Intermittent Oral Dosing of Roxadustat in Peritoneal Dialysis Chronic Kidney Disease Patients with Anemia: A Randomized, Phase 3, Multicenter, Open‐Label Study

Akizawa, Tadao; Otsuka, Tetsuro; Reusch, Michael; Ueno, Mai

doi:10.1111/1744-9987.12888

Cited by 87 publications

(117 citation statements)

References 15 publications

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“…A decrease in the levels of hepcidin was also observed throughout the study. Overall, these findings confirm those of previous studies in ESA-naïve patients [17] (CL-0308) and patients converted from ESAs [17] (307 and 312) and suggest that treatment with roxadustat improves iron metabolism and mobilization.…”

Section: Discussionsupporting

confidence: 89%

“…In line with previous studies, roxadustat was generally well tolerated in NDD-CKD patients who were ESA-naïve [14,17]. Common TEAEs were nasopharyngitis (20.2%), hypertension (6.1%), diarrhea (5.1%), and hyperkalemia (5.1%), and no deaths occurred throughout the study.…”

Section: Discussionsupporting

confidence: 85%

“…Roxadustat has previously demonstrated efficacy and tolerability in phase 2 studies in patients with dialysis-dependent (DD) [9][10][11] and NDD [10,[12][13][14] anemia of CKD. Phase 3 studies conducted in China [15,16] and Japan [17] have demonstrated roxadustat's efficacy and safety in both DD-CKD and NDD-CKD patients, and roxadustat has recently been approved in China in DD and NDD patients and in Japan in DD patients. Development is ongoing in Europe, Japan (NDD only), the USA, and other countries in DD and NDD patients [15][16][17].This study investigated the efficacy and safety of oral roxadustat administered at 2 different initial doses and titrated to achieve and maintain target Hb levels in Japanese ESA-naïve NDD-CKD patients with renal anemia.…”

Section: Introductionmentioning

confidence: 99%

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A Phase 3, Multicenter, Randomized, Two-Arm, Open-Label Study of Intermittent Oral Dosing of Roxadustat for the Treatment of Anemia in Japanese Erythropoiesis-Stimulating Agent-Naïve Chronic Kidney Disease Patients Not on Dialysis

Akizawa

Yamaguchi

Otsuka

et al. 2020

Nephron

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Introduction: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved for the treatment of anemia in Japan for patients with dialysis-dependent (DD) chronic kidney disease (CKD). Objective: Multicenter, randomized, open-label, noncomparative, phase 3 study to evaluate roxadustat for anemia of non-dialysis-dependent (NDD) CKD in Japan. Methods: Erythropoiesis stimulating agent (ESA)-naïve NDD-CKD patients were randomized to roxadustat (initial dose, 50 or 70 mg 3 times weekly), titrated to maintain hemoglobin (Hb) within 10.0-12.0 g/dL, for ≤24 weeks. Patients with either transferrin saturation of ≥5% or serum ferritin of ≥30 ng/mL during the screening period were eligible. Endpoints included response rate (proportion of patients achieving Hb ≥10.0 or ≥10.5 g/dL and Hb increase ≥1.0 g/dL from baseline) at end of treatment; average Hb (weeks 18-24); change of average Hb from baseline to weeks 18-24; maintenance rate (proportion of patients achieving Hb 10.0-12.0 g/dL at weeks 18-24); rate of rise (RoR) of Hb from weeks 0-4, discontinuation, or dose adjustment. Adverse events were monitored throughout the study. Results: Of 135 patients who provided informed consent, 100 were randomized and 99 received roxadustat (50 mg, n = 49; 70 mg, n = 50). The mean (SD) dose of roxadustat per intake at week 22 was 36.3 (22.7) mg in the roxadustat 50 mg group and 36.8 (16.0) mg in the roxadustat 70 mg group. Prior medications included oral iron therapy (20.2%) and intravenous iron therapy (1.0%). Overall response rate (95% CI) was 97.0% (91.4, 99.4; Hb ≥10.0 g/dL) and 94.9% (88.6, 98.3; Hb ≥10.5 g/ dL). Mean (SD) Hb (weeks 18-24) was 11.17 (0.62) g/dL. Mean (SD) change of Hb from baseline (weeks 18-24) was 1.34 (0.86) g/dL. Maintenance rate (95% CI) was 88.8% (80.3, 94.5) among patients with ≥1 Hb measurement during weeks 18-24. Mean (SD) RoR of Hb was 0.291 (0.197) g/dL/week (50 mg) and 0.373 (0.235) g/dL/week (70 mg). Nasopharyngitis and hypertension were the most common adverse events. Conclusion: Roxadustat increased and maintained Hb in ESA-naïve, partially iron-depleted NDD-CKD patients with anemia.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

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A Phase 3, Multicenter, Randomized, Two-Arm, Open-Label Study of Intermittent Oral Dosing of Roxadustat for the Treatment of Anemia in Japanese Erythropoiesis-Stimulating Agent-Naïve Chronic Kidney Disease Patients Not on Dialysis

Akizawa

Yamaguchi

Otsuka

et al. 2020

Nephron

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“…Similar findings were also reported in two recent phase 3 studies. A Japanese study showed that in CKD patients on PD who were ESA‐naïve, roxadustat increased and maintained Hb in the target range; however, the time to reach the target was shorter (2‐4 weeks) than that observed in this study (6 weeks), possibly due to higher Hb levels at baseline 14 . Comparable results were also reported in a Chinese study in CKD patients on HD or PD 15 .…”

Section: Discussionsupporting

confidence: 50%

Oral roxadustat three times weekly in ESA‐naïve and ESA‐converted patients with anemia of chronic kidney disease on hemodialysis: Results from two phase 3 studies

et al. 2020

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Roxadustat is a hypoxia‐inducible factor prolyl hydroxylase inhibitor approved in China for anemia of dialysis‐dependent chronic kidney disease (CKD). Japanese hemodialysis patients with anemia of CKD previously naïve to, or converted from, erythropoiesis‐stimulating agents (ESAs) were enrolled in two open‐label, noncomparative studies of titrated oral roxadustat administered three times weekly. ESA‐naïve patients (n = 75) were randomized to roxadustat (initial dose, 50 or 70 mg) for 24 weeks; ESA‐converted patients (n = 164) were assigned to roxadustat (initial dose, 70 or 100 mg based on prior ESA dose) for 52 weeks. Efficacy outcomes included average hemoglobin (Hb, weeks 18‐24 or 46‐52), change of Hb from baseline to weeks 18 to 24 (ΔHb18‐24) or weeks 46 to 52 (ΔHb46‐52), and maintenance rate (proportion of patients who achieved average Hb of 10.0‐12.0 g/dL for weeks 18‐24 or weeks 46‐52). Treatment‐emergent adverse events (TEAEs) were monitored. Mean (SD) Hb was 10.93 (0.79) g/dL (weeks 18‐24) (ESA‐Naïve Study), and 10.93 (0.69; weeks 18‐24) g/dL and 11.11 (0.67; weeks 46‐52) g/dL (ESA‐Converted Study). Mean (SD) ΔHb18‐24 was 2.26 (1.02) g/dL (ESA‐Naïve Study) and −0.03 (0.90) g/dL (ESA‐Converted Study); mean (SD) ΔHb46‐52 was 0.12 (0.83) g/dL (ESA‐Converted Study). The overall maintenance rate was 73.0% (54/74) (ESA‐Naïve Study) (weeks 18‐24), and 79.1% (129/163; weeks 18‐24) and 71.2% (116/163; weeks 46‐52) (ESA‐Converted Study). Nasopharyngitis was the most common TEAE. Two deaths, considered unrelated to roxadustat, occurred in the ESA‐Converted Study. Roxadustat effectively corrected and maintained Hb, regardless of previous ESA treatment, in Japanese anemic CKD patients on hemodialysis.

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“…HIF-PHIs increase Hb levels by activating the body's natural response to hypoxia independent of cellular oxygen levels [5]. Roxadustat is an orally administered HIF-PHI that has shown safety and efficacy in phase 3 trials [6][7][8], and was recently approved in China for the treatment of anemia in dialysis-dependent and non-dialysis-dependent CKD patients, and in Japan for the treatment of anemia in dialysis-dependent CKD patients. Roxadustat is currently being investigated internationally in both dialysisdependent and non-dialysis-dependent patients.…”

Section: Methodsmentioning

confidence: 99%

Effect of Kidney Function and Dialysis on the Pharmacokinetics and Pharmacodynamics of Roxadustat, an Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor

Meent

Kerbusch

Kaspera

et al. 2020

Eur J Drug Metab Pharmacokinet

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Background and Objectives Roxadustat is an orally active hypoxia-inducible factor prolyl hydroxylase inhibitor for anemia in chronic kidney disease. The pharmacokinetics, metabolic profile, and pharmacodynamics of roxadustat were investigated in subjects with different degrees of kidney function. Methods This phase 1 open-label study enrolled subjects with normal and severely impaired kidney function, and end-stage renal disease (ESRD) on continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal dialysis (APD) or hemodialysis/hemodiafiltration (HD/HDF). All subjects received a single 100-mg dose of oral roxadustat. Within a single-sequence, two-treatment period design (P1/P2), subjects with ESRD on HD/HDF received roxadustat 2 h after (P1) and 2 h before (P2) a dialysis session. Area under the plasma concentration–time curve (AUC) from administration to infinity (AUC inf ), maximum concentration ( C max ), and terminal elimination half-life ( t 1/2 ) were assessed for roxadustat; AUC and C max were assessed for erythropoietin. Results Thirty-four subjects were enrolled and received roxadustat (normal kidney function, n = 12; severely impaired kidney function, n = 9; ESRD on CAPD/APD, n = 1; ESRD on HD/HDF, n = 12). The geometric least-square mean ratio of AUC inf was 223% and 195% in subjects with severely impaired kidney function and ESRD on HD/HDF, respectively, relative to subjects with normal kidney function; C max and t 1/2 were comparable. The pharmacokinetic profile of roxadustat was not affected by HD/HDF. AUC inf and t 1/2 for the metabolites of roxadustat increased in subjects with kidney impairment. The AUC and C max of erythropoietin increased in subjects with severely impaired kidney function or ESRD on HD/HDF. Roxadustat was well tolerated. Conclusions Kidney function impairment increased the AUC of roxadustat and its metabolites. The C max and t 1/2 of roxadustat were comparable among groups. Roxadustat and its metabolites were not cleared by HD/HDF. Clinical Trials Registration Number: NCT02965040. Electronic supplementary material The online version of this article (10.1007/s13318-020-00658-w) contains supplementary material, which is available to authorized users.

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Intermittent Oral Dosing of Roxadustat in Peritoneal Dialysis Chronic Kidney Disease Patients with Anemia: A Randomized, Phase 3, Multicenter, Open‐Label Study

Cited by 87 publications

References 15 publications

A Phase 3, Multicenter, Randomized, Two-Arm, Open-Label Study of Intermittent Oral Dosing of Roxadustat for the Treatment of Anemia in Japanese Erythropoiesis-Stimulating Agent-Naïve Chronic Kidney Disease Patients Not on Dialysis

A Phase 3, Multicenter, Randomized, Two-Arm, Open-Label Study of Intermittent Oral Dosing of Roxadustat for the Treatment of Anemia in Japanese Erythropoiesis-Stimulating Agent-Naïve Chronic Kidney Disease Patients Not on Dialysis

Oral roxadustat three times weekly in ESA‐naïve and ESA‐converted patients with anemia of chronic kidney disease on hemodialysis: Results from two phase 3 studies

Effect of Kidney Function and Dialysis on the Pharmacokinetics and Pharmacodynamics of Roxadustat, an Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor

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