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Transfusion Medicine and Hemotherapy :... Oct 2013Human erythropoietin (Epo) is a 30.4 kDa glycoprotein hormone composed of a single 165 amino acid residues chain to which four glycans are attached. The kidneys are the... (Review)
Review
Human erythropoietin (Epo) is a 30.4 kDa glycoprotein hormone composed of a single 165 amino acid residues chain to which four glycans are attached. The kidneys are the primary sources of Epo, its synthesis is controlled by hypoxia-inducible transcription factors (HIFs). Epo is an essential factor for the viability and proliferation of erythrocytic progenitors. Whether Epo exerts cytoprotection outside the bone marrow still needs to be clarified. Epo deficiency is the primary cause of the anemia in chronic kidney disease (CKD). Treatment with recombinant human Epo (rhEpo, epoetin) can be beneficial not only in CKD but also for other indications, primarily anemia in cancer patients receiving chemotherapy. Considering unwanted events, the administration of rhEpo or its analogs may increase the incidence of thromboembolism. The expiry of the patents for the original epoetins has initiated the production of similar biological medicinal products ('biosimilars'). Furthermore, analogs (darbepoetin alfa, methoxy PEG-epoetin beta) with prolonged survival in circulation have been developed ('biobetter'). New erythropoiesis-stimulating agents are in clinical trials. These include compounds that augment erythropoiesis directly (e.g. Epo mimetic peptides or activin A binding protein) and chemicals that act indirectly by stimulating endogenous Epo synthesis (HIF stabilizers).
PubMed: 24273483
DOI: 10.1159/000356193 -
Nephrology, Dialysis, Transplantation :... Oct 2022Anaemia is common in chronic kidney disease (CKD) and assessment of the risks and benefits of new therapies is important. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Anaemia is common in chronic kidney disease (CKD) and assessment of the risks and benefits of new therapies is important.
METHODS
The Anaemia Study in CKD: Erythropoiesis via a Novel prolyl hydroxylase inhibitor Daprodustat-Non-Dialysis (ASCEND-ND) trial includes adult patients with CKD Stages 3-5, not using erythropoiesis-stimulating agents (ESAs) with screening haemoglobin (Hb) 8-10 g/dL or receiving ESAs with screening Hb of 8-12 g/dL. Participants were randomized to daprodustat or darbepoetin alfa (1:1) in an open-label trial (steering committee- and sponsor-blinded), with blinded endpoint assessment. The co-primary endpoints are mean change in Hb between baseline and evaluation period (average over Weeks 28-52) and time to first adjudicated major adverse cardiovascular (CV) event. Baseline characteristics were compared with those of participants in similar anaemia trials.
RESULTS
Overall, 3872 patients were randomized from 39 countries (median age 67 years, 56% female, 56% White, 27% Asian and 10% Black). The median baseline Hb was 9.9 g/dL, blood pressure was 135/74 mmHg and estimated glomerular filtration rate was 18 mL/min/1.73 m2. Among randomized patients, 53% were ESA non-users, 57% had diabetes and 37% had a history of CV disease. At baseline, 61% of participants were using renin-angiotensin system blockers, 55% were taking statins and 49% were taking oral iron. Baseline demographics were similar to those in other large non-dialysis anaemia trials.
CONCLUSION
ASCEND-ND will define the efficacy and safety of daprodustat compared with darbepoetin alfa in the treatment of patients with anaemia associated with CKD not on dialysis.
Topics: Aged; Female; Humans; Male; Anemia; Darbepoetin alfa; Erythropoietin; Hematinics; Hemoglobins; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Iron; Prolyl-Hydroxylase Inhibitors; Renal Dialysis; Renal Insufficiency, Chronic
PubMed: 34865143
DOI: 10.1093/ndt/gfab318 -
Journal of Molecular and Cellular... Aug 2008Dilated human cardiomyopathy is associated with suppression of the prosurvival phosphatidylinositol-3-kinase (PI3K)/Akt and STAT3 pathways. The present study was carried...
Dilated human cardiomyopathy is associated with suppression of the prosurvival phosphatidylinositol-3-kinase (PI3K)/Akt and STAT3 pathways. The present study was carried out to determine if restoration of the PI3K/Akt and STAT3 activity by darbepoetin alfa improved cardiac function or reduced cardiomyocyte apoptosis in rabbit autoimmune cardiomyopathy induced by a peptide corresponding to the second extracellular loop of the ss(1)-adrenergic receptor (ss(1)-EC(II)). We found that ss(1)-EC(II) immunization produced progressive LV dilation, systolic dysfunction and myocyte apoptosis as measured by TUNEL, single-stranded DNA antibody, and active caspase-3. These changes were associated with activation of p38 mitogen-activated protein kinase (MAPK), endoplasmic reticulum stress markers (GRP78 and CHOP), and increased cleavage of procaspase-12, as well as decreased phosphorylation of Akt and STAT3, and decreased Bcl2/Bax ratio. As expected, darbepoetin alfa treatment increased phosphorylation of Akt and STAT3. It also increased the myocardial expression of erythropoietin receptor which was reduced in the failing myocardium, and improved cardiac function in the ss(1)-EC(II)-immunized animals. The latter was associated with reductions of myocyte apoptosis and cleaved caspase-3, as well as reversal of increased phosphorylation of p38-MAPK, increased ER stress, and decline in Bcl2/Bax ratio. The anti-apoptotic effects of darbepoetin alfa via Akt and STAT activation were also demonstrated in cultured cardiomyocytes treated with the anti-ss(1)-EC(II) antibody. These effects of darbepoetin alfa in vitro were prevented by LY294002 and STAT3 peptide inhibitor. Thus, we conclude that darbepoetin alfa improves cardiac function and prevents progression of dilated cardiomyopathy probably by activating the PI3K/Akt and STAT3 pathways and reducing ER stress.
Topics: Animals; Animals, Newborn; Autoimmune Diseases; Cardiomyopathy, Dilated; Cardiotonic Agents; Cells, Cultured; Darbepoetin alfa; Endoplasmic Reticulum; Endoplasmic Reticulum Chaperone BiP; Erythropoietin; Humans; Myocytes, Cardiac; Oxidative Stress; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rabbits; Rats; Rats, Sprague-Dawley; STAT3 Transcription Factor; Signal Transduction
PubMed: 18586265
DOI: 10.1016/j.yjmcc.2008.05.010 -
Kidney Medicine 2021Anemia is an important complication in patients with chronic kidney disease. Peritoneal dialysis (PD) is one of the most common modalities of kidney replacement therapy... (Review)
Review
Anemia is an important complication in patients with chronic kidney disease. Peritoneal dialysis (PD) is one of the most common modalities of kidney replacement therapy for patients with end-stage kidney disease. PD is particularly prevalent in the Asian Pacific region. Among the different countries and regions, including mainland China, Hong Kong, Japan, Malaysia, Singapore, South Korea, and Thailand, PD accounts for 2.8% to 74.6% of the dialysis population. In addition, 82% to 96% of the PD populations from these countries and regions are receiving erythropoiesis-stimulating agents (ESAs). Asian Pacific countries and regions follow the latest KDIGO (Kidney Disease: Improving Global Outcomes) guidelines for the initiation of treatment of anemia in PD patients. The types of ESAs commonly used include shorter-acting (epoetin alfa and beta) and longer-acting agents, including darbepoetin alfa or methoxy polyethylene glycol-epoetin beta. The most commonly used ESAs in Mainland China, Malaysia, Singapore, and Thailand are the shorter-acting agents, whereas in Hong Kong, Japan, and South Korea, longer-acting ESAs are most common. Oral iron therapy is still the most commonly used iron supplement. The route and dosage of iron administration in PD patients requires more research studies. With the introduction of oral hypoxia-inducible factor prolyl hydroxylase inhibitors into clinical use, the landscape of treatment of anemia in the PD population in the Asia Pacific region may change in the coming years.
PubMed: 34136787
DOI: 10.1016/j.xkme.2021.01.011 -
Kidney International. Supplement May 2002Darbepoetin alfa is a super-sialylated analog of human erythropoietin that has a longer circulating half-life in vivo compared to both native and recombinant hormone. It... (Review)
Review
Darbepoetin alfa is a super-sialylated analog of human erythropoietin that has a longer circulating half-life in vivo compared to both native and recombinant hormone. It has the same mechanism of action as erythropoietin, stimulating the same surface membrane receptor and triggering the same intracellular chain of events. An extra two N-linked carbohydrate chains, however, gives darbepoetin alfa greater metabolic stability in vivo, and its terminal half-life after intravenous administration is approximately three times longer than for intravenous erythropoietin. This in turn allows injections of the drug to be given less frequently, and studies have shown that once-weekly and once-every-other-week dosing can maintain the hemoglobin concentration in patients with renal anemia. The recommended starting dose for darbepoetin alfa is 0.45 microg/kg once weekly for both IV and SC administration, with subsequent titration based on the hemoglobin concentration. The adverse event profile is very similar to that seen with rHuEPO, and no antibodies have been detected in several thousand patients exposed to the drug, some of whom have been treated for up to five years now. Following a clinical research program that began in November 1996, darbepoetin alfa was finally approved by the European Commission in June 201, and by the FDA in September 201.
Topics: Anemia; Animals; Antibodies; Darbepoetin alfa; Drug Evaluation, Preclinical; Erythropoietin; Humans; Kidney Failure, Chronic
PubMed: 11982814
DOI: 10.1046/j.1523-1755.61.s80.11.x -
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 -
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 -
British Journal of Haematology Jan 2019Many patients with lower-risk myelodysplastic syndrome (MDS) experience anaemia, which has negative consequences. Erythropoiesis-stimulating agents (ESAs) and their... (Review)
Review
Clinical effectiveness and safety of erythropoietin-stimulating agents for the treatment of low- and intermediate-1-risk myelodysplastic syndrome: a systematic literature review.
Many patients with lower-risk myelodysplastic syndrome (MDS) experience anaemia, which has negative consequences. Erythropoiesis-stimulating agents (ESAs) and their biosimilars are used to treat anaemia in MDS and, currently, epoetin alfa and darbepoetin alfa are commonly used and recommended by clinical guidelines. To better understand the evidence available on the use of ESAs for anaemia in lower-risk MDS, we conducted a systematic literature review to identify randomized and nonrandomized prospective studies reporting on clinical efficacy/effectiveness, patient-reported quality of life (QoL), and safety. We extended our review to include retrospective studies for darbepoetin alfa specifically and to ascertain the feasibility of completing an indirect network meta-analysis comparing epoetin and darbepoetin alfa. Overall, 53 articles reporting on 35 studies were included. The studies indicated a clinical benefit of ESAs, with benefits observed across key clinical outcomes. ESAs showed consistent improvement in erythroid response rates (ESA-naïve, 45-73%; previous ESA exposure, 25-75%) and duration of response. Comparative studies demonstrated similar progression to acute myeloid leukaemia and several showed improved overall survival and QoL. Limited safety concerns were identified. This analysis confirmed ESA therapy should be the foremost first-line treatment of anaemia in most patients with lower-risk MDS who lack the 5q deletion.
Topics: Biosimilar Pharmaceuticals; Darbepoetin alfa; Epoetin Alfa; Hematinics; Humans; Myelodysplastic Syndromes; Prospective Studies; Quality of Life; Randomized Controlled Trials as Topic
PubMed: 30549002
DOI: 10.1111/bjh.15707 -
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 -
Oncology (Williston Park, N.Y.) Jul 2006Chemotherapy-induced anemia is common in patients who have cancer. Erythropoiesis-stimulating proteins such as epoetin alfa (Procrit) and darbepoetin alfa (Aranesp) have... (Review)
Review
Chemotherapy-induced anemia is common in patients who have cancer. Erythropoiesis-stimulating proteins such as epoetin alfa (Procrit) and darbepoetin alfa (Aranesp) have been shown to improve hematologic and clinical outcomes in these patients. Darbepoetin alfa has a longer serum half-life than epoetin alfa, making less frequent administration possible and offering the possibility of synchronizing the administration of erythropoietic therapy and chemotherapy. Several clinical trials have evaluated the utility of darbepoetin alfa given every 3 weeks (q3wk) in patients with chemotherapy-induced anemia. An exploratory study showed that darbepoetin alfa q3wk stabilized hemoglobin levels and reduced transfusion requirements. It was also shown that giving darbepoetin alfa q3wk at the same time as the chemotherapy produced hematopoietic benefits similar to those observed when it is given later in the chemotherapy cycle. The q3wk dosing schedule was effective in patients with mild and moderate anemia, and treatment goals were achieved in most of them. The equivalence of q3wk and qwk darbepoetin alfa has also been established. Synchronous administration of darbepoetin alfa with chemotherapy is a convenient option for patients with chemotherapy-induced anemia, with clinical trials showing it to be an effective treatment strategy.
Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Hematinics; Humans; Neoplasms
PubMed: 16925109
DOI: No ID Found