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Therapeutic Apheresis and Dialysis :... Aug 2022Enarodustat, a newly developed hypoxia-inducible factor prolyl hydroxylase inhibitor, is used in clinical practice in Japan. Several clinical studies showed that... (Review)
Review
Enarodustat, a newly developed hypoxia-inducible factor prolyl hydroxylase inhibitor, is used in clinical practice in Japan. Several clinical studies showed that enarodustat corrected and maintained hemoglobin (Hb) levels by stimulating endogenous erythropoietin production and improving iron utilization in anemic patients with chronic kidney disease, regardless of whether they were on dialysis. In addition, Phase III comparative studies demonstrated that enarodustat was noninferior to darbepoetin alfa in controlling Hb levels. Furthermore, enarodustat was well tolerated during the treatment. Enarodustat is currently being developed in the Republic of Korea and China and is expected to be developed worldwide. This article reviews the data on enarodustat, including the findings from preclinical studies, pharmacokinetics/pharmacodynamics, and efficacy and safety results of clinical studies.
Topics: Anemia; Erythropoietin; Hematinics; Humans; N-substituted Glycines; Prolyl-Hydroxylase Inhibitors; Pyridines; Renal Insufficiency, Chronic; Triazoles
PubMed: 35218616
DOI: 10.1111/1744-9987.13820 -
Frontiers in Pharmacology 2021Vadadustat is a novel drug for treating anemia patients with chronic kidney disease (CKD), but its effect and safety remain uncertain. This study aimed to summarize the... (Review)
Review
Vadadustat is a novel drug for treating anemia patients with chronic kidney disease (CKD), but its effect and safety remain uncertain. This study aimed to summarize the evidence for vadadustat in the treatment of CKD patients with anemia. PubMed, Ovid Medline, Embase, Cochrane CENTRAL, Wanfang Data, China National Knowledge Infrastructure and an international trial register were searched from their inception to June 2021 for randomized controlled trials (RCTs) comparing the efficacy and safety of vadadustat to those of placebo or erythropoiesis-stimulating agents (ESAs) in treating anemia in CKD patients. Data were pooled in a meta-analysis, with results expressed as the mean difference for continuous outcomes and relative risk for categorical outcomes with 95% confidence intervals (95% CIs). The certainty of evidence was rated according to Cochrane methods and the GRADE approach. Ten RCTs comparing vadadustat with placebo (4 RCTs) or darbepoetin alfa (6 RCTs) were included ( = 8,438 participants). Compared with placebo, vadadustat increased the hemoglobin (Hb) response rate (risk ratio 5.27; 95% CI: 2.69 to 10.31; < 0.001; high certainty of evidence) and Hb level from baseline (∆Hb) (mean difference (MD) 1.28; 95% CI: 0.83 to 1.73; < 0.001; low certainty of evidence). Compared with placebo or darbepoetin alfa, vadadustat decreased hepcidin (MD -36.62; 95% CI: -54.95 to -18.30; < 0.001) and ferritin (MD -56.24; 95% CI: -77.37 to -35.11; < 0.001) levels and increased iron-binding capacity (MD 24.38; 95% CI: 13.69 to 35.07; < 0.001), with a low to moderate certainty of evidence. Moderate to high certainty evidence suggested that compared with placebo or darbepoetin alfa, vadadustat significantly increased the risk of nausea and diarrhea but did not significantly increase the risk of serious adverse events, especially all-cause mortality, cardiac events and nonfatal stroke. Vadadustat may safely improve Hb levels and promote iron utilization in CKD patients with anemia without increasing the incidence of serious adverse events.
PubMed: 35115942
DOI: 10.3389/fphar.2021.795214 -
BioDrugs : Clinical Immunotherapeutics,... Feb 2020Darbepoetin-alfa is an erythropoiesis-stimulating agent (ESA) with a long elimination half-life that achieves better hemoglobin (Hb) stability than short-acting ESAs. (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and Safety of CKD-11101 (Proposed Biosimilar of Darbepoetin-Alfa) Compared with Darbepoetin-Alfa in Patients on Hemodialysis: A Randomized, Double-Blinded, Parallel-Group Phase III Study.
BACKGROUND
Darbepoetin-alfa is an erythropoiesis-stimulating agent (ESA) with a long elimination half-life that achieves better hemoglobin (Hb) stability than short-acting ESAs.
OBJECTIVE
We aimed to evaluate the efficacy and safety of intravenous CKD-11101 (a biosimilar of darbepoetin-alfa) compared with those of darbepoetin-alfa in hemodialysis patients.
METHODS
The study was performed in 24 centers in Korea between June 2015 and June 2017. The study subjects were randomized in a double-blind manner. The follow-up duration was 24 weeks, which consisted of 20 weeks of maintenance and 4 weeks of evaluation period. All patients underwent a stabilization period to achieve a target baseline Hb of 10-12 g/dL before randomization. Following randomization, patients received darbepoetin-alfa or CKD-11101 weekly or biweekly.
RESULTS
A total of 403 patients were randomized into two groups, and a total of 325 patients (80.6%) completed the investigation. The differences between the two groups in terms of change in the average Hb level from baseline to evaluation were not significant. The average administered dose of ESA was similar between the groups. There was no difference in the proportion of patients who maintained the target Hb during the evaluation period [60.4% vs. 66.2% in the CKD-11101 and darbepoetin-alfa groups, respectively (p = 0.3038)]. In addition, the safety analysis, consisting of adverse events and adverse drug reactions, showed comparable results between the two groups.
CONCLUSION
The changes in the level of Hb, dose of erythropoietin, and achievement rate of the target Hb during the study period were comparable between the groups. CKD-11101 has an equivalent efficacy and safety compared with darbepoetin-alfa in patients undergoing hemodialysis.
Topics: Adult; Biosimilar Pharmaceuticals; Darbepoetin alfa; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Epoetin Alfa; Female; Hemoglobins; Humans; Male; Middle Aged; Renal Dialysis; Renal Insufficiency, Chronic
PubMed: 31749113
DOI: 10.1007/s40259-019-00396-9 -
Clinical and Experimental Nephrology Aug 2023Erythropoiesis-stimulating agents (ESAs) are the standard treatment for patients with renal anemia to increase hemoglobin (Hb) levels and reduce the need for blood... (Clinical Trial)
Clinical Trial
BACKGROUND
Erythropoiesis-stimulating agents (ESAs) are the standard treatment for patients with renal anemia to increase hemoglobin (Hb) levels and reduce the need for blood transfusions. However, treatments targeting high Hb levels require high doses of ESAs administered intravenously, which is associated with an elevated risk of adverse cardiovascular events. Furthermore, there have been some problems such as hemoglobin variability and low achievement of target hemoglobin due to the shorter half-lives of ESAs. Consequently, erythropoietin-promoting medications, such as hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors, have been developed. This study aimed to evaluate changes in the Treatment Satisfaction Questionnaire for Medicine version II (TSQM-II) domain scores relative to baseline in each trial, to assess patient satisfaction with molidustat versus darbepoetin alfa.
METHODS
This post-hoc analysis of two clinical trials compared treatment satisfaction with an HIF-PH inhibitor, molidustat, versus a standard ESA, darbepoetin alfa, as part of therapy in patients with non-dialysis chronic kidney disease (CKD) and renal anemia.
RESULTS
Exploratory outcome data using the TSQM-II showed that both arms in both trials had enhanced treatment satisfaction over the course of the study period, as well as improvements in most TSQM-II domains at week 24 of treatment. Molidustat was associated with convenience domain scores at multiple time points depending on the trial. More patients were highly satisfied with the convenience of molidustat than that of darbepoetin alfa. Patients treated with molidustat had increased global satisfaction domain scores compared with those treated with darbepoetin alfa; however, the differences in global satisfaction domain scores were not significant.
CONCLUSION
These patient-reported satisfaction outcomes support the use of molidustat as a patient-centered treatment option for CKD-related anemia.
REGISTRATION OF CLINICAL TRIALS
ClinicalTrials.gov Identifier: NCT03350321 (November 22, 2017).
CLINICALTRIALS
gov Identifier: NCT03350347 (November 22, 2017).
Topics: Humans; Anemia; Chronic Disease; Darbepoetin alfa; Erythropoietin; Hematinics; Hemoglobins; Patient Satisfaction; Renal Insufficiency, Chronic
PubMed: 37095342
DOI: 10.1007/s10157-023-02353-x -
[Rinsho Ketsueki] the Japanese Journal... 2020Myelodysplastic syndromes (MDS) are neoplastic diseases of the hematopoietic stem cells, caused by genetic mutations. The clinical courses of MDS are highly variable...
Myelodysplastic syndromes (MDS) are neoplastic diseases of the hematopoietic stem cells, caused by genetic mutations. The clinical courses of MDS are highly variable based on the underlying genetic aberrations, ranging from slowly progressing cytopenia to rapidly-manifesting fatal diseases, including the development of acute myelogenous leukemia. The management of lower-risk MDS, which is risk-stratified based on the revised International Prognostic Scoring System (IPSS-R), mainly consists of a supportive therapy, including blood transfusion to treat anemia and thrombocytopenia. Recently, three novel drugs were approved, which became available in Japan. These include darbepoetin alfa, an erythropoiesis-stimulating agent; lenalidomide, which is specifically active for anemia of 5q- syndrome; and deferasirox, an oral iron-chelating agent. Decision analyses also provide evidence in determining the optimal timing for the potentially curative allogeneic hematopoietic stem cell transplantation for lower-risk MDS. Thus, the management of lower-risk MDS should be optimized using these novel agents and newly available evidence.
Topics: Anemia, Macrocytic; Darbepoetin alfa; Humans; Japan; Lenalidomide; Myelodysplastic Syndromes; Risk Assessment
PubMed: 33162518
DOI: 10.11406/rinketsu.61.1212 -
Therapeutic Apheresis and Dialysis :... Apr 2020The objective of this study was to evaluate the safety and efficacy of JR-131, a biosimilar of darbepoetin alfa, for long-term treatment of renal anemia patients... (Comparative Study)
Comparative Study
The objective of this study was to evaluate the safety and efficacy of JR-131, a biosimilar of darbepoetin alfa, for long-term treatment of renal anemia patients undergoing hemodialysis. In this multicenter, single-arm, phase 3 study, 159 patients with renal anemia who had been receiving darbepoetin alfa or recombinant human erythropoietins were treated with intravenous JR-131 for 52 weeks. In patients receiving darbepoetin alfa, JR-131 was administered at the same dose, while in patients receiving recombinant human erythropoietin the dose was determined based on the 1:200 conversion ratio following the Japanese darbepoetin alfa package insert. No notable adverse drug reactions were reported, and no anti-JR-131 antibodies were detected. The hemoglobin levels were maintained in the range of 10.0-12.0 g/dL throughout the study. JR-131 proved to be a useful and lower-cost alternative to darbepoetin alfa in the management of renal anemia in patients undergoing hemodialysis.
Topics: Adult; Aged; Aged, 80 and over; Anemia; Biosimilar Pharmaceuticals; Darbepoetin alfa; Female; Hematinics; Hemoglobins; Humans; Japan; Male; Middle Aged; Prospective Studies; Renal Dialysis; Renal Insufficiency, Chronic; Time Factors
PubMed: 31304637
DOI: 10.1111/1744-9987.13420 -
American Journal of Nephrology 2021Molidustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that predominantly induces renal production of erythropoietin (EPO). Molidustat was evaluated... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Molidustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that predominantly induces renal production of erythropoietin (EPO). Molidustat was evaluated for the treatment of anemia associated with chronic kidney disease (CKD) in the "Molidustat Once Daily Improves Renal Anemia by Inducing EPO" (MIYABI) program, which comprises 5 phase 3 clinical trials. The present MIYABI Non-Dialysis Correction (ND-C) study investigated the efficacy and safety of molidustat in Japanese patients with renal anemia who were not undergoing dialysis and were not receiving erythropoiesis-stimulating agent (ESA) treatment.
METHODS
This was a 52-week, randomized (1:1), open-label, active-control, parallel-group, multicenter, phase 3 study in Japanese patients with renal anemia associated with CKD (stages 3-5). Molidustat or the ESA darbepoetin alfa (hereinafter referred to as darbepoetin) were initiated at 25 mg once daily or 30 μg every 2 weeks, respectively, and doses were regularly titrated to correct and to maintain hemoglobin (Hb) levels in the target range of ≥11.0 g/dL and <13.0 g/dL. The primary efficacy outcome was the mean Hb level and its change from baseline during the evaluation period (weeks 30-36). The safety outcomes included evaluation of all adverse events.
RESULTS
In total, 162 patients were randomized to receive molidustat (n = 82) or darbepoetin (n = 80). Baseline characteristics were generally well balanced between treatment groups. The mean (standard deviation) Hb levels at baseline were 9.84 (0.64) g/dL for molidustat and 10.00 (0.61) g/dL for darbepoetin. The mean (95% confidence interval [CI]) for mean Hb levels during the evaluation period for molidustat (11.28 [11.07, 11.50] g/dL) and darbepoetin (11.70 [11.50, 11.90] g/dL) was within the target range. Based on a noninferiority margin of 1.0 g/dL, molidustat was noninferior to darbepoetin in the change in mean Hb level during the evaluation period from baseline; the least-squares mean (95% CI) difference (molidustat-darbepoetin) was -0.38 (-0.67, -0.08) g/dL. The proportion of patients who reported at least 1 treatment-emergent adverse event (TEAE) was 93.9% for molidustat and 93.7% for darbepoetin. Most TEAEs were mild (54.9% for molidustat and 63.3% for darbepoetin) or moderate (22.0% for molidustat and 22.8% for darbepoetin) in intensity. There were 3 deaths in the molidustat group and 1 in the darbepoetin group.
DISCUSSION/CONCLUSION
In the MIYABI ND-C study, molidustat appeared to be an efficacious and generally well-tolerated alternative to darbepoetin for the treatment of renal anemia in Japanese patients who were not undergoing dialysis and were not receiving ESA treatment.
Topics: Aged; Aged, 80 and over; Anemia; Female; Humans; Male; Middle Aged; Pyrazoles; Renal Insufficiency, Chronic; Treatment Outcome; Triazoles
PubMed: 34569489
DOI: 10.1159/000518071 -
Current Atherosclerosis Reports Aug 2021In this review paper, we examine the latest evidence regarding the use of iron supplementation, erythropoiesis-stimulating agents (ESAs), and blood transfusions as... (Review)
Review
PURPOSE OF THE REVIEW
In this review paper, we examine the latest evidence regarding the use of iron supplementation, erythropoiesis-stimulating agents (ESAs), and blood transfusions as therapeutic targets for anemia to mitigate morbidity and mortality in patients with cardiovascular disease.
RECENT FINDINGS
Intravenous ferric carboxymaltose (FC) injections in heart failure (HF) have resulted in improved self-reported patient symptoms; higher exercise capacity, as measured by 6-min walk test distance in anemic patients; and lower re-hospitalization rates in iron deficient patients. Darbepoetin alfa has shown evidence of improved Kansas City Cardiomyopathy Questionnaire scores. No mortality benefits have been noted thus far with FC injections or darbepoetin in HF, with an increase in adverse events with darbepoetin. Aggressive transfusions (Hg < 10 g/dL) are not associated with improved outcomes in cardiovascular disease. Quality of life metrics, rather than mortality, appear to improve with IV FC and ESA use in HF. More studies are required to see if these treatments have a role in coronary artery disease. Current evidence suggests that anemia is a marker of underlying disease severity, with a limited role in disease modification. Further studies are required to solidify our understanding of this topic.
Topics: Anemia; Cardiovascular Diseases; Erythropoietin; Humans; Quality of Life; Severity of Illness Index
PubMed: 34374878
DOI: 10.1007/s11883-021-00960-1 -
Journal of Thoracic Oncology : Official... Feb 2020This study evaluated noninferiority of darbepoetin alfa versus placebo for overall survival (OS) and progression-free survival (PFS) in anemic patients with NSCLC... (Randomized Controlled Trial)
Randomized Controlled Trial
A Randomized, Double-Blind, Placebo-Controlled, Phase III Noninferiority Study of the Long-Term Safety and Efficacy of Darbepoetin Alfa for Chemotherapy-Induced Anemia in Patients With Advanced NSCLC.
INTRODUCTION
This study evaluated noninferiority of darbepoetin alfa versus placebo for overall survival (OS) and progression-free survival (PFS) in anemic patients with NSCLC treated to a 12.0-g/dL hemoglobin (Hb) ceiling.
METHODS
Adults with stage IV NSCLC expected to receive two or more cycles of myelosuppressive chemotherapy and Hb less than or equal to 11.0 g/dL were randomized 2:1 to blinded 500 μg darbepoetin alfa or placebo every 3 weeks. The primary endpoint was OS; a stratified Cox proportional hazards model was used to evaluate noninferiority (upper confidence limit for hazard ratio [HR] < 1.15). Secondary endpoints were PFS and incidence of transfusions or Hb less than or equal to 8.0 g/dL from week 5 to end of the efficacy treatment period.
RESULTS
The primary analysis set included 2516 patients: 1680 were randomized to darbepoetin alfa; 836 to placebo. The study was stopped early per independent Data Monitoring Committee recommendation after the primary endpoint was met with no new safety concerns. Darbepoetin alfa was noninferior to placebo for OS (stratified HR = 0.92; 95% confidence interval [CI]: 0.83‒1.01) and PFS (stratified HR = 0.95; 95% CI: 0.87‒1.04). Darbepoetin alfa was superior to placebo for transfusion or Hb less than or equal to 8.0 g/dL from week 5 to end of the efficacy treatment period (stratified odds ratio = 0.70; 95% CI: 0.57‒0.86; p < 0.001). Objective tumor response was similar between the groups (darbepoetin alfa, 36.4%; placebo, 32.6%). Incidence of serious adverse events was 31.1% in both groups. No unexpected adverse events were observed.
CONCLUSIONS
Darbepoetin alfa dosed to a 12.0-g/dL Hb ceiling was noninferior to placebo for OS and PFS and significantly reduced odds of transfusion or Hb less than or equal to 8.0 g/dL in anemic patients with NSCLC receiving myelosuppressive chemotherapy.
Topics: Adult; Anemia; Antineoplastic Agents; Darbepoetin alfa; Double-Blind Method; Erythropoietin; Hemoglobins; Humans; Lung Neoplasms; Treatment Outcome
PubMed: 31629060
DOI: 10.1016/j.jtho.2019.10.005 -
Turkish Journal of Haematology :... May 2023This study was undertaken to evaluate the long-term clinical efficacy of epoetin alfa and darbepoetin alfa in patients with myelodysplastic syndrome (MDS) in a real-life...
OBJECTIVE
This study was undertaken to evaluate the long-term clinical efficacy of epoetin alfa and darbepoetin alfa in patients with myelodysplastic syndrome (MDS) in a real-life setting.
MATERIALS AND METHODS
A total of 204 patients with low-risk or intermediate-1-risk MDS who received epoetin alfa or darbepoetin alfa were included. Hemoglobin levels and transfusion needs were recorded before treatment and at 12 months, 24 months, 36 months, and 48 months of treatment.
RESULTS
At the 36-month (p=0.025) and 48-month (p=0.022) visits, epoetin alfa yielded significantly higher hemoglobin levels compared to darbepoetin alfa. Transfusion needs were also significantly lower with epoetin alfa compared to darbepoetin alfa at 24 months (p=0.012) and in the low-risk group compared to the intermediate-risk group at 24 months (p=0.018), 36 months (p=0.025), and 48 months (p<0.001). Treatment response rates at the 24-month, 36-month, and 48-month visits in the epoetin alfa (43.0%, 33.6%, and 27.1%), darbepoetin alfa (29.9%, 22.7%, and 16.5%), low-risk (39.3%, 30.0%, and 26.0%), and intermediate-risk (29.6%, 24.1%, and 11.1%) groups were lower than those obtained at 12 months, and the values differed significantly for the 36-month and 48-month visits with values ranging from p<0.05 to p<0.001.
CONCLUSION
This real-life long-term ESA extension study investigated the clinical efficacy of epoetin alfa and darbepoetin alfa for up to 48 months, revealing that treatment efficacy reached a plateau starting from the 24 month of therapy with a continuing decrease in treatment response rates regardless of treatment type, risk status, or gender. Nonetheless, significantly higher hemoglobin levels and marked improvement in transfusion needs were evident in epoetin-treated patients compared to darbepoetin-treated patients and in the low-risk group compared to the intermediate-risk group.
Topics: Humans; Anemia; Darbepoetin alfa; Epoetin Alfa; Erythropoiesis; Erythropoietin; Hematinics; Hemoglobins; Myelodysplastic Syndromes; Recombinant Proteins
PubMed: 36799095
DOI: 10.4274/tjh.galenos.2023.2022.0437