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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 -
Journal of the American Society of... Feb 2021Exposure to high doses or a high cumulative dose of erythropoiesis-stimulating agents (ESAs) may contribute to cardiovascular events in patients with CKD and anemia.... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Exposure to high doses or a high cumulative dose of erythropoiesis-stimulating agents (ESAs) may contribute to cardiovascular events in patients with CKD and anemia. Whether using a low fixed ESA dose versus dosing based on a hemoglobin-based, titration-dose algorithm in such patients might reduce risks associated with high ESA doses and decrease the cumulative exposure-while reducing the need for red blood cell transfusions-is unknown.
METHODS
In this phase-3, randomized trial involving 756 adults with stage-3 to -5 CKD and anemia, we evaluated incidence of red blood cell transfusions for participants randomized to receive darbepoetin given as a fixed dose (0.45 g/kg every 4 weeks) versus administered according to a hemoglobin-based, titration-dose algorithm, for up to 2 years. Participants received transfusions as deemed necessary by the treating physician.
RESULTS
There were 379 patients randomized to the fixed-dose group, and 377 to the titration-dose group. The percentage of participants transfused did not differ (24.1% and 24.4% for the fixed-dose and titration-dose group, respectively), with similar time to first transfusion. The titration-dose group achieved significantly higher median hemoglobin (9.9 g/dl) compared with the fixed-dose group (9.4 g/dl). The fixed-dose group had a significantly lower median cumulative dose of darbepoetin (median monthly dose of 30.9 g) compared with the titration-dose group (53. µg median monthly dose). The FD and TD group received a median (Q1, Q3) cumulative dose per 4 weeks of darbepoetin of 30.9 (21.8, 40.0) g and 53.6 (31.1, 89.9) g, respectively; the median of the difference between treatment groups was -22.1 (95% CI, -26.1 to -18.1) g.
CONCLUSIONS
These findings indicate no evidence of difference in incidence of red blood cell transfusion for a titration-dose strategy versus a fixed-dose strategy for darbepoetin. This suggests that a low fixed dose of darbepoetin may be used as an alternative to a dose-titration approach to minimize transfusions, with less cumulative dosing.
Topics: Aged; Aged, 80 and over; Algorithms; Anemia; Darbepoetin alfa; Drug Administration Schedule; Erythrocyte Transfusion; Female; Hematinics; Hemoglobins; Humans; Male; Middle Aged; Renal Insufficiency, Chronic
PubMed: 33288629
DOI: 10.1681/ASN.2020050556 -
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 -
Drug Design, Development and Therapy 2021Darbepoetin alfa (NESP and ARANESP) has a sustained erythropoietic activity with a longer half-life than conventional recombinant human erythropoietin. CKD-11101 is... (Clinical Trial)
Clinical Trial Comparative Study
Comparison of Pharmacokinetic, Pharmacodynamic and Tolerability Profiles of CKD-11101, Darbepoetin Alfa (NESP) Biosimilar, to Those of NESP After a Single Subcutaneous or Intravenous Administration to Healthy Subjects.
INTRODUCTION
Darbepoetin alfa (NESP and ARANESP) has a sustained erythropoietic activity with a longer half-life than conventional recombinant human erythropoietin. CKD-11101 is under clinical development as a biosimilar of darbepoetin alfa. The purpose of this study was to compare the pharmacokinetic (PK), pharmacodynamic (PD), and tolerability profiles of CKD-11101 with those of reference drug in healthy subjects.
METHODS
This study was performed in two parts for healthy subjects. In each period, CKD-11101 and reference, both at 60 μg, were administered via intravenous (IV) or subcutaneous (SC) route of administration.
RESULTS
After both IV or SC dose, the geometric mean ratio (GMR) of CKD-11101 to reference drug and its 90% confidence intervals (CIs) for C, AUC and AUC were all within 0.8-1.25. No statistically significant differences were noted in the maximum baseline adjusted reticulocyte count or the area under the baseline adjusted reticulocyte count-time between the CKD-11101 and reference drug after IV or SC dose (all -value>0.05). Both CKD-11101 and reference drug were generally well tolerated.
DISCUSSION
After a single IV or SC dose, the CKD-11101 was well tolerated and showed comparable PK and PD characteristics with reference drug.
Topics: Adult; Cross-Over Studies; Darbepoetin alfa; Drug Tolerance; Healthy Volunteers; Humans; Injections, Intravenous; Injections, Subcutaneous; Male; Middle Aged; Young Adult
PubMed: 33953543
DOI: 10.2147/DDDT.S303772 -
American Journal of Nephrology 2021Erythropoiesis-stimulating agents (ESAs) are the current standard of care for anemia due to chronic kidney disease (CKD) in patients not undergoing dialysis. Molidustat,... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Erythropoiesis-stimulating agents (ESAs) are the current standard of care for anemia due to chronic kidney disease (CKD) in patients not undergoing dialysis. Molidustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, is being investigated as an alternative treatment for renal anemia. Molidustat was evaluated in five phase 3 studies, the molidustat once daily improves renal anemia by inducing erythropoietin (MIYABI) program. The present study investigated the safety and efficacy of molidustat in Japanese patients with renal anemia not undergoing dialysis and previously treated with ESAs.
METHODS
This was a 52-week, active-controlled, randomized (1:1), open-label, parallel-group, multicenter, phase 3 study in Japanese patients with anemia due to CKD (stages 3-5). Molidustat was initiated at 25 mg or 50 mg once daily according to previous ESA dose. The ESA darbepoetin alfa (darbepoetin) was initiated at a starting dose in accordance with the previous ESA dose and injected subcutaneously once every 2 or 4 weeks. Doses were regularly titrated to maintain hemoglobin (Hb) levels in the target range of 11.0-13.0 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, 164 patients were randomized to receive molidustat (n = 82) or darbepoetin (n = 82). Baseline characteristics were well balanced. Mean (standard deviation) Hb levels at baseline were 11.31 (0.68) g/dL for molidustat and 11.27 (0.64) g/dL for darbepoetin. The mean (95% confidence interval [CI]) for mean Hb levels during the evaluation period for molidustat (11.67 [11.48-11.85] g/dL) and darbepoetin (11.53 [11.31-11.74] g/dL) was within the target range. Based on a noninferiority margin of 1.0 g/dL, molidustat was noninferior to darbepoetin regarding the change in mean Hb level during the evaluation period from baseline, with a least squares mean (95% CI) difference (molidustat-darbepoetin) of 0.13 (-0.15, 0.40) g/dL. The proportion of patients who reported at least 1 treatment-emergent adverse event (TEAE) was 92.7% for molidustat and 96.3% for darbepoetin. TEAEs leading to death were reported in 2 patients (2.4%) in the molidustat group and none in the darbepoetin group; serious TEAEs were reported in 32.9% and 26.8% of patients, respectively.
DISCUSSION/CONCLUSION
Molidustat was noninferior to darbepoetin and maintained Hb levels in the prespecified target range in patients with renal anemia not undergoing dialysis and previously treated with ESA. Molidustat was well tolerated, and no new safety signal was observed.
Topics: Aged; Aged, 80 and over; Anemia; Female; Hematinics; Humans; Male; Middle Aged; Pyrazoles; Renal Insufficiency, Chronic; Triazoles
PubMed: 34569482
DOI: 10.1159/000518072 -
Clinical Lymphoma, Myeloma & Leukemia May 2024Real-world studies of lower-risk myelodysplastic syndromes (LR-MDS) are limited. We evaluated treatment patterns, clinical outcomes, and healthcare resource utilization...
INTRODUCTION
Real-world studies of lower-risk myelodysplastic syndromes (LR-MDS) are limited. We evaluated treatment patterns, clinical outcomes, and healthcare resource utilization (HCRU) among patients with LR-MDS treated with erythropoiesis-stimulating agents (ESAs) in the United States.
PATIENTS AND METHODS
This retrospective study included patients with LR-MDS who initiated treatment with ESAs between January 1, 2016 and June 30, 2019. The primary analysis assessed patient demographic and clinical characteristics, treatment patterns, clinical outcomes (hematologic response, transfusion requirements, disease progression), and HCRU (medical encounters, laboratory tests, and medication use). Subgroup analyses of patients repeatedly treated with ESA therapy evaluated selected clinical outcomes and primary ESA failure by SF3B1 mutational status, per recently updated NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines©).
RESULTS
A total of 142 patients were included with a median follow-up time of 17 months (interquartile range [IQR], 7-33). Median age at ESA initiation was 79 years (IQR, 73-85). Patients were predominantly male (54%), overweight or obese (32% and 23%, respectively), of White race (96%) and non-Hispanic ethnicity (89%). Overall, 57% patients were initially treated with darbepoetin alfa and 43% with epoetin alfa. Clinical outcomes were poor, and there was a significant burden on both the health system and individual patients treated with ESA therapies. Hematologic improvement- erythroid was only seen in 26% of 142 patients treated with ESAs, and 65% of 82 retreated patients experienced primary ESA failure.
CONCLUSION
Our results indicate that primary ESA failure is largely unrecognized and that many patients should be considered for alternative treatments.
PubMed: 38871557
DOI: 10.1016/j.clml.2024.05.007 -
PloS One 2022Among non-dialysis-dependent chronic kidney disease (ND-CKD) patients, a low hematopoietic response to erythropoiesis-stimulating agents (ESAs) is a predictor for poor... (Observational Study)
Observational Study
Among non-dialysis-dependent chronic kidney disease (ND-CKD) patients, a low hematopoietic response to erythropoiesis-stimulating agents (ESAs) is a predictor for poor renal and cardiovascular outcome. To assess the method for evaluating hyporesponsiveness to ESA in patients with ND-CKD, a multicenter, prospective, observational study of 1,980 adult patients with ND-CKD with renal anemia was conducted. Darbepoetin alfa (DA) and iron supplement administrations were provided according to the recommendation of the attached document and the guidelines of JSDT (Japanese Society of Dialysis and Transplantation). The primary outcomes were progression of renal dysfunction and major adverse cardiovascular events. ESA responsiveness was assessed using pre-defined candidate formulae. During the mean follow-up period of 96 weeks, renal and cardiovascular disease (CVD) events occurred in 683 (39.6%) and 174 (10.1%) of 1,724 patients, respectively. Among pre-set candidate formulae, the one expressed by dividing the dose of DA by Hb level at the 12-week DA treatment was statistically significant in predicting renal (hazard ratio [HR], 1.449; 95% confidence interval [CI], 1.231-1.705; P<0.0001) and CVD events (HR, 1.719; 95% CI, 1.239-2.386; P = 0.0010). The optimum cut-off values for both events were close to 5.2. In conclusion, hyporesponsiveness to ESA in ND-CKD cases, which is associated with a risk for renal and CVD events, may be evaluated practicably as the dose of DA divided by the Hb level at the 12-week DA treatment, and the cut-off value of this index is 5.2. A search for the causes of poor response and measures for them should be recommended in such patients. Trial registration: ClinicalTrials. gov Identifier: NCT02136563; UMIN Clinical Trial Registry Identifier: UMIN000013464.
Topics: Adult; Humans; Hematinics; Renal Dialysis; Erythropoiesis; Prospective Studies; Renal Insufficiency, Chronic; Darbepoetin alfa; Cardiovascular Diseases
PubMed: 36445882
DOI: 10.1371/journal.pone.0277921 -
Asian Pacific Journal of Allergy and... Sep 2023Erythropoiesis-stimulating agents (ESA) are commonly used in clinical practice to improve anaemia. Despite a number of patients successfully treated without adverse... (Review)
Review
BACKGROUND
Erythropoiesis-stimulating agents (ESA) are commonly used in clinical practice to improve anaemia. Despite a number of patients successfully treated without adverse events, the complications have been previously reported.
OBJECTIVE
To report and review the characteristics and management of ESA hypersensitivities.
METHODS
Case reports and related articles associated with ESA use, published between January 1999 and December 2018, were retrieved through Electronic databases (MEDLINE® and PubMed®).
RESULTS
Forty-seven ESA patients with various immediate and delayed hypersensitivity reactions caused by epoetin and pharmaceutical excipients were identified from nineteen studies and one case report in this paper. Fatal hypersensitivity to ESA and ESA-allergic cross-reactivities have been documented. Desensitization or change of EPO molecular structure has been reported as successful methods of re-introducing the drug.
CONCLUSIONS
ESA hypersensitivity in the various allergic reactions and cross-reactivity have been documented. Desensitization and Epoetin structural changes could be successful methods to re-introduce the drug.
Topics: Humans; Epoetin Alfa; Darbepoetin alfa; Hematinics; Anemia; Pruritus; Recombinant Proteins
PubMed: 32563229
DOI: 10.12932/AP-040719-0592 -
PloS One 2021Hypoxia-inducible factor (HIF) prolyl hydroxylase domain inhibitors, which have recently become clinically available for treating renal anemia, are attracting attention...
Hypoxia-inducible factor prolyl hydroxylase domain inhibitor may maintain hemoglobin synthesis at lower serum ferritin and transferrin saturation levels than darbepoetin alfa.
BACKGROUND
Hypoxia-inducible factor (HIF) prolyl hydroxylase domain inhibitors, which have recently become clinically available for treating renal anemia, are attracting attention for their novel mechanisms of action.
METHODS
Relationships of reticulocyte hemoglobin content (CHr), which reflects recent Hb synthesis, with serum ferritin (s-ft) and transferrin saturation (TSAT) were examined in 30 patients on hemodialysis after switching from darbepoetin alfa (DA) to roxadustat (Rox). Iron deficiency was defined as CHr < 32.0 pg. Cutoff values of s-ft and TSAT were determined using receiver operating characteristic curves for the endpoint CHr ≥ 32.0 pg. Logistic analysis was performed with the reference group having s-ft or TSAT below the corresponding cutoff value (low vs high).
RESULTS
With the endpoint CHr ≥ 32.0 pg on Day 0, cutoff values for s-ft and TSAT were respectively 49.7 ng/mL and 21.6% on Day 0 and 35.5 ng/mL and 16.2% on Day 28. With the endpoint CHr ≥ 32.0 pg on Day 28, cutoff values for s-ft and TSAT on Day 0 were 81.6 ng/mL and 23.9%, respectively. According to multivariable logistic analysis, the odds ratios of CHr ≥ 32.0 pg on Day 0 were significantly higher for high TSAT on Day 0 [34.7 (95% CI 2.42-131.0), p<0.003] and Day 28 [24.8 (95% CI 2.75-224.0), p = 0.004]. There were no significant differences by s-ft. Odd ratios of CHr ≥ 32.0 pg on Day 28 were also significantly higher for high s-ft on Day 0 [16.0 (95% CI 1.57-163.0), p = 0.019] and high TSAT on Day 0 [13.5 (95% CI 1.24-147.0), p<0.033].
CONCLUSIONS
Our results suggest Hb synthesis was maintained with lower TSAT and s-ft during Rox therapy compared with DA therapy. To avoid iron deficiency during the 4 weeks after switching DA to Rox, ideal s-ft and TSAT levels before the switch are 81.6 ng/mL and 23.9%, respectively.
Topics: Aged; Darbepoetin alfa; Female; Ferritins; Hemoglobins; Hepcidins; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Male; Middle Aged; Prolyl-Hydroxylase Inhibitors; Transferrin
PubMed: 34143801
DOI: 10.1371/journal.pone.0252439 -
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