A retrospective study on the efficacy of Roxadustat in peritoneal dialysis patients with erythropoietin hyporesponsiveness.

BACKGROUND/AIMS: Roxadustat, an oral medication for treating renal anemia, is a hypoxia-inducible factor prolyl hydroxylase inhibitor used for regulating iron metabolism and promoting erythropoiesis. To investigate the efficacy and safety of roxadustat in patients undergoing peritoneal dialysis (PD) with erythropoietin hyporesponsiveness. METHODS: Single-center, retrospective study, 81 PD patients (with erythropoietin hyporesponsiveness) were divided into the roxadustat group (n = 61) and erythropoiesis-stimulating agents (ESAs) group (n = 20). Hemoglobin (Hb), total cholesterol, intact parathyroid hormone (iPTH), brain natriuretic peptide (BNP), related indicators of cardiac function and high-sensitivity C-reactive protein (hs-CRP) were collected. Additionally, adverse events were also recorded. The follow-up period was 16 weeks. RESULTS: The two groups exhibited similar baseline demographic and clinical characteristics. At baseline, the roxadustat group had a mean Hb level of 89.8 ± 18.9 g/L, while the ESAs group had a mean Hb level of 95.2 ± 16.0 g/L. By week 16, the Hb levels had increased to 118 ± 19.8 g/L (p < 0.05) in the roxadustat group and 101 ± 19.3 g/L (p > 0.05) in the ESAs group. The efficacy of roxadustat in improving anemia was not influenced by baseline levels of hs-CRP and iPTH. Cholesterol was decreased in the roxadustat group without statin use. An increase in left ventricular ejection fraction and stabilization of BNP were observed in the roxadustat group. CONCLUSION: For PD patients with erythropoietin hyporesponsiveness, roxadustat can significantly improve renal anemia. The efficacy of roxadustat in improving renal anemia was not affected by baseline levels of hs-CRP0 and iPTH.

Hypoxia-inducible Factor Prolyl Hydroxylase Inhibitors and Hypothyroidism: An Analysis of the Japanese Pharmacovigilance Database.

BACKGROUND/AIM: Hypothyroidism induced by roxadustat, a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, was recently reported; however, information regarding roxadustat-associated hypothyroidism is still lacking. We explored the risk and time to onset of hypothyroidism associated with HIF-PH inhibitors using the Japanese Adverse Drug Event Report (JADER), a pharmacovigilance database. PATIENTS AND METHODS: The participants of this study were registered in the JADER database between April 2004 and March 2023. The association between HIF-PH inhibitors and hypothyroidism was evaluated using the reporting odds ratio (ROR) and information component (IC). We also calculated the period from the start of drug administration to the onset of hypothyroidism and determined the onset pattern using Weibull distribution. RESULTS: Roxadustat had positive signals for hypothyroidism among the HIF-PH inhibitors based on the ROR [31.03, 95% confidence interval (CI)=27.81-34.62] and IC (4.51, 95%CI=4.36-4.67) values, and a strong relationship was confirmed. In addition, the median time to roxadustat-associated hypothyroidism onset was 92 days, and over 50% of cases occurred within 100 days of starting treatment. Furthermore, the onset pattern was an early failure type. CONCLUSION: There is a possible association between roxadustat and hypothyroidism. Therefore, enhanced thyroid function testing within 100 days of treatment initiation may help detect roxadustat-associated hypothyroidism. However, further research is required to confirm these findings, considering study limitations using databases of spontaneous adverse event reports.

Cardiovascular and renal safety outcomes of hypoxia-inducible factor prolyl-hydroxylase inhibitor roxadustat for anemia patients with chronic kidney disease: a systematic review and meta-analysis.

This systematic review and meta-analysis were conducted to evaluate the cardiac and kidney-related adverse effects of roxadustat for the treatment of anemia in CKD patients. 18 trials with a total of 8806 participants were identified for analysis. We employed a fixed-effects model for analysis. The pooled result revealed no significant difference in the risk of occurrence of cardiac disorders when comparing CKD patients receiving roxadustat with the placebo (RR = 1.049; CI [0.918 to 1.200]) or ESA (RR = 1.066; CI [0.919 to 1.235]), in both dialysis-dependent (DD) (RR = 1.094; CI [0.925 to 1.293]) or non-dialysis-dependent (NDD) (RR = 1.036; CI [0.916 to 1.171]) CKD patients. No significant difference was observed in the risk of kidney-related adverse events when comparing roxadustat with the placebo (RR = 1.088; CI [0.980 to 1.209]) or ESA (RR = 0.968; CI [0.831 to 1.152]), in DD (RR = 2.649; CI [0.201 to 34.981]) or NDD (RR = 1.053; CI [0.965 to 1.149]) CKD patients. A high risk of hyperkalemia was observed in the roxadustat group in DD (RR = 0.939; CI [0.898 to 0.981]). Incidence of hypertension was higher in the roxadustat for NDD patients (RR = 1.198; CI [1.042 to 1.377]), or compared to the placebo (RR = 1.374; CI [1.153 to 1.638]). In summary, the risk of cardiac or kidney-related events observed in the roxadustat was not significantly increase whether in DD or NDD patients. However, attention must be paid to the occurrence of hyperkalemia for DD patients and hypertension in NDD patients using roxadustat.

An updated meta-analysis on the efficacy and safety of hypoxia-inducible factor prolyl hydroxylase inhibitor treatment of anemia in nondialysis-dependent chronic kidney disease.

BACKGROUND: Renal anemia, a common complication and threat factor of chronic kidney disease (CKD), has long been treated with injectable erythropoietin-stimulating agents (ESAs). As concerns regarding cardiovascular safety and erythropoietin resistance to ESAs have emerged, alternative therapies are urgently needed. Hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), an oral agent, has been proven to be effective in improving renal anemia. However, the effects of HIF-PHIs on nondialysis-dependent CKD (NDD-CKD) have yet to be supported by updated meta-analyses. METHODS: A meta-analysis of clinical randomized controlled trials (RCTs) on HIF-PHI treatment of NDD-CKD patients based on PubMed, EMBASE, and Cochrane databases as of July 16th, 2023, was conducted. The primary outcomes were the level of hemoglobin (Hb) postintervention and the ratio of Hb responses. Most of the analysis was conducted via RevMan 5.3 software using a random-effects model. Stata (version 15.0) was used to analyze the publication bias. RESULTS: Twenty-two studies with a total of 7178 subjects in the HIF-PHI group, 3501 subjects in the ESA group and 2533 subjects in the placebo group were enrolled. HIF-PHIs increased the level of Hb and improved iron metabolism but were not inferior to ESAs in terms of safety. CONCLUSIONS: HIF-PHIs may be a convenient and safe alternative to ESAs in patients with NDD-CKD and anemia.

Efficacy and Safety of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor Therapy for Anemia in Renal Transplantation Patients by Prior Erythropoiesis Stimulating Agent Use.

BACKGROUND: The present study aimed to clarify the efficacy and safety of hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) therapy for anemia in renal transplant (RTx) patients. METHODS: After successful RTx, 26 patients requiring treatment for anemia were divided into 2 groups (erythropoiesis-stimulating agent [ESA] group and non-ESA group) based on whether an ESA was used before starting HIF-PHI therapy. The chronological changes in hemoglobin (Hb) values during the 6 months after the start of HIF-PHI therapy were investigated in each group, and the incidence of adverse events was compared. RESULTS: There were 18 patients in the ESA group and 8 patients in the non-ESA group. The median (IQR) Hb values in the 2 groups were 11.35 (10.4-12.3) and 10.15 (8.9-10.4) g/dL, respectively. The chronological changes in the median (IQR) Hb values pre-HIF-PHI and 1, 3, and 6 months after starting HIF-PHI were 11.4 (10.4-12.4), 12.0 (10.7-12.4), 11.9 (10.9-13.4), and 11.5 (10.6-12.7) g/dL, respectively, in the ESA group, and 10.2 (8.7-10.4), 11.0 (10.4-11.7), 12.2 (11.6-13.2), and 12.5 (11.3-12.7) g/dL, respectively, in the non-ESA group. In the ESA group, Hb values were not significantly decreased after HIF-PHI administration (P = .14); in the non-ESA group, Hb values improved significantly (P = .002). Two patients developed diarrhea in the ESA group, and one patient developed appetite loss in the non-ESA group. CONCLUSIONS: Hypoxia-inducible factor prolyl hydroxylase inhibitor was effective and safe for RTx patients regardless of prior ESA use.

Cardiac and Kidney Adverse Effects of HIF Prolyl-Hydroxylase Inhibitors for Anemia in Patients With CKD Not Receiving Dialysis: A Systematic Review and Meta-analysis.

RATIONALE & OBJECTIVE: Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are novel, orally administered agents for anemia management in chronic kidney disease (CKD). We evaluated the cardiac and kidney-related adverse effects of HIF-PHIs among patients with CKD and anemia. STUDY DESIGN: Systematic review and meta-analysis of randomized controlled trials (RCTs). SETTING & STUDY POPULATIONS: Patients with anemia and CKD not receiving maintenance dialysis. SELECTION CRITERIA FOR STUDIES: RCTs comparing HIF-PHIs to placebo or an erythropoiesis-stimulating agent (ESA) with primary outcomes of cardiac and kidney-related adverse events (AEs). DATA EXTRACTION: Two independent reviewers evaluated RCTs for eligibility and extracted relevant data. ANALYTICAL APPROACH: Dichotomous variables were pooled using the Mantel-Haenszel method and presented as risk ratios (RRs). Subgroup analyses evaluated different intervention times and HIF-PHIs, as well as phase 2 versus phase 3 trials. The certainty of findings was rated according to GRADE criteria. RESULTS: Twenty-three studies with 15,144 participants were included. No significant difference in the risk of cardiac AEs was observed between the HIF-PHIs group and the placebo (RR, 1.02 [95% CI, 0.89-1.16]; moderate certainty) or ESA (RR, 1.06 [95% CI, 0.98-1.14]; low certainty) groups. No significant difference in the risk of kidney-related AEs was observed between the HIF-PHIs group and the placebo (RR, 1.09 [95% CI, 0.98-1.20]; moderate certainty) or ESA (RR, 1.00 [95% CI, 0.94-1.06]; low certainty) groups. The occurrence of hypertension and hyperkalemia was higher in the HIF-PHIs group than in the placebo group (RRs of 1.35 [95% CI, 1.14-1.60] and 1.25 [95% CI, 1.03-1.51], respectively; both findings had high certainty). The occurrence of hypertension was lower in the HIF-PHIs group than in the ESA group (RR, 0.89 [95% CI, 0.81-0.98]; moderate certainty). LIMITATIONS: The reporting criteria of cardiac and kidney-related AEs and dosage of HIF-PHIs were inconsistent across trials. CONCLUSIONS: The occurrence of cardiac or kidney-related AEs in the HIF-PHI groups were not different compared with placebo or ESA groups. REGISTRATION: Registered at PROSPERO with registration number CRD42021228243.

Hypoxia-inducible factor prolyl hydroxylase inhibitors for anaemia in maintenance dialysis: a meta-analysis.

BACKGROUND: Anaemia is a common complication of end-stage renal disease (ESRD) that relies on dialysis. Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI) is a new class of small-molecule oral drugs for the treatment of anaemia in chronic kidney disease. They demonstrate several advantages over traditional exogenous erythropoietin (EPO). We conducted a meta-analysis of studies that compared the efficacy of HIF-PHI in erythropoiesis and iron metabolism, and its safety with EPO in maintenance dialysis patients. METHODS: A sensitive search strategy in the PubMed, EMBASE and Cochrane databases identified all citations for randomised controlled trials (RCTs) comparing HIF-PHI agents with EPO/placebo through December 2021. RESULTS: Fourteen RCTs were identified, which included 2738 patients. No statistical difference was found in haemoglobin increase (p = 0.37) between HIF-PHI treatment and EPO using the random-effects model. HIF-PHI administration upregulated transferrin (MD 36.12, 95% CI 27.04-45.20) and soluble transferrin receptors (sTfR) (MD 1.28, 95% CI 0.44-2.13), but did not statistically reduce hepcidin level (p = 0.37). Total and LDL-cholestrol levels were suppressed by HIF-PHI (MD - 0.99, 95% CI - 1.34 to - 0.63) (MD - 0.99, 95% CI - 1.34 to - 0.64), while triglyceride (TG) was not different between HIF-PHI and EPO (p = 0.74). The total incident rates of treatment-emergent adverse events (TEAE) (p = 0.20) from HIF-PHI treatment were not different from those of erythropoietin, while the treatment-emergent serious adverse events (TSAE) (p = 0.02) were higher in the HIF-PHI group than those in the EPO controls with the fixed-effect model. CONCLUSION: HIF-PHI could effectively upregulate and maintain haemoglobin levels in patients with anaemia receiving maintenance dialysis. Furthermore, HIF-PHI could elevate iron metabolism activity and utility without inducing treatment-associated serious adverse events. Robust data from larger RCTs with longer treatment duration and follow-up are needed.

Three Times Weekly Dosing of Daprodustat versus Conventional Epoetin for Treatment of Anemia in Hemodialysis Patients: ASCEND-TD: A Phase 3 Randomized, Double-Blind, Noninferiority Trial.

BACKGROUND AND OBJECTIVES: Daprodustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) being investigated for the treatment of anemia of CKD. In this noninferiority trial, we compared daprodustat administered three times weekly with epoetin alfa (epoetin) in patients on prevalent hemodialysis switching from a prior erythropoiesis-stimulating agent (ESA). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients on hemodialysis with a baseline hemoglobin of 8-11.5 g/dl receiving an ESA were randomized 2:1 to daprodustat three times weekly (n=270) or conventional epoetin (n=137) for 52 weeks. Dosing algorithms aimed to maintain hemoglobin between 10 and 11 g/dl. The primary end point was mean change in hemoglobin from baseline to the average during the evaluation period (weeks 28-52). The principal secondary end point was average monthly intravenous iron dose. Other secondary end points included BP and hemoglobin variability. RESULTS: Daprodustat three times weekly was noninferior to epoetin for mean change in hemoglobin (model-adjusted mean treatment difference [daprodustat-epoetin], -0.05; 95% confidence interval, -0.21 to 0.10). During the evaluation period, mean (SD) hemoglobin values were 10.45 (0.55) and 10.51 (0.85) g/dl for daprodustat and epoetin groups, respectively. Responders (defined as mean hemoglobin during the evaluation period in the analysis range of 10 to 11.5 g/dl) were 80% in the daprodustat group versus 64% in the epoetin group. Proportionately fewer participants in the daprodustat group versus the epoetin group had hemoglobin values either below 10 g/dl or above 11.5 g/dl during the evaluation period. Mean monthly intravenous iron use was not significantly lower with daprodustat versus epoetin. The effect on BP was similar between groups. The percentage of treatment-emergent adverse events was similar between daprodustat (75%) and epoetin (79%). CONCLUSIONS: Daprodustat was noninferior to epoetin in hemoglobin response and was generally well tolerated. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Anemia Studies in Chronic Kidney Disease: Erythropoiesis via a Novel Prolyl Hydroxylase Inhibitor Daprodustat-Three Times Weekly Dosing in Dialysis (ASCEND-TD), NCT03400033.

Future perspectives of anemia management in chronic kidney disease using hypoxia-inducible factor-prolyl hydroxylase inhibitors.

For the past 3 decades, erythropoiesis-stimulating agents (ESA) in conjunction with iron supplementation has been the mainstay of treatment for anemia in chronic kidney disease (CKD). Although ESAs are well-established and highly efficacious treatment, clinical trials demonstrated that the use of ESAs with a high hemoglobin (Hb) target was associated with increased risk of cardiovascular events. This safety concern raised considerable interest in developing an alternative therapeutic strategy. Hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) are such novel agents to treat anemia in CKD. They stimulate endogenous erythropoietin production via HIF activation and thereby induce erythropoiesis. At least 6 small-molecule HIF-PHIs have been developed to date. The phase 3 clinical trials demonstrated that their effects were noninferior to ESAs. HIF-PHIs may have several advantages over the conventional treatment, such as oral route of administration and their ability to raise Hb levels in patients with chronic inflammation. Although many of the phase 3 clinical trials demonstrated that HIF-PHIs were noninferior to placebo or ESAs with respect to cardiovascular safety, one of the compounds failed to meet the prespecified noninferiority criterion in non-dialysis-dependent CKD patients, and some studies of another HIF-PHI indicated potential risks for thromboembolic events. While the regulatory agencies of some countries including Japan and the European Union concluded that roxadustat, one of the HIF-PHIs, had a favorable benefit-risk profile, the U.S. Food and Drug Administration decided not to approve the drug because of safety reasons. In order to establish the optimal anemia management in CKD, further studies are needed to evaluate important aspects of HIF-PHIs, such as long-term safety, appropriate Hb target, and the types of patients who would gain benefits from these new drugs.

Hypoxia-inducible factor prolyl hydroxylase enzyme inhibitors: ready for primetime?

PURPOSE OF REVIEW: Hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors have recently been developed as a new treatment for anemia associated with chronic kidney disease (CKD). Several of these have been approved in Europe (roxadustat), China, and Japan, but none approved in the United States to date, although daprodustat has been submitted as a new drug application to the Food and Drug Administration. The aim of this review is to critically appraise the available data, particularly the most recent publications, and offer a personal viewpoint on whether or not these drugs are ready for primetime. RECENT FINDINGS: The efficacy of HIF prolyl hydroxylase inhibitors in improving CKD anemia and maintaining a higher hemoglobin is undisputed, but there remain some concerns about safety, particularly in the long term. Some of the safety concerns may result from an exaggerated pharmacological response, while other potential adverse effects could be due to transcriptional effects of these agents beyond genes involved in erythropoiesis. SUMMARY: HIF prolyl hydroxylase inhibitors are already being used in clinical practice in several countries of the world, and ongoing research is being conducted to define the role of these drugs not only in the management of anemia but also beyond into other clinical settings.

Pharmacokinetics of Daprodustat and Metabolites in Individuals with Normal and Impaired Hepatic Function.

Daprodustat is a hypoxia-inducible factor-prolyl hydroxylase inhibitor in development for treatment of anemia of chronic kidney disease. We evaluated the role of hepatic impairment on daprodustat pharmacokinetics, pharmacodynamics, and tolerability. Participants with mild (Child-Pugh Class A, score 5-6) and moderate (Child-Pugh Class B, score 7-9) hepatic impairment and matched healthy controls were administered single 6-mg doses of daprodustat. Exposure parameters were determined for daprodustat and its six metabolites. Comparisons resulted in 1.5- and 2.0-fold higher daprodustat Cmax and area under the curve (AUC) exposures in participants with mild and moderate hepatic impairment, respectively, versus controls; Cmax in mild hepatic impairment was comparable to controls. Similarly, aligned with parent drug, unbound daprodustat Cmax and AUC exposures increased 1.6- to 2.3-fold in hepatic-impaired participants versus controls, and metabolite exposures were 1.2- to 2.0-fold higher in participants with hepatic impairment. Erythropoeitin (EPO) baseline-corrected AUC exposures were between 0.3-fold lower and 2.2-fold higher in matched controls versus hepatic-impaired participants. No serious or study drug-related adverse events were reported. Daprodustat exposure was increased in participants with moderate and mild hepatic impairment compared with matched controls; however, no meaningful differences in EPO were observed and no new safety concerns were identified (ClinicalTrials.gov: NCT03223337).

Experience With the Use of a Novel Agent, Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor, for Posttransplant Anemia in Renal Transplant Recipients: A Case Report.

In this study, we report on an experience with the use of a novel agent "roxadustat," a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), for posttransplant anemia (PTA) in renal transplant recipients. Five renal transplant recipients treated as outpatients receiving 150 or 250 µg of "epoetin beta pegol," an erythropoiesis-stimulating agent (ESA), once every 3 months were converted to roxadustat, an HIF-PHI. The dose was 100 mg 3 times a week taken orally on Monday, Wednesday, and Friday. Data check was conducted at 1 month and every 3 months after its introduction, and hemoglobin (Hb), ferritin, and transferrin saturation (TSAT) levels were compared. At 1 month after conversion to roxadustat, Hb levels increased in all cases, the use of roxadustat was suspended/decreased in 2 cases who had Hb overshoot at 1 month, and ferritin and TSAT levels decreased in the initial stage of roxadustat conversion. During a 9-month period, Hb levels tended to increase in cases receiving oral iron administration, graft function was hardly affected, and there were no complications such as thrombosis. In conclusion, conversion from ESA to roxadustat was effective in the treatment of PTA. However, our overshoot case suggested that it might be better to start at a low dose in patients with low body weight, those undergoing iron administration, and those receiving a low dose of ESA. Furthermore, the low levels of ferritin and TSAT we observed at an early stage after roxadustat conversion suggested that there was an increased efficiency in iron utilization.

Treatment with the Prolyl Hydroxylase Inhibitor JNJ Promotes Abdominal Aortic Aneurysm Progression in Diabetic Mice.

OBJECTIVE: Prolyl hydroxylase domain containing proteins (PHD) rigorously regulate intracellular hypoxia inducible factor-1 (HIF-1) protein expression and activity. Diabetes impairs PHD activity and attenuates abdominal aortic aneurysm (AAA) progression. The extent to which dysregulated PHD activity contributes to diabetes mediated AAA suppression remains undetermined. METHODS: AAAs were induced in diabetic and non-diabetic male C57BL/6J mice via intra-aortic elastase infusion. A PHD inhibitor (JNJ-42041935, aka "JNJ", 150 mmol/kg) or vehicle alone was administered daily starting one day prior to AAA induction for 14 days. Influences on AAA progression was assessed via ultrasonography and histopathology. Expression of aortic HIF-1α, three of its target genes and macrophage derived mediators were assayed via quantitative reverse transcription polymerase chain reaction. Aneurysmal sections from AAA patients with and without diabetes (two patients in each group) were immunostained for HIF-1α and vascular endothelial growth factor (VEGF)-A. RESULTS: Expression of HIF-1α target genes (erythropoietin, VEGF-A, and glucose transporter-1) was reduced by 45% - 95% in experimental diabetic aortas. Diameter enlargement was similarly limited, as were mural elastin degradation, leukocyte infiltration, and neo-angiogenesis (reduced capillary density and length) on histopathology. Pre-treatment with JNJ prior to AAA initiation augmented aortic HIF-1α target gene expression and aneurysm progression in diabetic mice, along with macrophage VEGF-A and matrix metalloproteinase 2 mRNA expression. No differences were noted in HIF-1α or VEGF-A expression on aortic immunohistochemical staining of human aortic tissue as a function of diabetes status. CONCLUSION: Small molecule PHD inhibitor treatment reduces or offsets impairment of experimental AAA progression in hyperglycemic mice, highlighting the potential contribution of dysregulated PHD activity to diabetes mediated aneurysm suppression.

Safety and Efficacy of Vadadustat for Anemia in Patients Undergoing Dialysis.

BACKGROUND: Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, a class of compounds that stimulate endogenous erythropoietin production. METHODS: We conducted two randomized, open-label, noninferiority phase 3 trials to evaluate the safety and efficacy of vadadustat, as compared with darbepoetin alfa, in patients with anemia and incident or prevalent dialysis-dependent chronic kidney disease (DD-CKD). The primary safety end point, assessed in a time-to-event analysis, was the first occurrence of a major adverse cardiovascular event (MACE, a composite of death from any cause, a nonfatal myocardial infarction, or a nonfatal stroke), pooled across the trials (noninferiority margin, 1.25). A key secondary safety end point was the first occurrence of a MACE plus hospitalization for either heart failure or a thromboembolic event. The primary and key secondary efficacy end points were the mean change in hemoglobin from baseline to weeks 24 to 36 and from baseline to weeks 40 to 52, respectively, in each trial (noninferiority margin, -0.75 g per deciliter). RESULTS: A total of 3923 patients were randomly assigned in a 1:1 ratio to receive vadadustat or darbepoetin alfa: 369 in the incident DD-CKD trial and 3554 in the prevalent DD-CKD trial. In the pooled analysis, a first MACE occurred in 355 patients (18.2%) in the vadadustat group and in 377 patients (19.3%) in the darbepoetin alfa group (hazard ratio, 0.96; 95% confidence interval [CI], 0.83 to 1.11). The mean differences between the groups in the change in hemoglobin concentration were -0.31 g per deciliter (95% CI, -0.53 to -0.10) at weeks 24 to 36 and -0.07 g per deciliter (95% CI, -0.34 to 0.19) at weeks 40 to 52 in the incident DD-CKD trial and -0.17 g per deciliter (95% CI, -0.23 to -0.10) and -0.18 g per deciliter (95% CI, -0.25 to -0.12), respectively, in the prevalent DD-CKD trial. The incidence of serious adverse events in the vadadustat group was 49.7% in the incident DD-CKD trial and 55.0% in the prevalent DD-CKD trial, and the incidences in the darbepoetin alfa group were 56.5% and 58.3%, respectively. CONCLUSIONS: Among patients with anemia and CKD who were undergoing dialysis, vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and correction and maintenance of hemoglobin concentrations. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; INNO2VATE ClinicalTrials.gov numbers, NCT02865850 and NCT02892149.).

Vadadustat in Patients with Anemia and Non-Dialysis-Dependent CKD.

BACKGROUND: Vadadustat is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, a class of drugs that stabilize HIF and stimulate erythropoietin and red-cell production. METHODS: In two phase 3, randomized, open-label, active-controlled, noninferiority trials, we compared vadadustat with the erythropoiesis-stimulating agent (ESA) darbepoetin alfa in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) not previously treated with an ESA who had a hemoglobin concentration of less than 10 g per deciliter and in patients with ESA-treated NDD-CKD and a hemoglobin concentration of 8 to 11 g per deciliter (in the United States) or 9 to 12 g per deciliter (in other countries). The primary safety end point, assessed in a time-to-event analysis, was the first major adverse cardiovascular event (MACE; a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke), pooled across the two trials. Secondary safety end points included expanded MACE (MACE plus hospitalization for either heart failure or a thromboembolic event). The primary and key secondary efficacy end points in each trial were the mean change in hemoglobin concentration from baseline during two evaluation periods: weeks 24 through 36 and weeks 40 through 52. RESULTS: A total of 1751 patients with ESA-untreated NDD-CKD and 1725 with ESA-treated NDD-CKD underwent randomization in the two trials. In the pooled analysis, in which 1739 patients received vadadustat and 1732 received darbepoetin alfa, the hazard ratio for MACE was 1.17 (95% confidence interval [CI], 1.01 to 1.36), which did not meet the prespecified noninferiority margin of 1.25. The mean between-group differences in the change in the hemoglobin concentration at weeks 24 through 36 were 0.05 g per deciliter (95% CI, -0.04 to 0.15) in the trial involving ESA-untreated patients and -0.01 g per deciliter (95% CI, -0.09 to 0.07) in the trial involving ESA-treated patients, which met the prespecified noninferiority margin of -0.75 g per deciliter. CONCLUSIONS: Vadadustat, as compared with darbepoetin alfa, met the prespecified noninferiority criterion for hematologic efficacy but not the prespecified noninferiority criterion for cardiovascular safety in patients with NDD-CKD. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; PRO2TECT ClinicalTrials.gov numbers, NCT02648347 and NCT02680574.).

Effect of Moderate Hepatic Impairment on the Pharmacokinetics of Vadadustat, an Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor.

Vadadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor in development for the treatment of anemia of chronic kidney disease. This phase 1, open-label, parallel-group, single-dose study evaluated the pharmacokinetics of 450-mg vadadustat in adults with moderate hepatic impairment (Child-Pugh class B) vs those with normal hepatic function. Primary end points were area under the plasma concentration-time curve (AUC) from dosing to last concentration and to infinity, as well as maximum concentration (Cmax ); additional pharmacokinetic parameters included time to Cmax (Tmax ) and half-life. Safety and tolerability were also assessed. All enrolled participants (n = 16) completed the study. Demographics were similar in both groups (overall, 100% White; 62.5% female; mean age, 59.2 years). Vadadustat plasma exposure was higher in the moderate hepatic impairment group, whereas maximum concentration was similar between groups. Point estimates of the hepatic impairment : normal geometric mean ratios (90% confidence interval) for AUC from dosing to last concentration, AUC from dosing to infinity, and Cmax were 1.05 (0.82-1.35), 1.06 (0.82-1.36), and 1.02 (0.79-1.32), respectively. Mean elimination half-life was 5.8 and 7.8 hours in the normal and hepatic impairment groups, respectively. Treatment-emergent adverse events were mostly mild in severity, and vadadustat was generally well tolerated. In conclusion, moderate hepatic impairment did not significantly impact vadadustat systemic exposure, and mild hepatic impairment is unlikely to alter vadadustat exposure.

Roxadustat for Treating Anemia in Patients with CKD Not on Dialysis: Results from a Randomized Phase 3 Study.

BACKGROUND: Current anemia therapies for patients with non-dialysis-dependent CKD may require injection and medical visits. Roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, stimulates erythropoiesis and improves iron homeostasis. METHODS: In this double-blind phase 3 study, we randomized patients with non-dialysis-dependent CKD stages 3-5 and hemoglobin <10.0 g/dl (1:1) to thrice-weekly 70-mg oral roxadustat or placebo. Doses were titrated throughout the study based on hemoglobin levels. The primary efficacy end point was mean change from baseline in hemoglobin averaged over weeks 28-52 versus placebo, irrespective of rescue therapy use. We assessed patients for adverse events. RESULTS: The study included 2781 patients, 1393 who received roxadustat and 1388 who received placebo. Mean baseline hemoglobin was 9.1 g/dl for both groups. The mean change in hemoglobin from baseline was 1.75 g/dl (95% confidence interval [95% CI], 1.68 to 1.81) with roxadustat versus 0.40 g/dl (95% CI, 0.33 to 0.47) with placebo, (P<0.001). Among 411 patients with baseline elevated high-sensitivity C-reactive protein, mean change in hemoglobin from baseline was 1.75 g/dl (95% CI, 1.58 to 1.92) with roxadustat versus 0.62 g/dl (95% CI, 0.44 to 0.80) with placebo, (P<0.001). Roxadustat reduced the risk of red blood cell transfusion by 63% (hazard ratio, 0.37; 95% CI, 0.30 to 0.44). The most common adverse events with roxadustat and placebo, respectively, were ESKD (21.0% versus 20.5%), urinary tract infection (12.8% versus 8.0%), pneumonia (11.9% versus 9.4%), and hypertension (11.5% versus 9.1%). CONCLUSIONS: Roxadustat effectively increased hemoglobin in patients with non-dialysis-dependent CKD and reduced the need for red blood cell transfusion, with an adverse event profile comparable to that of placebo. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Safety and Efficacy Study of Roxadustat to Treat Anemia in Patients With CKD, Not on Dialysis, NCT02174627.

Iron Therapy in Chronic Kidney Disease: Days of Future Past.

Anemia affects millions of patients with chronic kidney disease (CKD) and prompt iron supplementation can lead to reductions in the required dose of erythropoiesis-stimulating agents, thereby reducing medical costs. Oral and intravenous (IV) traditional iron preparations are considered far from ideal, primarily due to gastrointestinal intolerability and the potential risk of infusion reactions, respectively. Fortunately, the emergence of novel iron replacement therapies has engendered a paradigm shift in the treatment of iron deficiency anemia in patients with CKD. For example, oral ferric citrate is an efficacious and safe phosphate binder that increases iron stores to maintain hemoglobin levels. Additional benefits include reductions in fibroblast growth factor 23 levels and the activation of 1,25 dihydroxyvitamin D. The new-generation IV iron preparations ferumoxytol, iron isomaltoside 1000, and ferric carboxymaltose are characterized by a reduced risk of infusion reactions and are clinically well tolerated as a rapid high-dose infusion. In patients undergoing hemodialysis (HD), ferric pyrophosphate citrate (FPC) administered through dialysate enables the replacement of ongoing uremic and HD-related iron loss. FPC transports iron directly to transferrin, bypassing the reticuloendothelial system and avoiding iron sequestration. Moreover, this paper summarizes recent advancements of hypoxia-inducible factor prolyl hydroxylase inhibitors and future perspectives in renal anemia management.

Recommendations by the Asian Pacific society of nephrology (APSN) on the appropriate use of HIF-PH inhibitors.

Renal anaemia is a common and important complication in patients with chronic kidney disease (CKD). The current standard-of-care treatment for renal anaemia in CKD patients involves ensuring adequate iron stores and administration of erythropoietin stimulating agents (ESA). Hypoxia inducible factor (HIF) is a key transcription factor primarily involved in the cellular regulation and efficiency of oxygen delivery. Manipulation of the HIF pathway by the use of HIF-prolyl hydroxylase inhibitors (HIF-PHI) has emerged as a novel approach for renal anaemia management. Despite it being approved for clinical use in various Asia-Pacific countries, its novelty mandates the need for nephrologists and clinicians generally in the region to well understand potential benefits and harms when prescribing this class of drug. The Asian Pacific society of nephrology HIF-PHI Recommendation Committee, formed by a panel of 11 nephrologists from the Asia-Pacific region who have clinical experience or have been investigators in HIF-PHI studies, reviewed and deliberated on the clinical and preclinical data concerning HIF-PHI. This recommendation summarizes the consensus views of the committee regarding the use of HIF-PHI, taking into account both available data and expert opinion in areas where evidence remains scarce.