Randomized placebo-controlled dose-ranging and pharmacodynamics study of roxadustat (FG-4592) to treat anemia in nondialysis-dependent chronic kidney disease (NDD-CKD) patients

Besarab, Anatole; Provenzano, Robert; Hertel, Joachim; Zabaneh, Raja; Klaus, Stephen J.; Lee, Tyson; Leong, Robert; Hemmerich, Stefan; Yu, Kin-Hung Peony; Neff, Thomas B.

doi:10.1093/ndt/gfv302

Cited by 241 publications

(318 citation statements)

References 40 publications

(41 reference statements)

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“…Six phase II studies have been published: three in non-dialysis-dependent (NDD)-CKD participants and three in dialysis-dependent (DD)-CKD participants. HIF-PH hypoxia inducible factor prolyl-hydroxylase, HIF-α hypoxia inducible factor alpha, HIF-β hypoxia inducible factor beta, HRE hypoxia response element, O 2 oxygen, OH hydroxyl group, VHL von Hippel-Lindau, EPO erythropoietin gene In a single-blind, placebo-controlled study, 117 NDD-CKD stage 3 or 4 patients were randomized to receive four escalating doses (0.7, 1.0, 1.5, 2.0 mg/kg) of roxadustat either twice or thrice weekly over 28 days [45]. The study found that roxadustat increased Hb from baseline in a dose-dependent manner.…”

Section: Roxadustat (Fg-4592/asp1517)mentioning

confidence: 99%

HIF stabilizers in the management of renal anemia: from bench to bedside to pediatrics

Kular

Macdougall

2018

Pediatr Nephrol

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Anemia is a common complication of chronic kidney disease (CKD) in adult and pediatric patients. It has traditionally been treated with erythropoietin therapy and iron supplementation, with great success. With the discovery of the major transcription factor hypoxia inducible factor (HIF) for the erythropoietin gene in 1992, molecules were created that inhibit the HIF prolylhydroxylase enzyme. This new class of drug-called HIF stabilizers, or HIF prolyl-hydroxylase inhibitors-prevents the proteasomal degradation of HIF-α, thereby inducing upregulation of the erythropoietin gene. This new strategy for treating CKD anemia is already in phase III clinical trials in adults, and the potential advantages of this therapy are that it is orally active (thereby avoiding injections), and patients are exposed to lower circulating levels of erythropoietin. The long-term safety of this strategy, however, requires elucidation in these trials, particularly since there are many other hypoxia-sensitive genes, notably, angiogenic factors such as vascular endothelial growth factors (VEGF), as well as glycolytic enzymes. As with all new therapies, it is only once a positive benefit: risk profile has been ascertained in adults that the treatment will translate across into pediatrics. Specific issues in the pediatric CKD population are discussed in this review.

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Section: Roxadustat (Fg-4592/asp1517)mentioning

confidence: 99%

HIF stabilizers in the management of renal anemia: from bench to bedside to pediatrics

Kular

Macdougall

2018

Pediatr Nephrol

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“…Roxadustat offers a novel way of utilizing the body's natural compensatory mechanisms in response to hypoxia [4,12,14,15]. Hypoxia-inducible factors (HIF) are transcription factors that regulate expression of genes that stimulate erythropoiesis.…”

Section: Scientific Summary Pharmacodynamicsmentioning

confidence: 99%

“…When HIFα accumulates it dimerizes with HIFβ and translocate to the nucleus to activate the transcriptional response to hypoxia by promoting erythropoiesis. Pase I and phase II roduxadustat trials provided evidence that erythropoiesis was stimulated by an accumulation of plasma endogenous erythropoietin and suppression of hepcidin, an indirect regulator of iron absorption and utilization [12]. When hepcidin levels are suppressed intestinal absorption of iron increases and the release of iron from storage sites are utilized.…”

Section: Scientific Summary Pharmacodynamicsmentioning

confidence: 99%

“…In a placebo controlled dose-ranging study (NCT00761657) select patients who were being studied for treatment efficacy of roxadustat in NDD-CKD were also evaluated for pharmacokinetic and pharmacodynamics parameters [12]. Evaluations included measurement of endogenous erythropoietin (eEPO), iron indices including total iron-binding capacity (TIBC) and transferrin saturation (TSAT), as well as hepcidin levels.…”

Section: Pharmacokineticsmentioning

confidence: 99%

“…Roxadustat, also known as FD-4592 is a first in class small molecule oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) currently in Phase III development [12,13]. Fibrogen, Inc. has collaborated with Astellas Pharma Inc. and AstraZeneca in the development and commercialization of roxadustat and estimates completion of the Phase III trials for U.S approval in 2017.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A New Approach to the Management of Anemia in CKD Patients: A Review on Roxadustat

Becker¹,

Saad²

2017

J Kidney

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A New Approach to the Treatment of Chronic Kidney Disease is an article that informs the reader of the current information available on a novel therapeutic agent and new class of drug for the treatment of anemia. The data shows promising results against erythropoietin stimulating agents and offers a time line of when Phase III data will be available. The information on this new drug and new drug class will change how nephrologists approach treating anemia within their patients.

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Association of Testosterone Levels With Anemia in Older Men

et al. 2017

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In one-third of older men with anemia, no recognized cause can be found.OBJECTIVE To determine if testosterone treatment of men 65 years or older with unequivocally low testosterone levels and unexplained anemia would increase their hemoglobin concentration. DESIGN, SETTING, AND PARTICIPANTSA double-blinded, placebo-controlled trial with treatment allocation by minimization using 788 men 65 years or older who have average testosterone levels of less than 275 ng/dL. Of 788 participants, 126 were anemic (hemoglobin Յ12.7 g/dL), 62 of whom had no known cause. The trial was conducted in 12 academic medical centers in the United States from June 2010 to June 2014.INTERVENTIONS Testosterone gel, the dose adjusted to maintain the testosterone levels normal for young men, or placebo gel for 12 months. MAIN OUTCOMES AND MEASURESThe percent of men with unexplained anemia whose hemoglobin levels increased by 1.0 g/dL or more in response to testosterone compared with placebo. The statistical analysis was intent-to-treat by a logistic mixed effects model adjusted for balancing factors. RESULTSThe men had a mean age of 74.8 years and body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) of 30.7; 84.9% were white. Testosterone treatment resulted in a greater percentage of men with unexplained anemia whose month 12 hemoglobin levels had increased by 1.0 g/dL or more over baseline (54%) than did placebo (15%) (adjusted OR, 31.5; 95% CI, 3.7-277.8; P = .002) and a greater percentage of men who at month 12 were no longer anemic (58.3%) compared with placebo (22.2%) (adjusted OR, 17.0; 95% CI, 2.8-104.0; P = .002). Testosterone treatment also resulted in a greater percentage of men with anemia of known cause whose month 12 hemoglobin levels had increased by 1.0 g/dL or more (52%) than did placebo (19%) (adjusted OR, 8.2; 95% CI, 2.1-31.9; P = .003). Testosterone treatment resulted in a hemoglobin concentration of more than 17.5 g/dL in 6 men who had not been anemic at baseline. CONCLUSIONS AND RELEVANCE Among older men with low testosterone levels, testosterone treatment significantly increased the hemoglobin levels of those with unexplained anemia as well as those with anemia from known causes. These increases may be of clinical value, as suggested by the magnitude of the changes and the correction of anemia in most men, but the overall health benefits remain to be established. Measurement of testosterone levels might be considered in men 65 years or older who have unexplained anemia and symptoms of low testosterone levels.TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00799617

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Randomized placebo-controlled dose-ranging and pharmacodynamics study of roxadustat (FG-4592) to treat anemia in nondialysis-dependent chronic kidney disease (NDD-CKD) patients

Cited by 241 publications

References 40 publications

HIF stabilizers in the management of renal anemia: from bench to bedside to pediatrics

HIF stabilizers in the management of renal anemia: from bench to bedside to pediatrics

A New Approach to the Management of Anemia in CKD Patients: A Review on Roxadustat

Association of Testosterone Levels With Anemia in Older Men

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