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Kidney International Reports Oct 2021Molidustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor for renal anemia treatment, was evaluated in 5 phase 3 studies (MIYABI program). We report the...
INTRODUCTION
Molidustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor for renal anemia treatment, was evaluated in 5 phase 3 studies (MIYABI program). We report the results of the MIYABI hemodialysis-maintenance study.
METHODS
This 52-week, randomized, double-blinded, double-dummy study compared the efficacy and safety of molidustat and darbepoetin in Japanese patients receiving hemodialysis and erythropoiesis-stimulating agents. Molidustat (starting dose: 75 mg/day) and darbepoetin were titrated to maintain hemoglobin (Hb) levels in the target range (≥10.0 and <12.0 g/dl). Primary outcomes were mean Hb level during the evaluation period (weeks 33-36) and its change from baseline. Safety outcomes included adverse events.
RESULTS
Overall, 229 patients were randomized (molidustat, = 153; darbepoetin, = 76). Baseline characteristics were well balanced. Mean baseline Hb level was 10.8 g/dl. Mean (95% confidence interval [CI]) for mean Hb levels during the evaluation period were within the target range in both groups (molidustat: 10.63 [10.42-10.84] g/dl; darbepoetin: 10.77 [10.59-10.95] g/dl). Least-squares mean (95% CI) change in mean Hb level during the evaluation period from baseline was -0.14 (-0.37 to 0.09) g/dl for molidustat and -0.07 (-0.30 to 0.16) g/dl for darbepoetin; molidustat was noninferior to darbepoetin (least-squares mean difference [95% CI] [molidustat-darbepoetin]: -0.13 [-0.46 to 0.19] g/dl), based on a noninferiority margin of 1.0 g/dl. In line with published literature, and as expected in this patient population, most participants had ≥1 treatment-emergent adverse event.
CONCLUSION
Molidustat maintained Hb levels throughout the trial in patients receiving dialysis and previously treated with erythropoiesis-stimulating agents, and was noninferior to darbepoetin.
PubMed: 34622100
DOI: 10.1016/j.ekir.2021.07.015 -
Kidney Medicine Jul 2023Prespecified analyses of the PROTECT trials comparing the safety of the oral hypoxia-inducible factor prolyl hydroxylase inhibitor vadadustat with darbepoetin alfa in...
Safety Endpoints With Vadadustat Versus Darbepoetin Alfa in Patients With Non-Dialysis-Dependent CKD: A Post Hoc Regional Analysis of the PROTECT Randomized Clinical Trial of ESA-Naïve Patients.
RATIONALE & OBJECTIVE
Prespecified analyses of the PROTECT trials comparing the safety of the oral hypoxia-inducible factor prolyl hydroxylase inhibitor vadadustat with darbepoetin alfa in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) found no difference in major adverse cardiovascular events (MACE; death from any cause or nonfatal myocardial infarction or stroke) among US patients and a higher risk among patients treated with vadadustat outside the United States. We investigated regional differences in MACE in the PROTECT trial that enrolled 1,751 patients previously untreated with erythropoiesis-stimulating agents.
STUDY DESIGN
Phase 3, global, open-label, randomized, active-controlled clinical trial.
SETTING AND PARTICIPANTS
Erythropoiesis-stimulating agent-untreated patients with anemia and NDD-CKD.
INTERVENTION
Eligible patients were randomized 1:1 to receive vadadustat or darbepoetin alfa.
OUTCOMES
The primary safety end point was time to first MACE. Secondary safety end points included time to first expanded MACE (MACE plus hospitalization for heart failure or thromboembolic event, excluding vascular access thrombosis).
RESULTS
In the non-US/non-Europe region, there was a higher proportion of patients with baseline estimated glomerular filtration rate (eGFR) level of ≤10 mL/min/1.73 m in the vadadustat group [96 (34.7%)] than in the darbepoetin alfa group [66 (24.0%)]. In this region, there were 21 excess MACEs reported in the vadadustat group [78 events (n=276)] versus the darbepoetin alfa [57 events (n=275)], including 13 excess noncardiovascular deaths, largely from kidney failure. Noncardiovascular deaths were concentrated in Brazil and South Africa, which enrolled higher proportions of patients with an eGFR of ≤10 mL/min/1.73 m and who may not have had access to dialysis.
LIMITATIONS
Different regional treatment patterns of patients with NDD-CKD.
CONCLUSIONS
The higher MACE rate in the non-US/non-Europe vadadustat group may have been partly because of imbalances in the baseline eGFR level in countries where dialysis was not uniformly available resulting in many kidney-related deaths.
PubMed: 37427293
DOI: 10.1016/j.xkme.2023.100666 -
Nephrology, Dialysis, Transplantation :... Apr 2022The Anemia Studies in chronic kidney disease (CKD): Erythropoiesis via a Novel prolyl hydroxylase inhibitor Daprodustat-Dialysis (ASCEND-D) trial will test the... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The Anemia Studies in chronic kidney disease (CKD): Erythropoiesis via a Novel prolyl hydroxylase inhibitor Daprodustat-Dialysis (ASCEND-D) trial will test the hypothesis that daprodustat is noninferior to comparator epoetin alfa or darbepoetin alfa for two co-primary endpoints: hemoglobin (Hb) efficacy and cardiovascular (CV) safety.
METHODS
We report the trial design, key demographic, clinical and laboratory findings, and baseline therapies of 2964 patients randomized in the open-label (sponsor-blinded) active-controlled, parallel-group, randomized ASCEND-D clinical trial. We also compare baseline characteristics of ASCEND-D patients with patients who are on dialysis (CKD G5D) enrolled in other large CV outcome trials (CVOTs) and in the most relevant registries.
RESULTS
The median age of patients was 58 years, 43% were female; 67% were White and 16% were Black. The median Hb at baseline was 10.4 g/dL. Among randomized patients, 89% were receiving hemodialysis and 11% peritoneal dialysis. Among key comorbidities, 42% reported a history of diabetes mellitus and 45% a history of CV disease. Median blood pressure was 134/74 mmHg. The median weekly dose of epoetin was 5751 units. Intravenous and oral iron uses were noted in 64 and 11% of patients, respectively. Baseline demographics were similar to patients with CKD G5D enrolled in other CVOTs and renal patient registries.
CONCLUSIONS
ASCEND-D will evaluate the efficacy and safety of daprodustat compared with epoetin alfa or darbepoetin alfa in the treatment of patients with anemia with CKD G5D.This trial is registered with ClinicalTrials.gov: NCT02879305. EudraCT Number: 2016-000541-31; Sponsor Protocol Number: 200807.
Topics: Anemia; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic
PubMed: 33744933
DOI: 10.1093/ndt/gfab065 -
Cureus Apr 2021Background This post-marketing surveillance (PMS), observational, prospective, safety study evaluated the safety, tolerability, and long-term immunogenicity of...
Safety, Tolerability, and Immunogenicity of Prescribed Usage of Darbepoetin-Alfa (Hetero Biopharma) in Patients of Chronic Kidney Disease With Renal Anemia: A Post-Marketing Surveillance Study.
Background This post-marketing surveillance (PMS), observational, prospective, safety study evaluated the safety, tolerability, and long-term immunogenicity of prescribed usage of Darbepoetin alfa (DA-α, manufactured by Hetero Biopharma, Hyderabad, India) in Indian patients having chronic kidney disease (CKD) with anemia. Methods All patients having chronic kidney disease with anemia and prescribed Hetero-Darbepoetin were the target patient population. The present study gathered the data from 503 Hetero-Darbepoetin alfa prescribed patients. This study collected information of patient demography, patient's medical history, concomitant medications, action taken with respect to Hetero-Darbepoetin-alfa, adverse events details (AE term, start date, stop date, severity, action taken, outcome, and causality), periodic hemoglobin (Hb) levels, and abnormal laboratory tests results until treatment is discontinued or the patient is lost to follow-up. Immunogenicity data were collected in 121 patients at the end of treatment and after one year. Results Eighty-seven AEs were reported in this study and most of them were mild to moderate in intensity. No deaths or serious adverse events (SAEs) were reported in this study. Anti-drug antibodies were not detected in any subject at the end of the treatment phase and after 12 months long-term follow-up period. The baseline mean hemoglobin value was 8.34 (SD 1.24) g/dL and the last visit mean hemoglobin value was 10.42 ± 1.24 (mean ± SD) g/dL. The mean difference between baseline and last visit in hemoglobin value was 2.10 [2.00, 2.20], statistically significant (p-value <0.0001). Conclusions The safety and tolerability of the usage of DA-α are similar to that reported in the published literature of the innovator. No patients showed anti-drug antibodies after treatment. Additionally, the patients also showed significant improvement in hemoglobin levels, compared to baseline.
PubMed: 34079677
DOI: 10.7759/cureus.14730 -
American Journal of Nephrology 2022Anemia frequently occurs in chronic kidney disease (CKD), is associated with poor quality of life and cardiovascular outcomes, and its treatment represents a... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Anemia frequently occurs in chronic kidney disease (CKD), is associated with poor quality of life and cardiovascular outcomes, and its treatment represents a considerable economic burden to the healthcare system. Although effective, the current standard of care for the treatment of anemia in chronic kidney disease patients with erythropoiesis-stimulating agents requires chronic/ongoing injections, making the treatment less accessible or desirable to patients not treated by in-center maintenance hemodialysis. Furthermore, safety concerns, including an increased risk of cardiovascular events and mortality, have emerged from their use in studies targeting hemoglobin concentrations in the normal or near-normal range. The orally active hypoxia-inducible factor prolyl hydroxylase inhibitor vadadustat may offer advantages over erythropoiesis-stimulating agents by correcting anemia via pathways activating endogenous erythropoietin production.
METHODS
To comprehensively analyze the safety profile of vadadustat in patients with dialysis-dependent and non-dialysis-dependent CKD-related anemia, we pooled the safety populations from each of the four trials in the phase 3 clinical program (n = 7,373) and compared the risk of treatment-emergent adverse events (TEAEs) for each treatment arm.
RESULTS
In patients randomized to vadadustat versus darbepoetin alfa, rates of TEAEs (88.9% vs. 89.3%), treatment-emergent serious adverse events (58.0% vs. 59.3%), and TEAEs leading to death (16.1% vs. 16.2%) were similar, as were rates of adverse events of special interest, including cardiovascular-, hepatic-, and neoplasm-related adverse events.
DISCUSSION/CONCLUSION
Among patients with CKD-related anemia treated with vadadustat, we observed similar rates of adverse events relative to those treated with darbepoetin alfa.
Topics: Humans; Darbepoetin alfa; Quality of Life; Anemia; Erythropoietin; Renal Insufficiency, Chronic; Hematinics; Renal Dialysis; Hemoglobins
PubMed: 36450264
DOI: 10.1159/000528443 -
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 -
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 -
Clinical and Experimental Nephrology Feb 2021Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) is associated with cardiovascular events and poor renal outcome in patients with chronic kidney disease...
BACKGROUND
Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) is associated with cardiovascular events and poor renal outcome in patients with chronic kidney disease (CKD). This study aimed to investigate the initial responsiveness to darbepoetin alfa (DA) and its contributing factors using the data from the BRIGHTEN.
METHODS
Of 1980 patients enrolled at 168 facilities, 1695 were included in this analysis [285 patients were excluded mainly due to lack of hemoglobin (Hb) values]. The initial ESA response index (iEResI) was defined as a ratio of Hb changes over 12 weeks after DA administration per weight-adjusted total DA dose and contributing factors to iEResI were analyzed.
RESULTS
The mean age was 70 ± 12 years (male 58.8%; diabetic nephropathy 27.6%). The median creatinine and mean Hb levels at DA initiation were 2.62 mg/dL and 9.8 g/dL, respectively. The most frequent number of DA administration during 12 weeks was 3 times (41.1%), followed by 4 (15.6%) times with a wide distribution of the total DA dose (15-900 μg). Remarkably, 225 patients (13.3%) did not respond to DA. Multivariate analysis showed that male gender, hypoglycemic agent use, iron supplementation, high eGFR, low Hb, low CRP, low NT-proBNP, and low urinary protein-creatinine ratio were independently associated with better initial response to DA (P = < 0.0001, 0.0108, < 0.0001, 0.0476, < 0.0001, 0.0004, 0.0435, and 0.0009, respectively).
CONCLUSIONS
Non-responder to DA accounted for 13.3% of patients with non-dialysis CKD. Iron supplementation, low CRP, low NT-proBNP, and less proteinuria were predictive and modifiable factors associated with better initial response to DA.
Topics: Aged; Aged, 80 and over; Anemia; Cardiovascular Diseases; Darbepoetin alfa; Female; Humans; Male; Middle Aged; Renal Dialysis; Renal Insufficiency, Chronic
PubMed: 32949295
DOI: 10.1007/s10157-020-01969-7 -
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 -
PloS One 2020Renal anemia is predominantly caused by a relative deficiency in erythropoietin (EPO). Conventional treatment for renal anemia includes the use of recombinant human EPO...
Renal anemia is predominantly caused by a relative deficiency in erythropoietin (EPO). Conventional treatment for renal anemia includes the use of recombinant human EPO (rhEPO) or a long-acting erythropoiesis-activating agent named darbepoetin alfa, which is a modified rhEPO with a carbohydrate chain structure that differs from native hEPO. We have developed a biosimilar to darbepoetin alfa designated JR-131. Here, we comprehensively compare the physicochemical and biological characteristics of JR-131 to darbepoetin alfa. JR-131 demonstrated similar protein structure to the originator, darbepoetin alfa, by peptide mapping and circular dichroism spectroscopy. Additionally, mass spectroscopic analyses and capillary zone electrophoresis revealed similar glycosylation patterns between the two products. Human bone marrow-derived erythroblasts differentiated and proliferated to form colonies with JR-131 to a similar degree as darbepoetin alfa. Finally, JR-131 stimulated erythropoiesis and improved anemia in rats similarly to darbepoetin alfa. Our data show the similarity in physicochemical and biological properties of JR-131 to those of darbepoetin alfa, and JR-131 therefore represents a biosimilar for use in the treatment of renal anemia.
Topics: Anemia; Animals; Biosimilar Pharmaceuticals; CHO Cells; Cricetinae; Cricetulus; Darbepoetin alfa; Disease Models, Animal; Electrophoresis, Capillary; Erythropoiesis; Glycosylation; Kidney; Male; Molecular Weight; Nephrectomy; Peptide Mapping; Protein Structure, Secondary; Rats, Sprague-Dawley; Sugars; Treatment Outcome
PubMed: 32302352
DOI: 10.1371/journal.pone.0231830