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Kidney International Reports Apr 2022Roxadustat is an orally administered hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor that represents a novel therapeutic option for patients with anemia of...
INTRODUCTION
Roxadustat is an orally administered hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor that represents a novel therapeutic option for patients with anemia of chronic kidney disease (CKD).
METHODS
Conducted in Japan, CL-0307 (NCT02952092) and CL-310 (NCT02988973) were phase 3, darbepoetin alfa (DA)-controlled studies conducted in dialysis-dependent (DD) and non-DD (NDD) patients with CKD, respectively, where patients were randomized to receive roxadustat or DA. Ophthalmic imaging and assessments of visual acuity were performed up to week 24 or at study discontinuation. Ophthalmic imaging was centrally evaluated by independent readers masked to the study treatment.
RESULTS
In CL-0307, 302 patients (roxadustat, 150; DA, 152) received ≥1 dose of the study drug and were included in this analysis. In CL-0310, 262 patients (roxadustat, 131; DA, 131) received ≥1 dose of the study drug and were included in this analysis. Proportions of DD patients with new or worsening retinal hemorrhages (RHs) in the roxadustat group and DA group were 32.4% (46 of 142) and 36.6% (53 of 145), respectively. Proportions of NDD patients with CKD with new or worsening RH in the roxadustat and DA groups were 31.4% (38 of 121) and 39.8% (51 of 128), respectively. Similar trends were apparent in subgroup analyses: patients with/without RH at baseline and with/without diabetes mellitus at baseline. In both studies, there were no differences in retinal thickness, visual acuity, presence of hard exudates or cotton wool spots, or presence of intra- and subretinal fluid between groups, at any given time point.
CONCLUSION
In these studies, roxadustat, compared with DA, was not associated with an increased risk of adverse ophthalmologic events in these cohorts.
PubMed: 35497806
DOI: 10.1016/j.ekir.2022.01.1045 -
Nephrology, Dialysis, Transplantation :... Jul 2023The prespecified on-treatment analysis of ASCEND-ND (NCT02876835) raised concerns about a higher relative risk of cancer-related adverse events (AEs) with daprodustat vs...
Analysis of on-treatment cancer safety events with daprodustat versus conventional erythropoiesis-stimulating agents-post hoc analyses of the ASCEND-ND and ASCEND-D trials.
BACKGROUND
The prespecified on-treatment analysis of ASCEND-ND (NCT02876835) raised concerns about a higher relative risk of cancer-related adverse events (AEs) with daprodustat vs darbepoetin in patients with anaemia of CKD. This concern was not observed in dialysis patients in ASCEND-D (NCT02879305).
METHODS
ASCEND-ND randomized 3872 patients to daprodustat or darbepoetin. ASCEND-D randomized 2964 patients to daprodustat or conventional erythropoiesis-stimulating agents (ESAs). In both studies ESA comparators used different dosing intervals (3/week, 1/week, every 2 or every 4 weeks). The prespecified on-treatment approach examined relative risks for cancer AEs up to the last dose date + 1 day. In these analyses, owing to different dosing intervals between arms, Cox models were used to estimate the daprodustat effect by various follow-up periods (censoring at last dose date, last dose date + dosing intervals, or end of study).
RESULTS
In ASCEND-ND, the safety of daprodustat vs darbepoetin on cancer-related AEs depended on the duration of follow-up after last dose date: hazard ratio (HR) 1.04 [95% confidence interval (CI) 0.77, 1.40] at end of study [HR 1.12 (95% CI 0.81, 1.56) for last dose date + dosing interval; HR 1.50 (95% CI 1.04, 2.15) for last dose date + 1 day]. In ASCEND-D, no excess risk of cancer-related AEs was observed with any model examined.
CONCLUSIONS
Prespecified on-treatment analyses for cancer-related AEs appeared to result in biased risk estimates in ASCEND-ND by preferentially under-counting events from patients assigned to darbepoetin. Analyses accounting for longer darbepoetin dosing intervals, or extending follow-up, resulted in attenuation of effect estimates towards neutrality, similar to ASCEND-D, where ESA comparator dosing intervals are closer to daprodustat.
TRIAL REGISTRATION
The ASCEND-ND trial is registered with ClinicalTrials.gov (NCT02876835); the ASCEND-D trial is registered with ClinicalTrials.gov (NCT02879305).
Topics: Humans; Hematinics; Erythropoietin; Erythropoiesis; Renal Dialysis; Darbepoetin alfa; Neoplasms; Renal Insufficiency, Chronic; Hemoglobins
PubMed: 36565721
DOI: 10.1093/ndt/gfac342 -
Anales Del Sistema Sanitario de Navarra Apr 2020To establish adherence to treatment with erythropoiesis stimulating agents (ESA) in patients with anemia associated to chronic kidney disease (CKD), and analyze its... (Observational Study)
Observational Study
BACKGROUND
To establish adherence to treatment with erythropoiesis stimulating agents (ESA) in patients with anemia associated to chronic kidney disease (CKD), and analyze its relationship to response to ESA.
METHODS
Retrospective study of a cohort of 198 patients with CKD who started treatment with epoetin-ß or darbepoetin-a, followed for two years. Basal characteristics, effectiveness (% of hemoglobin (Hb) target attainment, percentage increase of Hb) and adherence (medication possession rate) were registered. A non-adherent patient was one whose mean adherence was <90%.
RESULTS
Average global adhesion was 89.6%, slightly higher in treatment with darbepoetin-a than with epoetin-ß; 8.6% of patients were non-adherents. Hb target was accomplished in 87% cases. Level of response to ESA treatment was independent of the degree of adherence to treatment.
CONCLUSIONS
Adherence to ESA treatment was good, without differences related to degree of response.
Topics: Aged; Anemia; Darbepoetin alfa; Erythropoietin; Female; Follow-Up Studies; Hematinics; Hemoglobin A; Humans; Male; Medication Adherence; Recombinant Proteins; Renal Insufficiency, Chronic; Retrospective Studies; Time Factors
PubMed: 32242547
DOI: 10.23938/ASSN.0858 -
Blood Aug 2020Recombinant erythropoietin (EPO) and iron substitution are a standard of care for treatment of anemias associated with chronic inflammation, including anemia of chronic...
Recombinant erythropoietin (EPO) and iron substitution are a standard of care for treatment of anemias associated with chronic inflammation, including anemia of chronic kidney disease. A black box warning for EPO therapy and concerns about negative side effects related to high-dose iron supplementation as well as the significant proportion of patients becoming EPO resistant over time explains the medical need to define novel strategies to ameliorate anemia of chronic disease (ACD). As hepcidin is central to the iron-restrictive phenotype in ACD, therapeutic approaches targeting hepcidin were recently developed. We herein report the therapeutic effects of a fully human anti-BMP6 antibody (KY1070) either as monotherapy or in combination with Darbepoetin alfa on iron metabolism and anemia resolution in 2 different, well-established, and clinically relevant rodent models of ACD. In addition to counteracting hepcidin-driven iron limitation for erythropoiesis, we found that the combination of KY1070 and recombinant human EPO improved the erythroid response compared with either monotherapy in a qualitative and quantitative manner. Consequently, the combination of KY1070 and Darbepoetin alfa resulted in an EPO-sparing effect. Moreover, we found that suppression of hepcidin via KY1070 modulates ferroportin expression on erythroid precursor cells, thereby lowering potentially toxic-free intracellular iron levels and by accelerating erythroid output as reflected by increased maturation of erythrocyte progenitors. In summary, we conclude that treatment of ACD, as a highly complex disease, becomes more effective by a multifactorial therapeutic approach upon mobilization of endogenous iron deposits and stimulation of erythropoiesis.
Topics: Anemia; Animals; Antibodies, Monoclonal; Arthritis; Bone Marrow; Bone Morphogenetic Protein 6; Cation Transport Proteins; Cytokines; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Synergism; Erythropoietin; Hep G2 Cells; Humans; Iron; Mice; Muscle Proteins; Polysaccharides, Bacterial; Random Allocation; Recombinant Proteins; Renal Insufficiency, Chronic
PubMed: 32438400
DOI: 10.1182/blood.2019004653 -
Biologicals : Journal of the... Jan 2020The expiry of patents protecting the manufacture and sale of therapeutic darbepoetin products is expected to lead to the emergence of biosimilar products. In response to...
The expiry of patents protecting the manufacture and sale of therapeutic darbepoetin products is expected to lead to the emergence of biosimilar products. In response to this, the first World Health Organization (WHO) International Standard (IS) for darbepoetin has been developed. A lyophilized preparation of darbepoetin, coded 17/204, was evaluated in an international collaborative study, the results of which suggest that the candidate preparation is suitable to serve as an IS. This material defines the International Unit (IU) of in vitro biological activity of darbepoetin and should be used to calibrate of in vitro potency assays of darbepoetin preparations. It is envisaged that widespread use of the IS will promote the consistency and harmonization of darbepoetin in vitro bioassay measurements in laboratories worldwide. Each ampoule contains 100,000 IU of darbepoetin activity. The IU is not intended to revise product labelling or dosing requirements, decisions regarding which lie solely with the regulatory authority. Additionally, the IS is not intended to define the specific activity of darbepoetin, as this may differ between products in the future. Finally, the IS is not intended to serve any regulatory role in defining biosimilarity (i.e. as a reference medicinal product).
Topics: Biosimilar Pharmaceuticals; Calibration; Darbepoetin alfa; Humans; Reference Standards; World Health Organization
PubMed: 31862294
DOI: 10.1016/j.biologicals.2019.12.004 -
International Journal of Hematology Nov 2022Darbepoetin alfa (DA) is used to treat anemia in lower-risk (IPSS low or int-1) myelodysplastic syndromes (MDS). However, whether mutations can predict the effectiveness...
Darbepoetin alfa (DA) is used to treat anemia in lower-risk (IPSS low or int-1) myelodysplastic syndromes (MDS). However, whether mutations can predict the effectiveness of DA has not been examined. The present study aimed to determine predictive gene mutations. The primary endpoint was a correlation between the presence of highly frequent (≥ 10%) mutations and hematological improvement-erythroid according to IWG criteria 2006 by DA (240 μg/week) until week 16. The study included 79 patients (age 29-90, median 77.0 years; 52 [65.8%] male). Frequently (≥ 10%) mutated genes were SF3B1 (24 cases, 30.4%), TET2 (20, 25.3%), SRSF2 (10, 12.7%), ASXL1 (9, 11.4%), and DNMT3A (8, 10.1%). Overall response rate to DA was 70.9%. Multivariable analysis including baseline erythropoietin levels and red blood cell transfusion volumes as variables revealed that erythropoietin levels and mutations of ASXL1 gene were significantly associated with worse response (odds ratio 0.146, 95% confidence interval 0.042-0.503; p = 0.0023, odds ratio 0.175, 95% confidence interval 0.033-0.928; p = 0.0406, respectively). This study indicated that anemic patients who have higher erythropoietin levels and harbor ASXL1 gene mutations may respond poorly to DA. Alternative strategies are needed for the treatment of anemia in this population. Trial registration number and date of registration: UMIN000022185 and 09/05/2016.
Topics: Humans; Male; Adult; Middle Aged; Aged; Aged, 80 and over; Female; Darbepoetin alfa; Erythropoietin; Anemia; Myelodysplastic Syndromes; Mutation; Repressor Proteins
PubMed: 35821550
DOI: 10.1007/s12185-022-03414-9 -
BMC Nephrology Nov 2019Following publication of the original article [1], the authors reported errors in the presentation of Tables 2, 4 and 5.
Correction to: Efficacy, tolerability and safety of darbepoetin alfa injection for the treatment of anemia associated with chronic kidney disease (CKD) undergoing dialysis: a randomized, phase-III trial.
Following publication of the original article [1], the authors reported errors in the presentation of Tables 2, 4 and 5.
PubMed: 31744458
DOI: 10.1186/s12882-019-1515-7 -
Frontiers in Pharmacology 2021Roxadustat is a new oral drug for anemia in chronic kidney disease (CKD). This study aimed to synthesize the evidence from randomized controlled trial (RCT)-based...
Roxadustat is a new oral drug for anemia in chronic kidney disease (CKD). This study aimed to synthesize the evidence from randomized controlled trial (RCT)-based studies that estimated the efficacy and safety of roxadustat in anemia patients with non-dialysis-dependent (NDD) and dialysis-dependent (DD) CKD. We searched the PubMed, Web of Science, and Cochrane Central Register of Controlled Trials (CENTRAL) databases for related published studies. Moreover, we manually searched relevant pharmaceutical company websites and two international clinical trial registers to search for published and unpublished RCTs comparing roxadustat with erythropoietin-stimulating agents (ESAs) or placebo. Fifteen RCTs (seven for DD-CKD patients, eight for NDD-CKD patients) were included in the meta-analysis, with 10,189 patients, 4,810 DD-CKD patients, and 5,379 NDD-CKD patients enrolled. Compared with ESAs (epoetin alfa or darbepoetin alfa) and placebo, roxadustat raised the hemoglobin level [weighted mean difference (WMD): 0.82 g/dL; 95% confidence interval (CI): 0.43-1.21], transferrin level (WMD: 0.5 g/L; 95% CI: 0.34-0.65), and TIBC level (WMD: 41.79 μg/dL; 95% CI: 38.67-44.92) and lowered the hepcidin level (WMD: -37.38 ng/ml; 95% CI: -46.63- -28.12) in both the DD-CKD and NDD-CKD patients with renal anemia. Roxadustat improved hemoglobin response and lowered the ferritin and TAST levels in the NDD-CKD patients but not in the DD-CKD patients. Furthermore, there was no difference between the treatment-emergent adverse events (TEAEs) of roxadustat and that of ESAs or placebo. But the incidence of serious TEAEs in the roxadustat group was significantly higher with NDD-CKD patients (OR: 1.15; 95% CI: 1.02-1.29). This study confirmed that roxadustat therapy could alleviate the anemia of DD-CKD and NDD-CKD patients by raising the hemoglobin level and regulating iron metabolism, but increased serious incidences of treatment-emergent adverse events (TEAEs) in NDD-CKD patients.
PubMed: 34276361
DOI: 10.3389/fphar.2021.658079 -
Therapeutic Apheresis and Dialysis :... Oct 2021Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of anemia in chronic kidney disease (CKD). Emerging evidence suggests that... (Comparative Study)
Comparative Study Randomized Controlled Trial
Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of anemia in chronic kidney disease (CKD). Emerging evidence suggests that roxadustat may be beneficial for patients who inadequately respond to erythropoiesis-stimulating agents (ESAs). This post-hoc analysis of a Japanese, double-blind, randomized, phase 3 study in hemodialysis-dependent CKD patients treated with traditional ESAs assessed the impact of factors associated with ESA hyporesponsiveness on roxadustat and darbepoetin alfa (DA) doses required to maintain target hemoglobin. Endpoints included mean of average doses of roxadustat and DA per administration in the last 6 weeks (AAD/6W) by prior ESA-resistance index (ERI), iron repletion (transferrin saturation; ferritin), and high-sensitivity C-reactive protein (hs-CRP). Of 415 enrolled patients, 303 were randomized (roxadustat, n = 151; DA, n = 152). Weight-adjusted AAD/6W increased with increasing ERI for roxadustat (ERI <3.3, 0.89 mg/kg; ERI ≥8.4, 1.51 mg/kg) and DA (ERI <3.3, 0.26 μg/kg; ERI ≥8.4, 0.91 μg/kg); the weight-adjusted AAD/6W relative to within-arm mean AAD/6W showed a trend toward increased DA doses for the ERI ≥8.4 category (P = .089). AAD/6W remained stable for roxadustat but increased for DA with decreasing baseline iron repletion markers. The relationship between roxadustat doses and end of treatment (EoT) hs-CRP was not significant (estimated slope, -0.494; P = .814); a trend toward increased DA doses was observed with increasing EoT hs-CRP (estimated slope, 2.973; P = .075). Roxadustat doses required to maintain target hemoglobin appear to be less affected by factors that underlie ESA hyporesponsiveness, relative to DA; roxadustat may be beneficial for patients hyporesponsive to ESAs.
Topics: Adult; Aged; Aged, 80 and over; Anemia; Darbepoetin alfa; Dose-Response Relationship, Drug; Double-Blind Method; Female; Glycine; Hematinics; Humans; Isoquinolines; Japan; Male; Middle Aged; Renal Dialysis; Renal Insufficiency, Chronic; Treatment Outcome; Young Adult
PubMed: 33200512
DOI: 10.1111/1744-9987.13609 -
International Journal of Environmental... Dec 2020The impact on health care of patients with myelodysplastic syndromes (MDS) is continuously rising. To investigate the perception of hemato-oncologists concerning the...
The impact on health care of patients with myelodysplastic syndromes (MDS) is continuously rising. To investigate the perception of hemato-oncologists concerning the recommended MDS patient care in Switzerland, we conducted a web-based survey on diagnosis, risk-stratification and treatment. 43/309 physicians (13.9%) replied to 135 questions that were based on current guidelines between 3/2017 and 2/2018. Only questions with feedback-rates >50% were further analysed and ratios >90% defined "high agreement", 70-90% "agreement", 30-70% "insufficient agreement" and <30% "disagreement". For diagnosis, we found insufficient agreement on using flow-cytometry, classifying MDS precursor conditions, performing treatment response assessment after hypomethylating agents (HMA) and evaluating patients with suspected germ-line predisposition. For risk-stratification, we identified agreement on using IPSS-R but insufficient agreement for IPSS and patient-based assessments. For treatment, we observed disagreement on performing primary infectious prophylaxis in neutropenia but agreement on using only darbepoetin alfa in anaemic, lower-risk MDS patients. For thrombopoietin receptor agonists, insufficient agreement was found for the indication, preferred agent and triggering platelet count. Insufficient agreement was also found for immunosuppressive treatment in hypoplastic MDS and HMA dose adjustments. In conclusion, we identified areas for improvement in MDS patient care, in need of further clinical trials, information, and guiding documents.
Topics: Adult; Delivery of Health Care; Humans; Immunosuppressive Agents; Myelodysplastic Syndromes; Platelet Count; Switzerland
PubMed: 33371225
DOI: 10.3390/ijerph17249562