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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 -
American Journal of Nephrology 2024Renal anemia is treated with erythropoiesis-stimulating agents (ESAs), even though epoetin alfa and darbepoetin increase the risk of cardiovascular death and... (Comparative Study)
Comparative Study Review
Mechanistic and Clinical Comparison of the Erythropoietic Effects of SGLT2 Inhibitors and Prolyl Hydroxylase Inhibitors in Patients with Chronic Kidney Disease and Renal Anemia.
Renal anemia is treated with erythropoiesis-stimulating agents (ESAs), even though epoetin alfa and darbepoetin increase the risk of cardiovascular death and thromboembolic events, including stroke. Hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) inhibitors have been developed as an alternative to ESAs, producing comparable increases in hemoglobin. However, in advanced chronic kidney disease, HIF-PHD inhibitors can increase the risk of cardiovascular death, heart failure, and thrombotic events to a greater extent than that with ESAs, indicating that there is a compelling need for safer alternatives. Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of major cardiovascular events, and they increase hemoglobin, an effect that is related to an increase in erythropoietin and an expansion in red blood cell mass. SGLT2 inhibitors increase hemoglobin by ≈0.6-0.7 g/dL, resulting in the alleviation of anemia in many patients. The magnitude of this effect is comparable to that seen with low-to-medium doses of HIF-PHD inhibitors, and it is apparent even in advanced chronic kidney disease. Interestingly, HIF-PHD inhibitors act by interfering with the prolyl hydroxylases that degrade both HIF-1α and HIF-2α, thus enhancing both isoforms. However, HIF-2α is the physiological stimulus to the production of erythropoietin, and upregulation of HIF-1α may be an unnecessary ancillary property of HIF-PHD inhibitors, which may have adverse cardiac and vascular consequences. In contrast, SGLT2 inhibitors act to selectively increase HIF-2α, while downregulating HIF-1α, a distinctive profile that may contribute to their cardiorenal benefits. Intriguingly, for both HIF-PHD and SGLT2 inhibitors, the liver is likely to be an important site of increased erythropoietin production, recapitulating the fetal phenotype. These observations suggest that the use of SGLT2 inhibitors should be seriously evaluated as a therapeutic approach to treat renal anemia, yielding less cardiovascular risk than other therapeutic options.
Topics: Humans; Anemia; Basic Helix-Loop-Helix Transcription Factors; Epoetin Alfa; Erythropoiesis; Erythropoietin; Hematinics; Hemoglobins; Hypoxia-Inducible Factor-Proline Dioxygenases; Prolyl-Hydroxylase Inhibitors; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 37231827
DOI: 10.1159/000531084 -
Clinical Kidney Journal May 2021Hypoxia-inducible factor prolyl-hydroxylase inhibitors belong to a new class of orally administered drugs for treating anemia in patients with chronic kidney disease...
Hypoxia-inducible factor prolyl-hydroxylase inhibitors belong to a new class of orally administered drugs for treating anemia in patients with chronic kidney disease (CKD). The prevalence of hypothyroidism is disproportionately high in patients with CKD on hemodialysis. We report a rapid suppression of thyroid-stimulating hormone (TSH) and decrease in free triiodothyronine (T3) and free tetraiodothyronine levels after switching from darbepoetin alfa to roxadustat in a hemodialysis patient with hypothyroidism on levothyroxine therapy. This was reversed after stopping roxadustat. Roxadustat has structural similarity with T3 and is a selective activating ligand for thyroid hormone receptor-β possibly suppressing TSH release.
PubMed: 33959275
DOI: 10.1093/ckj/sfab007 -
Journal of the American Society of... Nov 2020
Topics: Anemia; Darbepoetin alfa; Double-Blind Method; Glycine; Humans; Isoquinolines; Japan; Renal Dialysis; Renal Insufficiency, Chronic
PubMed: 32915765
DOI: 10.1681/ASN.2020071096 -
Erythropoietic effects of vadadustat in patients with anemia associated with chronic kidney disease.American Journal of Hematology Sep 2022Patients with chronic kidney disease (CKD) develop anemia largely because of inappropriately low erythropoietin (EPO) production and insufficient iron available to...
Patients with chronic kidney disease (CKD) develop anemia largely because of inappropriately low erythropoietin (EPO) production and insufficient iron available to erythroid precursors. In four phase 3, randomized, open-label, clinical trials in dialysis-dependent and non-dialysis-dependent patients with CKD and anemia, the hypoxia-inducible factor prolyl hydroxylase inhibitor, vadadustat, was noninferior to the erythropoiesis-stimulating agent, darbepoetin alfa, in increasing and maintaining target hemoglobin concentrations. In these trials, vadadustat increased the concentrations of serum EPO, the numbers of circulating erythrocytes, and the numbers of circulating reticulocytes. Achieved hemoglobin concentrations were similar in patients treated with either vadadustat or darbepoetin alfa, but compared with patients receiving darbepoetin alfa, those receiving vadadustat had erythrocytes with increased mean corpuscular volume and mean corpuscular hemoglobin, while the red cell distribution width was decreased. Increased serum transferrin concentrations, as measured by total iron-binding capacity, combined with stable serum iron concentrations, resulted in decreased transferrin saturation in patients randomized to vadadustat compared with patients randomized to darbepoetin alfa. The decreases in transferrin saturation were associated with relatively greater declines in serum hepcidin and ferritin in patients receiving vadadustat compared with those receiving darbepoetin alfa. These results for serum transferrin saturation, hepcidin, ferritin, and erythrocyte indices were consistent with improved iron availability in the patients receiving vadadustat. Thus, overall, vadadustat had beneficial effects on three aspects of erythropoiesis in patients with anemia associated with CKD: increased endogenous EPO production, improved iron availability to erythroid cells, and increased reticulocytes in the circulation.
Topics: Anemia; Clinical Trials, Phase III as Topic; Darbepoetin alfa; Erythropoiesis; Erythropoietin; Ferritins; Glycine; Hematinics; Hemoglobins; Hepcidins; Humans; Iron; Picolinic Acids; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Transferrins
PubMed: 35751858
DOI: 10.1002/ajh.26644 -
Blood Aug 2020Anemia is a very common comorbidity in patients with heart failure (HF), affecting ∼30% of stable ambulatory patients and 50% patients with acute decompensated HF.... (Review)
Review
Anemia is a very common comorbidity in patients with heart failure (HF), affecting ∼30% of stable ambulatory patients and 50% patients with acute decompensated HF. Absolute or functional iron deficiency (ID) is seen in ∼50% patients with HF. Both of these comorbidities often coexist and are independently associated with increased mortality and hospitalizations. These findings led several investigators to test the hypotheses that treatment of anemia and ID in HF would improve symptoms and long-term outcomes. Small studies showed that erythropoiesis-stimulating agents (ESAs) improve subjective measures of HF. However, a large pivotal outcome trial found that the ESA darbepoetin alfa did not improve long-term outcomes in patients with HF with reduced ejection fraction and instead was associated with adverse effects. Studies using IV iron have had somewhat greater success, showing improvements in subjective and some objective measures of HF. However, more research is needed to establish the best treatment options for these high-risk patients. We present 5 common scenarios of patients with HF and anemia and describe our personal approach on how we might treat them based on objective evidence where available. An algorithm that offers guidance in regard to personalized therapy for such patients is also presented.
Topics: Anemia; Comorbidity; Darbepoetin alfa; Heart Failure; Heart Function Tests; Hematinics; Humans; Practice Patterns, Physicians'; Treatment Outcome
PubMed: 31895946
DOI: 10.1182/blood.2019004004 -
Clinical and Experimental Nephrology Sep 2023In the primary analysis of the PREDICT trial, a higher hemoglobin target (11-13 g/dl) with darbepoetin alfa did not improve renal outcomes compared with a lower... (Randomized Controlled Trial)
Randomized Controlled Trial
Higher hemoglobin levels using darbepoetin alfa and kidney outcomes in advanced chronic kidney disease without diabetes: a prespecified secondary analysis of the PREDICT trial.
BACKGROUND
In the primary analysis of the PREDICT trial, a higher hemoglobin target (11-13 g/dl) with darbepoetin alfa did not improve renal outcomes compared with a lower hemoglobin target (9-11 g/dl) in advanced chronic kidney disease (CKD) without diabetes. Prespecified secondary analyses were performed to further study the effects of targeting higher hemoglobin levels on renal outcomes.
METHODS
Patients with an estimated glomerular filtration rate (eGFR) 8-20 ml/min/1.73 m without diabetes were randomly assigned 1:1 to the high- and low-hemoglobin groups. The differences between the groups were evaluated for the following endpoints and cohort sets: eGFR and proteinuria slopes, assessed using a mixed-effects model in the full analysis set and the per-protocol set that excluded patients with off-target hemoglobin levels; the primary endpoint of composite renal outcome, evaluated in the per-protocol set using the Cox model.
RESULTS
In the full analysis set (high hemoglobin, n = 239; low hemoglobin, n = 240), eGFR and proteinuria slopes were not significantly different between the groups. In the per-protocol set (high hemoglobin, n = 136; low hemoglobin, n = 171), the high-hemoglobin group was associated with reduced composite renal outcome (adjusted hazard ratio: 0.64; 95% confidence interval: 0.43-0.96) and an improved eGFR slope (coefficient: + 1.00 ml/min/1.73 m/year; 95% confidence interval: 0.38-1.63), while the proteinuria slope did not differ between the groups.
CONCLUSIONS
In the per-protocol set, the high-hemoglobin group demonstrated better kidney outcomes than the low-hemoglobin group, suggesting a potential benefit of maintaining higher hemoglobin levels in patients with advanced CKD without diabetes.
CLINICAL TRIAL REGISTRATION
Clinicaltrials.gov (identifier: NCT01581073).
Topics: Humans; Darbepoetin alfa; Anemia; Renal Insufficiency, Chronic; Kidney; Hemoglobins; Proteinuria; Neoplasms; Diabetes Mellitus
PubMed: 37289335
DOI: 10.1007/s10157-023-02362-w -
Nephrology, Dialysis, Transplantation :... Sep 2023Hypoxia-inducible factor prolyl hydroxylase inhibitors such as vadadustat may provide an oral alternative to injectable erythropoiesis-stimulating agents for treating... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Hypoxia-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.
METHODS
We 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).
RESULTS
Of 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.
CONCLUSIONS
In the subgroup of patients receiving peritoneal dialysis in the phase 3 INNO2VATE trials, safety and efficacy of vadadustat were similar to darbepoetin alfa.
Topics: Humans; Darbepoetin alfa; Renal Dialysis; Anemia; Renal Insufficiency, Chronic; Peritoneal Dialysis; Hematinics; Hemoglobins; Erythropoietin
PubMed: 37096396
DOI: 10.1093/ndt/gfad074 -
Journal of Pharmaceutical and... Feb 2020Erythropoiesis stimulating agents (ESAs) are a group of therapeutic glycoproteins used to treat anaemia caused by chronic kidney disease or chemotherapy. A variety of...
Erythropoiesis stimulating agents (ESAs) are a group of therapeutic glycoproteins used to treat anaemia caused by chronic kidney disease or chemotherapy. A variety of ESA products are available in the European Union, including innovator, biosimilar and second-generation medicines. Glycosylation is a critical quality attribute of ESA products, as it has a crucial influence upon in vivo biological activity. In this study, a combination of chromatography and mass spectrometry analysis has been used to characterise and compare the glycosylation profiles of five ESA products; Eprex® (epoetin alfa), NeoRecormon® (epoetin beta), Binocrit® (epoetin alfa biosimilar), Silapo (epoetin alfa biosimilar) and Aranesp® (darbepoetin alfa). The methods utilised include mixed-mode anion-exchange/hydrophilic interaction chromatography (AEX/HILIC-MS) for N-glycan identification and quantitation, and HILIC-MS for O-glycan characterisation. The products exhibit notable differences in N- and O-glycosylation, including attributes such as sialic acid occupation, O-acetylation, N-acetyllactosamine extended antennae and sulphated/penta-sialylated N-glycans, which have the potential to cause divergence of therapeutic potencies. The study highlights the need for continued monitoring of ESA product glycosylation, ideally allied to pharmacological data, in order to ensure consistency and therapeutic equivalence between products and enhance our understanding of ESA structure-activity-relationships.
Topics: Acetylation; Amino Sugars; Biosensing Techniques; Chromatography, High Pressure Liquid; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Glycosylation; Hematinics; Molecular Structure; N-Acetylneuraminic Acid; Polysaccharides; Recombinant Proteins; Tandem Mass Spectrometry
PubMed: 31838284
DOI: 10.1016/j.jpba.2019.113031 -
The Journal of Veterinary Medical... Apr 2021Iron metabolism, hepcidin and some blood profiles were investigated in 13 healthy and 31 chronic kidney disease (CKD) dogs. The study consisted of 2 experiments,...
Iron metabolism, hepcidin and some blood profiles were investigated in 13 healthy and 31 chronic kidney disease (CKD) dogs. The study consisted of 2 experiments, experiment I included healthy dogs (CONT) and CKD dogs (stage 2, 3 and 4), while experiment II consisted of anemic CKD dogs subjected to 28-day darbepoetin alfa treatment. The response to darbepoetin alfa could divide anemic CKD dogs into responder (RP) and non-responder (NRP) subgroups. The results from experiment I showed that packed cell volume (PCV) and plasma albumin concentration were significantly lower in CKD dogs of all stages while the total iron binding capacity (TIBC) was lower in only CKD stage 3 and 4 compared with dogs in CONT group. The PCV was related to both TIBC and albumin when considering among all dogs or only in CKD dogs. The hepcidin concentration in CKD dogs with anemia was lower than those without anemia (P<0.05). In experiment II before darbepoetin alfa treatment, RP subgroup had significantly higher iron and TIBC compared with NRP subgroup (P<0.05), the iron concentration was decreased only in RP subgroup after darbepoetin alfa treatment (P<0.05). The percent increase in PCV was correlated with initial TIBC (P<0.01). Plasma hepcidin concentration was not different between CONT and CKD groups and between RP and NRP subgroups both before and after darbepoetin alfa treatment. It is concluded that TIBC and plasma iron concentration play role on anemia and erythropoietic response to darbepoetin alfa treatment in CKD dogs.
Topics: Animals; Darbepoetin alfa; Dog Diseases; Dogs; Erythropoiesis; Erythropoietin; Hemoglobins; Iron; Renal Insufficiency, Chronic
PubMed: 33563860
DOI: 10.1292/jvms.20-0574