Clinical Trial of Vadadustat in Patients with Anemia Secondary to Stage 3 or 4 Chronic Kidney Disease

Martin, Edouard; Smith, Mark T.; Maroni, Bradley J.; Zuraw, Qing; deGoma, Emil M.

doi:10.1159/000464476

Cited by 116 publications

(128 citation statements)

References 25 publications

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“…Following oral administration with vadadustat, eEPO levels returned to baseline within 24 h, similar to the expected physiological diurnal response [56].…”

Section: Vadadustatsupporting

confidence: 72%

“…In contrast to roxadustat phase II studies, vadadustat administration has not been associated with a change in total cholesterol [56,57]. In phase II studies, it was well tolerated, Open label, randomized, 3-way, cross-over study to evaluate the relative bioavailability, PK, food effect, and palatability of the pediatric formulation versus adult tablet.…”

Section: Vadadustatmentioning

confidence: 99%

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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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“…Following oral administration with vadadustat, eEPO levels returned to baseline within 24 h, similar to the expected physiological diurnal response [56].…”

Section: Vadadustatsupporting

confidence: 72%

Section: Vadadustatmentioning

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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“…As with other HIF-PH inhibitors, the present study showed no change in plasma VEGF after enarodustat treatment [29,30]. AEs considered attributable to enhanced VEGF expression should be profiled in Phase 3 studies on the long-term safety of enarodustat.…”

Section: Discussion/conclusionmentioning

confidence: 49%

A Placebo-Controlled, Randomized Trial of Enarodustat in Patients with Chronic Kidney Disease Followed by Long-Term Trial

et al. 2019

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Background: Enarodustat (JTZ-951) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that mimics adaptive responses to hypoxic conditions and may provide a new therapeutic approach for managing anemia in patients with chronic kidney disease (CKD). We evaluated the efficacy, safety, and maintenance dose of enarodustat in anemic patients with CKD not on dialysis. Methods: Erythropoiesis-stimulating agent (ESA) naïve patients (correction group) and patients on a stable dose of ESA (conversion group) were randomized to receive 2, 4, or 6 mg of enarodustat or placebo once daily for 6 weeks in a double-blind manner (Period 1) followed by 24 weeks of open enarodustat treatment to maintain their hemoglobin (Hb) levels within a target range of 10.0–12.0 g/dL in reference to a dose adjustment algorithm (Period 2). Results: In the correction group, Hb level increase rate per week increased in a dose-response manner. The proportion of subjects in the conversion group who maintained Hb levels within ± 1.0 g/dL of baseline did not differ between each enarodustat arm and placebo arm during Period 1. Over 70% of subjects in both groups maintained Hb levels within the target range at the end of treatment in Period 2. The mean prescribed doses were 3.58 and 3.74 mg/day in the correction group and the conversion group, respectively. Enarodustat was associated with decreases in hepcidin and ferritin and increased total iron-binding capacity and was generally well tolerated. Conclusions: Enarodustat corrects and maintains Hb levels in anemic patients with CKD not on dialysis.

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“…In Martin et al [18] study, after 6 weeks of every day dosing of HIF-PHI mean Hb increase of 0.76, 0.70, 1.15, and 1.39 g/dL from baseline with 240, 370, 500, and 630 mg doses, respectively, was observed. In Besarab et al [26] study with twice or thrice (TIW) in a week treatment for 4 weeks, mean Hb increase of 0.8-2.2 g/dL from baseline was observed with 0.7-2.0 mg/kg dose.…”

Section: Discussionmentioning

confidence: 91%

“…The activation of HIF promotes erythropoiesis through the stimulation of endogenous EPO production, increased uptake of iron, and mobilization of iron stores [18]. There are 3 isoforms of HIF (HIF-1, 2, and 3), of which HIF-1 and HIF-2 regulate the vascular response to hypoxia.…”

Section: Introductionmentioning

confidence: 99%

Outcomes of Desidustat Treatment in People with Anemia and Chronic Kidney Disease: A Phase 2 Study

et al. 2019

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Background: Desidustat (ZYAN1) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) that stimulates erythropoiesis. Stabilizing HIF via PHI is developing as a new therapeutic approach to treat anemia secondary to chronic kidney disease (CKD). This trial evaluated the safety, tolerability, and efficacy of Desidustat in adult CKD patients with anemia, who were not on dialysis. Methods: This was a Phase 2, randomized, double-blind, 6-week, placebo-controlled, dose-ranging, safety and efficacy study. A total of 117 eligible patients were randomized to 4 arms: 100, 150, 200 mg, or placebo. The investigational product was administered every alternate day for 6 weeks in fasting conditions. The primary endpoint was change in hemoglobin (Hb) from baseline to week 6. Results: Baseline demographics were well balanced among all the treatment arms. In the modified intent-to-treat (mITT) population, a mean Hb increase of 1.57, 2.22, and 2.92 g/dL in Desidustat 100, 150, and 200 mg arms, respectively, was observed post 6 weeks treatment. The responder rate (≥1 g/dL increase) was 66% in 100 mg, 75% in 150 mg, and 83% in 200 mg treatment arms, in the mITT population. Eighteen patients had at least one treatment emergent adverse event (TEAE), and 5 patients reported at least one drug-related mild TEAE. No death or serious adverse event was reported during the trial. Conclusion: There was dose-related increase in Hb across all doses compared to placebo in mITT and per-protocol populations. Desidustat also increased pharmacokinetic parameters Cmax and AUC in dose-related manner. There was no significant change in vital signs, electrocardiographic parameters, or safety laboratory values. Clinical Trial Registration Number CTRI/2017/05/008534 (registered on May 11, 2017).

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Clinical Trial of Vadadustat in Patients with Anemia Secondary to Stage 3 or 4 Chronic Kidney Disease

Cited by 116 publications

References 25 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 Placebo-Controlled, Randomized Trial of Enarodustat in Patients with Chronic Kidney Disease Followed by Long-Term Trial

Outcomes of Desidustat Treatment in People with Anemia and Chronic Kidney Disease: A Phase 2 Study

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