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

2019 ◽  
Vol 49 (2) ◽  
pp. 165-174 ◽  
Author(s):  
Tadao Akizawa ◽  
Masaomi Nangaku ◽  
Takuhiro Yamaguchi ◽  
Masanobu Arai ◽  
Ryosuke Koretomo ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Binding Capacity ◽  
Hypoxia Inducible Factor ◽  
Target Range ◽  
Adaptive Responses ◽  
Double Blind ◽  
Hypoxic Conditions ◽  
Period 2 ◽  
Term Trial

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.

scholarly journals A Phase 3 Study of Enarodustat (JTZ-951) in Japanese Hemodialysis Patients for Treatment of Anemia in Chronic Kidney Disease: SYMPHONY HD Study

2021 ◽  
pp. 1-9
Author(s):  
Tadao Akizawa ◽  
Masaomi Nangaku ◽  
Takuhiro Yamaguchi ◽  
Ryosuke Koretomo ◽  
Kazuo Maeda ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Binding Capacity ◽  
Hypoxia Inducible Factor ◽  
Intravenous Iron ◽  
Target Range ◽  
Maintenance Hemodialysis ◽  
Phase 3 ◽  
Evaluation Period ◽  
The Mean

<b><i>Introduction:</i></b> Enarodustat (JTZ-951) is a new oral hypoxia-inducible factor-prolyl hydroxylase inhibitor for the treatment of anemia in chronic kidney disease (CKD). We conducted a phase 3 study to compare the efficacy and safety of enarodustat with darbepoetin alfa (DA) in Japanese anemic patients with CKD receiving maintenance hemodialysis. <b><i>Methods:</i></b> Subjects receiving maintenance hemodialysis were randomly assigned at a 1:1 ratio to receive oral enarodustat once daily or intravenous DA every week for 24 weeks with dose adjustment every 4 weeks to maintain hemoglobin (Hb) within a target range (≥10.0 to &#x3c;12.0 g/dL). The primary efficacy endpoint was difference in mean Hb level between arms during the evaluation period defined as weeks 20–24 (noninferiority margin: −1.0 g/dL). Intravenous iron preparations were prohibited during the screening period and during weeks 0–4. <b><i>Results:</i></b> The mean Hb level of each arm during the evaluation period was 10.73 g/dL (95% confidence interval [CI]: 10.56, 10.91) in the enarodustat arm and 10.85 g/dL (95% CI: 10.72, 10.98) in the DA arm. The difference in the mean Hb level between arms was −0.12 g/dL (95% CI: −0.33, 0.10), confirming the noninferiority of enarodustat to DA. The mean Hb level of each arm was maintained within the target range during the treatment period. Increased total iron-binding capacity and serum iron and decreased hepcidin were observed through week 4 in the enarodustat arm albeit after switching from erythropoiesis-stimulating agents. No apparent safety concerns of enarodustat were observed compared with DA. <b><i>Discussion/Conclusion:</i></b> Enarodustat was noninferior to DA for the treatment of anemia in CKD patients receiving maintenance hemodialysis and was generally well tolerated over 24 weeks.

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

2019 ◽  
Vol 49 (6) ◽  
pp. 470-478 ◽  
Author(s):  
Deven V. Parmar ◽  
Kevinkumar A. Kansagra ◽  
Jatin C. Patel ◽  
Shuchi N. Joshi ◽  
Nitin S. Sharma ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Adverse Event ◽  
Kidney Disease ◽  
Hypoxia Inducible Factor ◽  
Vital Signs ◽  
Pharmacokinetic Parameters ◽  
Phase 2 ◽  
Double Blind ◽  
Clinical Trial Registration ◽  
Mitt Population

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).

scholarly journals Association of Nuclear Receptor Coactivators with Hypoxia-Inducible Factor-1α in the Serum of Patients with Chronic Kidney Disease

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Tianbiao Zhou ◽  
Wenshan Lin ◽  
Shujun Lin ◽  
Zhiqing Zhong ◽  
Yuanyuan Luo ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Nuclear Receptor ◽  
Hypoxia Inducible Factor ◽  
Serum Levels ◽  
Control Group ◽  
Medical College ◽  
Hypoxic Conditions ◽  
Nuclear Receptor Coactivators ◽  
Healthy Control

Nuclear receptor coactivators (NCOAs), consisting of coactivators and corepressors, dramatically enhance the transcriptional activity of nuclear receptors. Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that plays a major role under hypoxic conditions. This study was performed with the focus on the association of NCOAs with HIF-1α in the serum of chronic kidney disease (CKD) patients. Sixty patients with stage 5 CKD and 30 healthy controls from The Second Affiliated Hospital of Shantou University Medical College, between March 21, 2019, and October 30, 2019, were recruited in this prospective cohort study. We analyzed the serum levels of NCOAs (NCOA1, NCOA2, and NCOA3), HIF-1α, vascular endothelial growth factor (VEGF), etc. and assessed whether there was any relationship between these parameters and CKD disease. We found that circulating NCOA1 was positively associated with circulating NCOA2, NCOA3, and HIF-1α. A positive correlation was also observed between NCOA2 and NCOA1, NCOA3, HIF-1α, and VEGF. Furthermore, statistically significant correlations between NCOA3 and NCOA1, NCOA2, and HIF-1α were observed. The serum levels of VEGF in the CKD group were higher than those of the healthy control group. Circulating NCOA1 and circulating NCOA2 were negatively associated with procalcitonin. In conclusion, there was an association between circulating NCOA1, NCOA2, NCOA3, and circulating HIF-1α, and circulating VEGF was a risk factor for CKD disease. However, more studies should be performed to confirm this hypothesis.

scholarly journals MO541HEMATOLOGIC EFFICACY OF VADADUSTAT FOR ANEMIA IN PATIENTS WITH NON--DIALYSIS-DEPENDENT CHRONIC KIDNEY DISEASE

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Mark Koury ◽  
Pablo E Pergola ◽  
Prabir Roy-Chaudhury ◽  
Youssef Farag ◽  
Dennis Vargo ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Darbepoetin Alfa ◽  
Hypoxia Inducible Factor ◽  
The United States ◽  
Target Range ◽  
Phase 3 ◽  
Two Phase ◽  
Prolyl Hydroxylases ◽  
Safety Outcome

Abstract Background and Aims Vadadustat is a small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylases under development to treat anemia associated with chronic kidney disease (CKD). The vadadustat phase 3 program includes four efficacy and cardiovascular safety outcome trials of vadadustat versus the erythropoiesis-stimulating agent (ESA) darbepoetin alfa. Here we describe detailed results on hematologic efficacy in two phase 3, randomized trials (the PRO2TECT trials) in adult patients with non–dialysis-dependent (NDD) CKD and anemia, in which vadadustat met prespecified noninferiority criteria compared to darbepoetin alfa, with respect to hematologic efficacy (correction/maintenance of hemoglobin [Hb] target concentrations). Method The mean screening Hb level for the ESA-untreated NDD-CKD trial (NCT02648347) had to be &lt;10.0 g/dL, and for the ESA-treated NDD-CKD trial (NCT02680574), the range had to be from 8.0-11.0 g/dL in the United States (US) and from 9.0-12.0 g/dL non-US. In the ESA-untreated trial, patients received no ESA within 8 weeks before randomization; in the ESA-treated trial, patients were maintained on ESA therapy, with ≥1 dose received within 6 weeks prior to or during screening. The vadadustat starting dose was 300 mg/day for all patients, whereas the initial darbepoetin alfa dose depended on each patient’s prior dose or the product label. Both vadadustat and darbepoetin alfa doses were titrated according to prespecified dosing algorithms to achieve target Hb concentrations (US: 10-11 g/dL; non-US: 10-12 g/dL) both during the primary (PEP; weeks 24-36) and secondary (SEP; weeks 40-52) evaluation periods. Herein, we present topline results from the PEP and SEP endpoints, in addition to more detailed erythrocyte parameters. Results A total of 3,476 patients (1751 ESA-untreated and 1725 ESA-treated) were randomized 1:1 to vadadustat or darbepoetin alfa. In both trials, vadadustat was noninferior to darbepoetin alfa with regard to the difference of mean change in Hb concentrations between baseline and PEP, as well as between baseline and SEP. The respective proportions of patients (vadadustat vs. darbepoetin alfa) with an average Hb value within the geography-specific target range in the PEP and SEP were 50.4% versus 50.2% and 43.1% versus 43.5% in the ESA-untreated trial and 60.1% versus 60.7% and 50.7% versus 49.0% in the ESA-treated trial. The proportion of patients (vadadustat vs darbepoetin alfa) who achieved an Hb increase &gt;1.0 g/dL from baseline to week 52 was assessed only for the ESA-untreated trial and was 87.7% (95% CI: 85.4%, 89.8%) for vadadustat versus 88.0% (95% CI: 85.6%, 90.0%) for darbepoetin alfa. Hematologic parameters at time points within the PEP and SEP are presented in Table 1. In both the ESA-untreated and ESA-treated trials, the reticulocyte count trended up from baseline through week 52 for vadadustat and trended down from baseline for darbepoetin alfa. Trends in erythrocyte mean corpuscular volume and erythrocyte mean corpuscular Hb were largely unremarkable by week 52 in both treatment groups. Conclusion Vadadustat demonstrated similar profiles across erythrocyte parameters compared with darbepoetin alfa in the treatment of adults with anemia in CKD not on dialysis, whether ESA-untreated or ESA-treated at study entry.

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

2017 ◽  
Vol 45 (5) ◽  
pp. 380-388 ◽  
Author(s):  
Edouard R. Martin ◽  
Mark T. Smith ◽  
Bradley J. Maroni ◽  
Qing C. Zuraw ◽  
Emil M. deGoma
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Binding Capacity ◽  
Small Sample Size ◽  
Small Sample ◽  
Dependent Manner ◽  
Short Treatment ◽  
Double Blind ◽  
Ckd Stage ◽  
Factor C

Background: Therapeutic options for the treatment of anemia secondary to chronic kidney disease (CKD) remain limited. Vadadustat (AKB-6548) is an oral hypoxia-inducible factor prolyl-hydroxylase domain (HIF-PHD) inhibitor that is being investigated for the treatment of anemia secondary to CKD. Methods: A phase 2a, multicenter, randomized, double-blind, placebo-controlled, dose-ranging trial (NCT01381094) was undertaken in adults with anemia secondary to CKD stage 3 or 4. Eligible subjects were evenly randomized to 5 groups: 240, 370, 500, or 630 mg of once-daily oral vadadustat or placebo for 6 weeks. All subjects received low-dose supplemental oral iron (50 mg daily). The primary endpoint was the mean absolute change in hemoglobin (Hb) from baseline to the end of treatment. Secondary endpoints included iron indices, safety, and tolerability. Results: Ninety-three subjects were randomized. Compared with placebo, vadadustat significantly increased Hb after 6 weeks in a dose-dependent manner (analysis of variance; p < 0.0001). Vadadustat increased the total iron-binding capacity and decreased concentrations of ferritin and hepcidin. The proportion of subjects with at least 1 treatment-emergent adverse event was similar between vadadustat- and placebo-treated groups. No significant changes in blood pressure, vascular endothelial growth factor, C-reactive protein, or total cholesterol were observed. Limitations of this study included its small sample size and short treatment duration. Conclusions: Vadadustat increased Hb levels and improved biomarkers of iron mobilization and utilization in patients with anemia secondary to stage 3 or 4 CKD. Global multicenter, randomized phase 3 trials are ongoing in non-dialysis-dependent and dialysis-dependent patients.

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