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Drugs 2001Darbepoetin alfa is a novel erythropoiesis-stimulating protein developed for the treatment of anaemia associated with chronic kidney disease. In single-dose studies in... (Review)
Review
Darbepoetin alfa is a novel erythropoiesis-stimulating protein developed for the treatment of anaemia associated with chronic kidney disease. In single-dose studies in patients undergoing dialysis, the mean terminal half-life for intravenous darbepoetin alfa was approximately 3-fold longer than for intravenous recombinant human erythropoitin (r-HuEPO, epoetin alfa; 25.3 vs 8.5 hours). The mean terminal half-life after subcutaneous administration of darbepoetin alfa was 48.8 hours. In randomised nonblind trials in patients undergoing dialysis, darbepoetin alfa (0.45 pg/kg) given once weekly for the correction of anaemia increased haemoglobin (Hb) levels to a similar extent as darbepoetin alfa three times weekly or r-HuEPO two or three times weekly. A double-blind, randomised clinical trial reported that switching patients from a three-times weekly regimen of r-HuEPO to once weekly darbepoetin alfa with additional placebo twice weekly (all intravenously) maintained Hb levels between 9.0 and 13.0 g/dl to a similar extent as continued treatment with r-HuEPO three times weekly. In a randomised nonblind study, r-HuEPO-naive patients with chronic renal insufficiency received either subcutaneous darbepoetin alfa once weekly or r-HuEPO twice weekly. 93% of patients receiving darbepoetin alfa and 92% of patients receiving r-HuEPO achieved a Hb increase of > or = 1.0 g/dl from baseline and the mean increase in Hb level over the initial 4 weeks was similar for both treatments. The number and frequency of adverse events, withdrawals and deaths reported in clinical trials did not differ between patients receiving darbepoetin alfa and patients receiving r-HuEPO. There have been no reports of immune responses to darbepoetin alfa in 1534 patients receiving treatment for up to 2 years.
Topics: Anemia; Darbepoetin alfa; Double-Blind Method; Drug Administration Schedule; Erythropoietin; Half-Life; Hemoglobins; Humans; Infusions, Intravenous; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 11735636
DOI: 10.2165/00003495-200161140-00007 -
Clinical Journal of the American... May 2020Large, randomized, controlled trials targeting higher hemoglobin level with erythropoiesis-stimulating agents for Western patients with CKD showed harm. However, the... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND OBJECTIVES
Large, randomized, controlled trials targeting higher hemoglobin level with erythropoiesis-stimulating agents for Western patients with CKD showed harm. However, the effect of anemia correction using erythropoiesis-stimulating agents may differ between CKD subpopulations. The Prevention of ESKD by Darbepoetin Alfa in CKD Patients with Non-diabetic Kidney Disease study, a multicenter, randomized, open-label, parallel-group study, aimed to examine the effect of targeting hemoglobin levels of 11-13 g/dl using darbepoetin alfa with reference to a low-hemoglobin target of 9-11 g/dl on kidney outcome in patients with advanced CKD without diabetes in Japan.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
We enrolled 491 patients with CKD without diabetes, and an eGFR of 8-20 ml/min per 1.73 m. Of these 491 patients, 239 and 240 were ultimately assigned to the high- and low-hemoglobin groups, respectively (12 patients were excluded). The primary outcome was a kidney composite end point (starting maintenance dialysis, kidney transplantation, eGFR≤6 ml/min per 1.73 m, and 50% reduction in eGFR).
RESULTS
Mean hemoglobin levels were 11.2±1.1 and 10.0±0.9 g/dl in the high- and low-hemoglobin groups, respectively, during the mean study period of 73.5±29.7 weeks. The kidney composite end point occurred in 105 (44%) and 116 (48%) patients in the high- and low-hemoglobin groups, respectively (log-rank test; =0.32). The adjusted Cox proportional hazards model showed that the hazard ratio for the high- versus low-hemoglobin group was 0.78 (95% confidence interval, 0.60 to 1.03; =0.08). Cardiovascular events occurred in 19 (8%) and 16 (7%) patients in each group, respectively, with no significant between-group difference (log-rank test; =0.66).
CONCLUSIONS
Targeting a higher hemoglobin level (11-13 g/dl) with darbepoetin alfa did not improve kidney outcome compared with targeting a lower hemoglobin level (9-11 g/dl) in patients with advanced CKD without diabetes.
CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER
Prevention of ESKD by Darbepoetin Alfa in CKD Patients with Non-diabetic Kidney Disease (PREDICT), NCT01581073.
Topics: Adult; Aged; Aged, 80 and over; Anemia; Biomarkers; Darbepoetin alfa; Disease Progression; Female; Glomerular Filtration Rate; Hematinics; Hemoglobins; Humans; Japan; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Renal Insufficiency, Chronic; Risk Factors; Time Factors; Treatment Outcome; Young Adult
PubMed: 32245781
DOI: 10.2215/CJN.08900719 -
Clinical Journal of the American... Aug 2020Daprodustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis and regulates genes related to iron metabolism. The efficacy...
BACKGROUND AND OBJECTIVES
Daprodustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis and regulates genes related to iron metabolism. The efficacy (noninferiority) and safety of daprodustat compared with standard therapy (darbepoetin alfa) was evaluated.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
This was a randomized, phase 3, double-blind, active-control study in Japanese patients receiving hemodialysis with anemia of CKD. Participants' treatment was switched from current erythropoiesis-stimulating agents (ESAs) to daprodustat 4 mg once daily or darbepoetin alfa 10-60 g once weekly (on the basis of the prestudy ESA dose). Dose was adjusted every 4 weeks for daprodustat or every 2 weeks for darbepoetin alfa, according to a protocol-specified algorithm. The primary end point was mean hemoglobin during weeks 40-52 in the intent-to-treat population.
RESULTS
Of 332 participants screened, 271 participants were randomized (safety evaluation: 271 participants; efficacy evaluation: 267 intent-to-treat population). The mean hemoglobin during weeks 40-52 were maintained within the target range in both groups (10.9 g/dl [95% confidence interval (95% CI), 10.8 to 11.0] for daprodustat, and 10.8 g/dl [95% CI, 10.7 to 11.0] for darbepoetin alfa). Daprodustat was noninferior to darbepoetin alfa, as the lower bound of the confidence interval for the treatment difference (0.1 g/dl; 95% CI, -0.1 to 0.2 g/dl) was greater than the noninferiority criterion of -1.0 g/dl. For most participants, hemoglobin was maintained within the target range (10.0-12.0 g/dl) during weeks 40-52 (88% daprodustat; 90% darbepoetin alfa). Geometric mean hepcidin levels decreased more at week 52 with daprodustat (-37%; 95% CI, -49 to -23) than with darbepoetin alfa (-20%; 95% CI, -36 to -1), and an increase in total iron-binding capacity was observed in the daprodustat group. Frequency of adverse events were generally similar between daprodustat and darbepoetin alfa.
CONCLUSIONS
Oral daprodustat was noninferior to darbepoetin alfa as measured by mean hemoglobin over weeks 40-52 in Japanese patients receiving hemodialysis switched from ESAs.
CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER
201754, Clinicaltrials.gov, NCT02969655.
Topics: Aged; Anemia; Barbiturates; Biomarkers; Darbepoetin alfa; Double-Blind Method; Female; Glycine; Hematinics; Hemoglobins; Humans; Japan; Male; Middle Aged; Renal Dialysis; Renal Insufficiency, Chronic; Time Factors; Treatment Outcome
PubMed: 32723804
DOI: 10.2215/CJN.16011219 -
Journal of the American Society of... Jul 2020Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved in China for dialysis-dependent CKD anemia. (Comparative Study)
Comparative Study
BACKGROUND
Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved in China for dialysis-dependent CKD anemia.
METHODS
This phase 3, 24-week, double-blind, double-dummy study evaluated roxadustat's noninferiority to darbepoetin alfa for hemodialysis-dependent CKD anemia. We randomly assigned Japanese patients to oral roxadustat three times weekly or to darbepoetin alfa injections once weekly, titrating doses to maintain hemoglobin between 10-12 g/dl. The primary end point was change of average hemoglobin from baseline to weeks 18-24 (Hb). Secondary end points were average hemoglobin and proportion of patients with hemoglobin between 10-12 g/dl (maintenance rate) at weeks 18-24, and iron parameters. Safety assessments included treatment-emergent adverse events and adjudicated ophthalmologic findings.
RESULTS
We randomly assigned 303 patients to roxadustat (=151) or darbepoetin alfa (=152). The difference between roxadustat and darbepoetin alfa in Hb was -0.02 g/dl (95% confidence interval, -0.18 to 0.15), confirming roxadustat's noninferiority to darbepoetin alfa. Average hemoglobin at weeks 18-24 with roxadustat was 10.99 g/dl (95% confidence interval: 10.88 to 11.10), confirming its efficacy. Among patients with one or more hemoglobin value during weeks 18-24, the maintenance rate was 95.2% with roxadustat and 91.3% with darbepoetin alfa. Serum iron, ferritin, and transferrin saturation remained clinically stable with roxadustat; transferrin and total iron binding capacity increased through week 4 before stabilizing. Common treatment-emergent adverse events were nasopharyngitis, shunt stenosis, diarrhea, contusion, and vomiting. The proportion of patients with new or worsening retinal hemorrhage was 32.4% with roxadustat and 36.6% with darbepoetin alfa. We observed no clinically meaningful changes in retinal thickness groups.
CONCLUSIONS
Roxadustat maintained hemoglobin within 10-12 g/dl in patients on hemodialysis and was noninferior to darbepoetin alfa. Treatment-emergent adverse events were consistent with previous reports.
CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER
A Study of Intermittent Oral Dosing of ASP1517 in Hemodialysis Chronic Kidney Disease Patients with Anemia, NCT02952092 (ClinicalTrials.gov).
Topics: Adult; Aged; Aged, 80 and over; Anemia; Contusions; Darbepoetin alfa; Diarrhea; Double-Blind Method; Female; Ferritins; Glycine; Hematinics; Hemoglobins; Hepcidins; Humans; Iron; Isoquinolines; Japan; Male; Middle Aged; Nasopharyngitis; Renal Dialysis; Renal Insufficiency, Chronic; Retinal Hemorrhage; Time Factors; Transferrin; Vomiting; Young Adult
PubMed: 32493693
DOI: 10.1681/ASN.2019060623 -
Current Opinion in Investigational... Aug 2001Amgen has launched darbepoetin alfa, synthetic recombinant novel erythropoiesis stimulating protein (NESP), for the treatment of anemia associated with renal disease.... (Review)
Review
Amgen has launched darbepoetin alfa, synthetic recombinant novel erythropoiesis stimulating protein (NESP), for the treatment of anemia associated with renal disease. The drug was approved by the European Commission in June 2001, under the tradename Aranesp, for the treatment of anemia in chronic kidney failure including patients on and not yet on dialysis. The company launched the drug on day one of its approval in the following countries: Germany, Sweden, Denmark, Portugal, the Netherlands, the UK and Austria. Roll out of the drug in Italy, Greece and France will follow as soon as pricing and reimbursement issues are resolved [412240], [412357]. By January 2001, the product was still under review and the company anticipated approval during the first half of 2001 in both the US and Europe [396802]. Launch in the US had originally been scheduled for 2000 [387293], [396802] and Japanese launch is planned for 2004 or 2005 [405915]. In January 2001, Amgen reported that the first pivotal trial of darbepoetin alfa in treating oncology patients with anemia was successful [396526], [396802]. The company anticipated a phase III trial in US patients in 2001 for the oncology indication 13977941. In the fourth quarter of 2000, darbepoetin alfa entered phase I trials in Japan. Japanese development of darbepoetin alfa was being conducted by Kirin Brewery (under the research code KRN-321) [396653]. In January 2001, Genesis Pharma licensed the rights to distribute, market and sell darbepoetin alfa for the treatment of anemia, in Greece and Cyprus [396437]. MegaPharm Ltd signed an agreement with Amgen in February 2001, granting MegaPharm certain exclusive rights to distribute, market and sell darbepoetin alfa in Israel [398897]. In February 2000, Merrill Lynch predicted that darbepoetin alfa sales will be in excess of $1.4 billion at maturity [355817]. In October 2000, darbepoetin alfa annual sales were predicted to hit $3 billion [387293].
Topics: Anemia; Animals; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Darbepoetin alfa; Erythropoietin; Humans; Structure-Activity Relationship
PubMed: 11892920
DOI: No ID Found -
Expert Review of Hematology Apr 2015The myelodysplastic syndromes are characterized by refractory cytopenias that lead to symptomatic anemia, bleeding, and increased risk for infections. For almost two... (Review)
Review
The myelodysplastic syndromes are characterized by refractory cytopenias that lead to symptomatic anemia, bleeding, and increased risk for infections. For almost two decades, the use of darbepoetin and other erythropoietin stimulating agents to treat symptomatic anemia in lower-risk myelodysplastic syndromes has been a standard of care. This practice is supported by numerous Phase I/II studies and one Phase III study demonstrating the benefit of using erythropoietin stimulating agents alone, or in combination with granulocyte colony stimulating factor, for treatment of symptomatic anemia with the goal of decreasing red blood cell transfusion requirements. This review summarizes the published experience regarding the use of erythropoietin stimulating agents, with a special focus on darbepoetin, in patients with myelodysplastic syndrome and symptomatic anemia.
Topics: Anemia; Darbepoetin alfa; Erythropoietin; Hematinics; Humans; Myelodysplastic Syndromes
PubMed: 25579702
DOI: 10.1586/17474086.2015.1000854 -
Nephrology, Dialysis, Transplantation :... Jun 2007The distinct molecular structure of darbepoetin alfa, in both its amino acid sequence and its carbohydrate content, results in a biologic profile with lower binding... (Review)
Review
The distinct molecular structure of darbepoetin alfa, in both its amino acid sequence and its carbohydrate content, results in a biologic profile with lower binding affinity, longer circulating half-life, and higher in vivo potency compared with the epoetins. The mechanisms responsible for these differences in biological effects have not been fully explained. Pharmacokinetic investigations of darbepoetin alfa using prolonged blood sampling times established that the mean terminal half-life after subcutaneous (SC) administration is 70 to 105 hours. Pharmacodynamic studies were conducted to assess the suitability of darbepoetin alfa for use in weekly or less frequent (once every other week or once a month) dosing regimens to maintain haemoglobin levels in patients with anaemia of renal disease. Regardless of dialysis status, route of administration, or prior treatment with an erythropoiesis-stimulating agent, darbepoetin alfa administered at extended intervals was able to raise or maintain hemoglobin levels to target. More rigorous studies will be needed to confirm these findings.
Topics: Anemia; Animals; Darbepoetin alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Injections, Intravenous; Injections, Subcutaneous
PubMed: 17526547
DOI: 10.1093/ndt/gfm160 -
The Lancet. Haematology Dec 2023Up to 88% of infants with haemolytic disease of the fetus and newborn who are treated with intrauterine transfusions require erythrocyte transfusions after birth. We... (Randomized Controlled Trial)
Randomized Controlled Trial
Darbepoetin alfa to reduce transfusion episodes in infants with haemolytic disease of the fetus and newborn who are treated with intrauterine transfusions in the Netherlands: an open-label, single-centre, phase 2, randomised, controlled trial.
BACKGROUND
Up to 88% of infants with haemolytic disease of the fetus and newborn who are treated with intrauterine transfusions require erythrocyte transfusions after birth. We aimed to investigate the effect of darbepoetin alfa on the prevention of postnatal anaemia in infants with haemolytic disease of the fetus and newborn.
METHODS
We conducted an open-label, single-centre, phase 2 randomised controlled trial to evaluate the effect of darbepoetin alfa on the number of erythrocyte transfusions in infants with haemolytic disease of the fetus and newborn. All infants who were treated with intrauterine transfusion and born at 35 weeks of gestation or later at the Leiden University Medical Center, Leiden, Netherlands, were eligible for inclusion. Included infants were randomised by computer at birth to treatment with 10 μg/kg darbepoetin alfa subcutaneously once a week for 8 weeks or standard care (1:1 allocation, in varying blocks of four and six, with no stratification). Treating physicians and parents were not masked to treatment allocation, but the research team, data manager, and statistician were masked to treatment allocation during the process of data collection. The primary outcome was the number of erythrocyte transfusion episodes per infant from birth up to 3 months of life in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT03104426) and has been completed.
FINDINGS
Between Oct 31, 2017, and April 31, 2022, we recruited 76 infants, of whom 44 (58%) were randomly assigned to a treatment group (20 [45%] were allocated to receive darbepoetin alfa and 24 [55%] were allocated to receive standard care). Follow-up lasted 3 months and one infant dropped out of the trial before commencement of treatment. A significant reduction in erythrocyte transfusion episodes was identified with darbepoetin alfa treatment compared with standard care (median 1·0 [IQR 1·0-2·0] transfusion episodes vs 2·0 [1·3-3·0] transfusion episodes; p=0·0082). No adverse events were reported and no infants died during the study.
INTERPRETATION
Darbepoetin alfa reduced the transfusion episodes after intrauterine transfusion treatment for haemolytic disease of the fetus and newborn. Treatment with darbepoetin alfa or other types of erythropoietin should be considered as part of the postnatal treatment of severe haemolytic disease of the fetus and newborn.
FUNDING
Sanquin Blood Supply.
TRANSLATION
For the Dutch translation of the abstract see Supplementary Materials section.
Topics: Infant, Newborn; Female; Pregnancy; Infant; Humans; Darbepoetin alfa; Blood Transfusion, Intrauterine; Hematinics; Netherlands; Hemolysis; Fetus
PubMed: 38030319
DOI: 10.1016/S2352-3026(23)00285-5 -
Expert Opinion on Biological Therapy Feb 2009Darbepoetin alfa is an erythropoiesis-stimulating agent (ESA), with a longer half-life than previous recombinant human erythropoietins. After its initial development for... (Review)
Review
BACKGROUND
Darbepoetin alfa is an erythropoiesis-stimulating agent (ESA), with a longer half-life than previous recombinant human erythropoietins. After its initial development for anaemia due to renal insufficiency, an extensive clinical trial program has defined its role in cancer patients.
OBJECTIVE/METHODS
Review of the initial registration studies, further development and recent progress, guidelines for use in clinical practice (EORTC, ASCO/ASH), and specific focus on recent safety concerns.
RESULTS
Darbepoetin alfa significantly decreases the number of red blood cell transfusions in patients with chemotherapy-induced anaemia, and has been shown to improve health-related quality of life in several studies. The prolonged half-life allows a prolonged dosing interval. Administration every three weeks, a suitable schedule to synchronise with day 1 of many chemotherapy regimens, is as efficient as the initially registered weekly administration. Recent data strongly suggest that the addition of intravenous iron improves haemoglobin response rates. The use of these agents in clinical practice has to be according to the guidelines. Recent safety data reported a negative effect on survival when ESAs were used to treat anaemia that was either not chemotherapy related, or when used to maintain high levels of haemoglobin and prevent anaemia. All of these studies were not in accordance with existing guidelines, while safety data from clinical trials using ESAs according to the guidelines remain reassuring.
CONCLUSION
Darbepoetin alfa has a well defined place in the treatment of chemotherapy-induced anaemia, and is safe when used in line with existing guidelines. Recent safety signals on cancer outcomes in studies not in accordance with these guidelines illustrate the need for further research into the complex interaction between anaemia and tumour hypoxia in cancer patients.
Topics: Anemia; Antineoplastic Agents; Darbepoetin alfa; Erythropoietin; Humans
PubMed: 19236252
DOI: 10.1517/14712590802652280 -
BioDrugs : Clinical Immunotherapeutics,... 2005Darbepoetin alfa (Aranesp), Nespo) is an amino acid substituted analog of human erythropoietin (EPO) that promotes erythrocyte survival, proliferation, and... (Review)
Review
Darbepoetin alfa (Aranesp), Nespo) is an amino acid substituted analog of human erythropoietin (EPO) that promotes erythrocyte survival, proliferation, and differentiation. Approved in Europe and the US for the treatment of anemia associated with chronic kidney disease (CKD), it is characterized by delayed clearance and a more prolonged elimination half-life than recombinant human erythropoietin (rhEPO; epoetin alfa and beta), permitting an extended interval between doses. Darbepoetin alfa is generally well tolerated, and clinical trials of 20-52 weeks' duration have demonstrated the efficacy of subcutaneous and intravenous administration at 1- or 2-week intervals in the initial treatment of anemia associated with CKD both in dialysis patients and in patients not yet on dialysis. Trials of up to 52 weeks' duration demonstrated that in the majority of patients with CKD, treatment with darbepoetin alfa at up to 4-week intervals maintained hemoglobin (Hb) levels established by prior erythropoietic treatment, while in patients undergoing dialysis, intravenous or subcutaneous darbepoetin alfa administered at 1- or 2-week intervals was noninferior to rhEPO administered once, twice, or three times per week in maintaining established Hb levels.
Topics: Anemia; Animals; Clinical Trials as Topic; Darbepoetin alfa; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Humans; Kidney Failure, Chronic; Treatment Outcome
PubMed: 16207074
DOI: 10.2165/00063030-200519050-00006