An Emerging Treatment Alternative for Anemia in Chronic Kidney Disease Patients: A Review of Daprodustat.
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SUBMITTER: Becker KA
PROVIDER: S-EPMC5778168 | biostudies-literature | 2018 Jan
REPOSITORIES: biostudies-literature
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An Emerging Treatment Alternative for Anemia in Chronic Kidney Disease Patients: A Review of Daprodustat.
Becker Kimberly A KA Jones John J JJ
Advances in therapy 20171228 1
This article reviews an emerging therapeutic agent, which is currently in phase III development for the treatment of anemia secondary to chronic kidney disease, covering promising phase II results, drug characteristics, and the current phase III trials, which, if approved, may significantly impact the management of anemia in this patient population. ...[more]
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Project description:Anemia is a major complication of chronic kidney disease (CKD), which mainly results from appropriate erythropoietin production impairment. Prolyl hydroxylase domain (PHD) inhibitors are currently being developed and approved in some countries as a new treatment for CKD patients with anemia due to the stabilization of intracellular hypoxia-inducible factor (HIF) 1α and HIF2α by PHD inhibition. Daprodustat is one of the orally administrated small-molecule HIF-PH inhibitors, leading to an increase in erythropoietin production, which is regulated by HIF. Also, daprodustat is expected to improve iron metabolism. Recently, several clinical trials showed its efficacy and safety in both hemodialysis- and non-hemodialysis- dependent CKD patients. In addition, some international Phase 3 studies are underway to confirm these effects and reveal the safety profile. This article summarizes the development process and results of each clinical trial.
| S-EPMC7898206 | biostudies-literature
Project description:Objective: Daprodustat is a novel oral agent in treating anemia of chronic kidney disease (CKD), and several clinical trials have been conducted to compare daprodustat with recombinant human erythropoietin (rhEPO) or placebo. Our systematic review aimed to investigate the efficacy and safety of daprodustat for anemia treatment in both dialysis-dependent (DD) and non-dialysis-dependent (NDD) patients. Methods: Six databases were searched for randomized controlled trials (RCTs) reporting daprodustat vs. rhEPO or placebo for anemia patients in CKD. The outcome indicators were focused on hemoglobin (Hb), ferritin, transferrin saturation (TSAT), total iron-binding capacity (TIBC), vascular endothelial growth factor (VEGF), and serious adverse events (SAEs). Results: Eight eligible studies with 1,516 participants were included. For both NDD and DD patients, changes in Hb levels from baseline were significantly higher in daprodustat group than that in the placebo (mean difference (MD) = 1.73, [95% confidence interval (CI), 0.34 to 3.12], p = 0.01; MD = 1.88, [95% CI, 0.68 to 3.09], p = 0.002; respectively), and there was no significant difference between daprodustat and rhEPO group (MD = 0.05, [95% CI, -0.49 to 0.59], p = 0.86; MD = 0.12, [95% CI, -0.28 to 0.52], p = 0.55; respectively). The indexes of iron metabolism were improved significantly in the daprodustat group compared to placebo- or rhEPO-treated patients, while there was no similar change in terms of TSAT for DD patients. Furthermore, no trend of increasing plasma VEGF was observed in daprodustat-treated subjects. As for safety, there was no significant difference in the incidence of SAEs between daprodustat and placebo treatment, while the incidence of SAEs in the daprodustat group was significantly lower than that in the rhEPO group. Conclusion: Daprodustat was efficacious and well tolerated for anemia in both NDD and DD patients in the short term based on current RCTs. And daprodustat may become an effective alternative for treatment of anemia with CKD. Since the application of daprodustat is still under exploration, future researches should consider the limitations of our study to evaluate the value of daprodustat.
| S-EPMC7883598 | biostudies-literature
Project description:ImportanceDaprodustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, is being evaluated as an oral alternative to conventional erythropoiesis-stimulating agent (ESA) therapy. Few studies of anemia treatment in an incident dialysis (ID) population have been reported.ObjectiveTo evaluate the efficacy and safety of daprodustat vs darbepoetin alfa in treating anemia of chronic kidney disease in ID patients.Design, setting, and participantsThis prospective, randomized, open-label clinical trial was conducted from May 11, 2017, through September 24, 2020, in 90 centers across 14 countries. Patients with advanced CKD were eligible if they planned to start dialysis within 6 weeks from screening or had started and received hemodialysis (HD) or peritoneal dialysis (PD) within 90 days before randomization, had a screening hemoglobin (Hb) concentration of 8.0 to 10.5 g/dL (to convert to grams per liter, multiply by 10) and a randomization Hb of 8.0 to 11.0 g/dL, were ESA-naive or had received limited ESA treatment, and were iron-replete.InterventionsRandomized 1:1 to daprodustat or darbepoetin alfa.Main outcomes and measuresThe primary analysis in the intent-to-treat population evaluated the mean change in Hb concentration from baseline to evaluation period (weeks 28-52) to assess noninferiority of daprodustat vs darbepoetin alfa (noninferiority margin, -0.75 g/dL). The mean monthly intravenous (IV) iron dose from baseline to week 52 was the principal secondary end point. Rates of treatment-emergent and serious adverse events (AEs) were also compared between treatment groups to assess safety and tolerability.ResultsA total of 312 patients (median [IQR] age, 55 [45-65] years; 194 [62%] male) were randomized to either daprodustat (157 patients; median [IQR] age, 52.0 [45-63] years; 96 [61%] male) or darbepoetin alfa (155 patients; median [IQR] age, 56.0 [45-67] years; 98 [63%] male); 306 patients (98%) completed the trial. The mean (SD) Hb concentration during the evaluation period was 10.5 (1.0) g/dL for the daprodustat and 10.6 (0.9) g/dL for the darbepoetin alfa group, with an adjusted mean treatment difference of -0.10 g/dL (95% CI, -0.34 to 0.14 g/dL), indicating noninferiority. There was a reduction in mean monthly IV iron use from baseline to week 52 in both treatment groups; however, daprodustat was not superior compared with darbepoetin alfa in reducing monthly IV iron use (adjusted mean treatment difference, 19.4 mg [95% CI, -11.0 to 49.9 mg]). Adverse event rates were 76% for daprodustat vs 72% for darbepoetin alfa.Conclusions and relevanceThis randomized clinical trial found that daprodustat was noninferior to darbepoetin alfa in treating anemia of CKD and may represent a potential oral alternative to a conventional ESA in the ID population.Trial registrationClinicalTrials.gov Identifier: NCT03029208.
| S-EPMC8981070 | biostudies-literature
Project description:Daprodustat, a novel oral hypoxia-inducible factor prolyl hydroxylase inhibitor is approved in the United States for the treatment of anemia due to chronic kidney disease (CKD) in adults receiving dialysis for at least 4 months. Pharmacodynamic dose-hemoglobin (Dose-Hgb) models were developed as daprodustat progressed through development. To support global phase III development, a dose-titration algorithm, guided by simulations from the initial Dose-Hgb model based on phase II clinical data, was implemented. This work was to update and re-calibrate this model to support the dose titration algorithm. Data from five pivotal phase III studies in CKD patients with anemia treated with daprodustat once daily (q.d.) and/or three times a week (t.i.w.) using a titration dosing schedule were included. The data comprised 2,770 CKD patients with anemia providing 53,535 Hgb observations over a period of 6 months up to 4 years. This final Dose-Hgb model consisted of a precursor cell compartment and 12 transit compartments to describe the red blood cell (RBC) lifespan. Treatment increased the precursor cell production rate (Kin) by a power of allometrically scaled dose. Disease progression, as an exponential decline of Hgb production rate over time, varied with dialysis status. The dose-titration algorithm resulted in comparable response for t.i.w. dosing relative to q.d. dosing. Titration-based visual predictive checks for Hgb target criteria for the analysis dataset and the prediction dataset showed that the model adequately predicted the observed data. This re-calibrated Dose-Hgb model will provide further support for the individualized dosing strategy in CKD patients with anemia treated with daprodustat.
| S-EPMC11835430 | biostudies-literature
Project description:IntroductionDaprodustat is an approved treatment for anemia of chronic kidney disease (CKD) in Japan.MethodsThis post hoc analysis evaluated pooled safety data for daprodustat from 3 phase 3 Japanese studies in dialysis-dependent and nondialysis patients with anemia of CKD.ResultsMedian drug exposure duration was 365 days for both daprodustat (N = 369) and injectable erythropoiesis-stimulating agent (ESA, N = 285). The incidence per 100 patient-years of on-therapy adverse events (AEs) was 363.1 and 306.4 in the daprodustat and ESA groups, respectively. The incidence per 100 patient-years of thromboembolic and retinal events were 5.55 and 6.91 (daprodustat) and 6.28 and 7.46 (ESA), respectively. Cardiovascular and malignancy events were similar between groups, although analysis of these were limited by sample size and study duration.ConclusionThe safety of daprodustat was comparable to ESA in this pooled analysis, although further large-scale research is needed to evaluate long-term risks including cardiovascular and malignancy events.
| S-EPMC9790622 | biostudies-literature
Project description:BackgroundThis study assessed the short-term safety and efficacy of daprodustat (an oral hypoxia-inducible factor-prolyl hydroxylase inhibitor) to achieve a target hemoglobin in patients with anemia of chronic kidney disease (CKD).MethodsPatients (n = 252) with Stages 3-5 CKD not receiving dialysis were enrolled in this 24-week, multicenter trial [hemoglobin entry criteria: 8-10 g/dL (Cohort 1) or 8-11 g/dL (Cohort 2) for recombinant human erythropoietin (rhEPO)-naïve participants; 9-10.5 g/dL (Cohort 1) or 9-11.5 g/dL (Cohort 2) for rhEPO users]. rhEPO-naïve participants were randomized 3:1 to daprodustat (1, 2 or 4 mg) or control (rhEPO per standard of care). rhEPO users were randomized 1:1 to daprodustat 2 mg or control. Study medication was titrated to maintain hemoglobin 9-10.5 g/dL (Cohort 1) or 10-11.5 g/dL (Cohort 2). Hemoglobin, iron metabolism markers and safety parameters were measured every 4 weeks.ResultsMean hemoglobin levels at Week 24 were 10.2 g/dL (Cohort 1) and 10.9 g/dL (Cohort 2) in the daprodustat group and 10.7 g/dL (Cohort 1) and 11.0 g/dL (Cohort 2) in the control group. Participants had hemoglobin levels within the target range a median of 82% and 66% of the time between Weeks 12 and 24 in the daprodustat and control groups, respectively. The adverse event profile was consistent with clinical events in the CKD population.ConclusionsDaprodustat effectively maintained target hemoglobin over 24 weeks in CKD patients with anemia who were rhEPO naïve or had switched from existing rhEPO therapy.
| S-EPMC6366145 | biostudies-literature
Project description:AimsHypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors have been developed for the treatment of renal anaemia; however, no study has evaluated the safety and efficacy of HIF-PH inhibitors in patients with heart failure (HF). This study was designed to evaluate the safety and efficacy of daprodustat, a HIF-PH inhibitor, in patients with HF and renal anaemia.Methods and resultsWe designed a pilot, multi-centre, open-label, randomized controlled study, in which 50 patients with HF complicated with chronic kidney disease and anaemia will be randomized 1:1 to either the daprodustat or control group at seven sites in Japan. Study entry requires New York Heart Association Class II HF symptoms or a history of hospitalization due to HF, an estimated glomerular filtration rate of <60 mL/min/1.73 m2 , and a haemoglobin level of 7.5 to <11.0 g/dl. Patients randomized to the daprodustat group will be treated with oral daprodustat, and the dose will be uptitrated according to the changes in the haemoglobin level from previous visits. In this study, we will evaluate the impact of HIF-PH inhibitors on cardiac function using advanced cardiovascular imaging modalities, including cardiac magnetic resonance imaging. The primary outcome is the haemoglobin level at 16 weeks of randomization, and all adverse events will be recorded and evaluated for any association with daprodustat treatment.ConclusionConsidering the hypothetical upside and downside of using HIF-PH inhibitors in anaemic patients with HF and chronic kidney disease, and because there are virtually no safe and effective treatments for patients with anaemia not caused by iron deficiency, our study results will contribute significantly to this field.
| S-EPMC9773652 | biostudies-literature
Project description:(1) Background: Anemia affects about 40% of patients with chronic kidney disease (CKD). Daprodustat improves serum hemoglobin in anemic patients by inhibiting prolyl hydroxylase of hypoxia-inducible factor. We conducted a network meta-analysis to investigate the direct and indirect effects of different doses of daprodustat compared to each other and erythropoietin and placebo. (2) Methods: We searched PubMed, Cochrane Library, Web of Science, and Scopus, for randomized clinical trials (RCTs) reporting data about different doses of daprodustat for anemia in nondialysis of CKDs. (3) Results: We eventually included five RCTs with a total sample size of 4566 patients. We found that the higher the dose of daprodustat, the greater the change in serum total iron binding capacity (TIBC), hemoglobin, and ferritin from baseline. Compared to placebo, daprodustat 25-30 mg was associated with the highest significant increase in serum hemoglobin (MD = 3.27, 95% CI = [1.89; 4.65]), a decrease in serum ferritin (MD = -241.77, 95% CI = [-365.45; -118.09]) and increase in serum TIBC (MD = 18.52, 95% CI = [12.17; 24.87]). (4) Conclusion: Higher daprodustat doses were associated with a higher impact on efficacy outcomes as serum total iron-binding capacity (TIBC), hemoglobin, and ferritin. However, data about the safety profile of different doses of daprodustat is still missing.
| S-EPMC9145143 | biostudies-literature
Project description:BackgroundNumerous studies have identified a relationship between hemoglobin (Hb) levels and mortality in patients with chronic kidney disease (CKD), which have raised concerns about the optimal Hb targets in correction of anemia. Our study is designed to investigate the potential effects of targeted Hb levels, aiming to give some evidence for therapy of renal anemia.Methodology/principal findingsA comprehensive search of Medline, Embase and the Cochrane Database of Systematic Reviews was performed in December 2011 and updated in February 2012 for any new trials. Randomized trials designed to evaluate effects of high (generally the Hb about 13.0 g/dL) and low Hb (generally the Hb about 10.0 g/dL) targets on clinical outcomes in CKD patients with anemia were collected. All statistical analysis was calculated using the RevMan software available free from the Cochrane Collaboration. 24 trials involving 10361 patients were identified. Our findings demonstrated a statistically significant increased risk of mortality in the high Hb levels (RR 1.18; 95% CI 1.02 to 1.37) while the high and low Hb groups were both treated with ESAs. Overall, compared with low Hb levels, high Hb levels are associated with increased risk of hypertension (RR 1.40; 95% CI 1.11 to 1.75), stroke (RR 1.73; 95% CI 1.31 to 2.29), and hospitalizations (RR 1.07; 95% CI 1.01 to 1.14). However, there are no significant differences in the risk of non-fatal myocardial infarction (RR 1. 13; 95% CI 0.79 to 1.61) and renal replacement therapy (RR 1. 00; 95% CI 0.85 to 1.18).Conclusions/significancesTargeting low Hb levels are beneficial to CKD patients especially in the predialysis population. The optimal Hb targets to aim for in CKD patients and at what Hb level the risks of adverse events begin to increase remain elusive. Future studies are still needed to elucidate these questions.
| S-EPMC3431367 | biostudies-literature
Project description:BackgroundHypoxia-inducible factor prolyl hydroxylase inhibitors such as vadadustat may provide an oral alternative to injectable erythropoiesis-stimulating agents for treating anemia in patients receiving peritoneal dialysis. In two randomized (1:1), global, phase 3, open-label, sponsor-blind, parallel-group, active-controlled noninferiority trials in patients with dialysis-dependent chronic kidney disease (INNO2VATE), vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and hematological efficacy. Vadadustat's effects in patients receiving only peritoneal dialysis is unclear.MethodsWe conducted a post hoc analysis of patients in the INNO2VATE trials receiving peritoneal dialysis at baseline. The prespecified primary safety endpoint was time to first major cardiovascular event (MACE; defined as all-cause mortality or nonfatal myocardial infarction or stroke). The primary efficacy endpoint was mean change in hemoglobin from baseline to the primary evaluation period (Weeks 24-36).ResultsOf the 3923 patients randomized in the two INNO2VATE trials, 309 were receiving peritoneal dialysis (vadadustat, n = 152; darbepoetin alfa, n = 157) at baseline. Time to first MACE was similar in the vadadustat and darbepoetin alfa groups [hazard ratio 1.10; 95% confidence interval (CI) 0.62, 1.93]. In patients receiving peritoneal dialysis, the difference in mean change in hemoglobin concentrations was -0.10 g/dL (95% CI -0.33, 0.12) in the primary evaluation period. The incidence of treatment-emergent adverse events (TEAEs) was 88.2% versus 95.5%, and serious TEAEs was 52.6% versus 73.2% in the vadadustat and darbepoetin alfa groups, respectively.ConclusionsIn the subgroup of patients receiving peritoneal dialysis in the phase 3 INNO2VATE trials, safety and efficacy of vadadustat were similar to darbepoetin alfa.
| S-EPMC10539221 | biostudies-literature