85 IU/kg/dose) and “hyporesponsive” patients required higher than typical doses of epoetin alfa (defined as = 125 IU/kg/dose in this study). Starting doses of FG-4592 were between 1.0 mg/kg and 2.0 mg/kg three times per week, orally.
In October 2010, after approximately 50 patients were enrolled in the phase 2a study, the FibroGen and Astellas co-development teams determined that clinical proof-of-principle in hemodialysis was established, and the Phase 2b program was commenced. For normoresponsive patients, the Phase 2b is a multicenter, randomized, open-label, comparator-controlled study, where patients receive FG-4592 or epoetin alfa for 19 weeks and are monitored for a total of 23 weeks. Four to six cohorts of normoresponsive patients with stable baseline epoetin alfa of from 25 to 115 IU/kg/dose thrice weekly (N=64 to N=96) are planned. For hyporesponsive patients who require > 115 IU/kg/dose epoetin alfa thrice weekly, the Phase 2b is a multi-center active and placebo controlled study (N=48). Screening began in Q4 2010. Certain patients from Phase 2a program will be permitted to continue treatment in the Phase 2b study. Use of IV iron and red blood cell transfusions are not allowed per protocol except as ‘rescue’ therapy.
In 2010, FibroGen completed a phase II a anaemia correction study involving 117 Stage 3 and Stage 4 CKD patients. The results of this study were discussed in an oral presentation at the American Society of Nephrology (ASN) Renal Week on November 20, 2010, by lead investigator Dr Anatole Besarab, MD, of Henry Ford Hospital in Detroit, Michigan. Results demonstrated the potential of FG-4592 to exhibit an efficacy and safety profile differentiated from that of ESAs used in current anemia therapy.1
The reported findings were: FG-4592 was well tolerated, with no drug-related serious adverse events; 100% of patients at the highest dose tested (2 mg/kg twice and thrice weekly) had a mean maximal haemoglobin increase of = 1 g/dL from baseline; median time to response was 21 days for the 1.5 and 2.0 mg/kg cohorts, considerably faster than the 49 days associated with the usual starting doses of IV administration of epoetin alfa and darbepoetin alfa; A median peak level of approximately 100 mIU/mL endogenous erythropoietin (EPO) was observed after a dose of 1 mg/kg FG-4592 and plasma endogenous EPO returned nearly to baseline levels by 24 hours after administration of FG-4592 (prior to the next dose); by comparison, the maintenance doses of ESA (epoetin alfa, IV) for the very best responding group of stably corrected dialysis patients (using the least amount of ESA) screened in the phase 2 dialysis study (patients receiving doses of 26-50 U/kg epoetin alfa versus the median dose of approximately 90 U/kg in the U.S. dialysis) resulted in a peak level of circulating EPO ranging from 400 to 750 mIU/mL.
There was no change in serum iron over time after a dose of FG-4592 compared to placebo, whereas the literature reports a significant drop in serum iron following IV administration of epoetin alfa in the absence of concurrent IV iron therapy; and Serum hepcidin, a key regulatory hormone that is elevated with inflammation and restricts availability of iron to the bone marrow, was reduced after treatment with FG-4592 compared to after treatment with placebo.
A phase 2b study of FG-4592 in anaemic non-dialysis patients was commenced in October 2010. This multi-centre, randomized, open-label, dose titration study is designed to evaluate the efficacy and safety of FG-4592 in correction of anaemia in CKD patients not on dialysis. Up to approximately 144 Stage 3 and Stage 4 CKD patients with anaemia are being enrolled in four to six cohorts, and treated with FG-4592 for a 16 or a 24 week period. A secondary objective is to evaluate FG-4592 dosing to optimize anaemia management in non-dialysis CKD patients. IV iron and red blood cell transfusions are not allowed per protocol except as ‘rescue’ 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 anaemia 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 in CKD, including the Normal Hematocrit Study in haemodialysis patients and the CHOIR and CREATE trials in non-dialysis patients, have suggested that increased frequency of thrombotic events results in higher mortality and morbidity in patients treated to higher haemoglobin targets with ESAs, particularly in ESA hyporesponders who require a median dose of ESA that is 1.5 to 4 times higher than that required for normoresponders to achieve target Hb levels.
The recently reported 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 that performed by Szczech et al4 on the results of the CHOIR study, correlate adverse patient outcomes with higher ESA doses and lower hemoglobin responsiveness to ESAs.
FG-4592 works through a mechanism of action distinct from that of ESAs.5-7 FG-4592 stabilizes HIF, a key regulatory protein that coordinates the elements of erythropoiesis necessary for proper formation of mature, iron-rich red blood cells, plump with oxygen-carrying hemoglobin molecules.
To date, FG-4592, with its distinct mechanism of action, has shown the potential for a safety profile different from that of ESAs used in current anemia therapy. Of the adverse events of special regulatory interest associated with ESA products as described in the phase 3 studies of epoetin alfa by Eschbach et al.,8 the FG-4592 database (N=529) has shown no evidence to date that administration of FG-4592 is related to onset or exacerbation of hypertension, seizures, thrombotic events of any type, or functional iron deficiency.
ESA therapy generally requires concomitant administration of IV iron to be effective. Other therapies are also employed to protect the body from side effects associated with ESAs and, possibly, overdosing of EPO, particularly in patients who are hyporesponsive to ESA therapy and require higher doses to achieve hemoglobin response. Inflammation is a significant factor in such ESA-hyporesponsive patients. Additional antihypertensive medicines are administered to a considerable percentage of patients when ESA therapy is commenced. Due to associations with several forms of thrombotic events, use of anticoagulants has become recommended protective therapy in patients who have increased risk of thrombotic events. ESA and IV iron therapies also necessitate recurring costs of medical personnel and supporting equipment.
“When the total cost associated with use of ESAs is considered, it appears that FG-4592 therapy, if proven safe and effective, can be both more convenient and substantially more cost effective,” said Mr. Neff. “We will continue to pursue these potential advantages in larger, longer clinical trials as we seek to bring a new anemia therapy to patients, physicians, and payors seeking new treatment options. We expect to complete phase 2 data collection to enable discussion of our proposed phase 3 program with the FDA by the second half of 2012.”
One of the body’s earliest and most sensitive responses to low tissue levels of oxygen, as experienced during anaemia, is an increase in EPO production. HIF-PHIs not only increase endogenous EPO levels transiently, but may also stimulate correspondent EPO receptor upregulation in the bone marrow. As a result, during HIF-PHI therapy, plasma EPO levels remain within observed physiologic levels in maintenance dosing regimens, potentially reducing the risk of any off-target effects that could result from abnormally high or supra-physiologic levels of EPO.
Another key component of erythropoiesis is regulation of iron bioavailability to the bone marrow. FibroGen discovered that HIF-PHIs can modulate multiple aspects of iron bioavailability, and obtained clinical proof-of-concept for this in two separate clinical trials conducted between 2005 and 2007, which demonstrated that HIF-PHIs make iron bioavailable in quantities needed to support red blood cell formation. This is another potential advantage of HIF-PHI therapy over ESA therapy, which has been shown to decrease serum iron during correction of hemoglobin.3 As a result, supplemental iron therapy (typically through IV infusion) is generally required to treat anemia using ESAs.
CKD patients with evidence of iron deficiency have been allowed to enter FibroGen studies without pre-study iron repletion, and more than 150 such patients, displaying a wide range of iron parameter values at baseline (TSAT levels of from 4% to 75% and ferritin levels of from 12 ng/mL to 1,444 ng/mL), have been treated with HIF-PHIs. Patients who were not iron replete at study entry (i.e., TSAT <20% and ferritin < 100 ng/mL) achieved treatment success equal to that of patients who were iron replete at baseline, even in the absence of protocol requirement for oral iron supplementation and prohibition of IV iron use.
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.11 FibroGen holds a proprietary position relating to various aspects of HIF-PHI regulation of iron for use in anemia and other HIF-mediated disorders.
Furthermore, Bernhardt and colleagues12 have reported increased levels ofendogenousEPO in hemodialysis patients after a single dose of a HIF-PHI. A study of non-anemic, age-matched healthy volunteers and hemodialysis patients with and without kidneys (anephric) showed that EPO response to a single dose of a HIF-PHI was greatest in hemodialysis patients with kidneys and lower, although similarly increased above baseline, in healthy volunteers and anephric patients. These data suggest that HIF-PHIs can induce EPO production in both liver and kidney cells, and that HIF-PHI anemia therapy is possible in hemodialysis patients, including anephric patients, as defective oxygen sensing, not a loss of EPO production capacity, causes renal anemia.
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 mid-2011. On September 20, 2010, FibroGen announced that the Chinese State Food and Drug Administration (SFDA) had granted FibroGen a Clinical Trial Application (CTA) approval to commence phase 1 and phase 2 clinical development for FG-4592 in the treatment of anemia associated with CKD in the People's Republic of China. FibroGen is currently conducting phase 1 trials in China, and plans to commence phase 2 studies in mid-2011.
Astellas has licensed certain rights to FG-4592 in Japan, Europe, the Commonwealth of Independent States (CIS), 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 EU and in Japan as well as for various other subsequent events. FibroGen retains rights to its anemia therapies in North and South America, remaining parts of Africa and all of Asia Pacific ex-Japan.
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.13
Anaemia is the condition of having fewer red blood cells and/or lower haemoglobin levels than is normal. As CKD progresses, prevalence rates of anaemia (haemoglobin =11 g/dL) increase. Anaemia 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 under treated due to the cost and complexity of treatment with injectable ESAs and IV iron supplements. Whereas nearly all patients on dialysis receive ESA therapy, the company estimates there are 1 million late-stage CKD patients (CKD Stages 3-5) with anemia, and less than 15% are treated with ESAs.12
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 CTGF, and matrix assembly enzymes, such as prolyl hydroxylases, FibroGen now is engaged in clinical development of anti-CTGF therapy and prolyl hydroxylase inhibitors for serious unmet medical needs.