Effect of ferric citrate hydrate on fibroblast growth factor 23 and platelets in non-dialysis-dependent chronic kidney disease and non-chronic kidney disease patients with iron deficiency anemia.

BACKGROUND: Iron deficiency anemia (IDA) increases levels of C-terminal fibroblast growth factor 23 (cFGF23) and platelet count (PLT), each of which is associated with cardiovascular events. Therefore, we hypothesized that iron replacement with ferric citrate hydrate (FC) would decrease cFGF23 levels and PLT in patients with IDA. METHODS: In a randomized, open-label, multicenter, 24-week clinical trial, patients with non-dialysis-dependent chronic kidney disease (CKD) and non-CKD complicated by IDA (8.0 ≤ hemoglobin < 11.0 g/dL; and serum ferritin < 50 ng/mL [CKD]; < 12 ng/mL [non-CKD]) were randomized 1:1 to FC-low (500 mg: approximately 120 mg elemental iron/day) or FC-high (1000 mg: approximately 240 mg elemental iron/day). If sufficient iron replacement had been achieved after week 8, further treatment was discontinued. RESULTS: Seventy-three patients were allocated to FC-low (CKD n = 21, non-CKD n = 15) and FC-high (CKD n = 21, non-CKD n = 16). Regardless of CKD status, FC increased serum ferritin and transferrin saturation, did not change intact FGF23 or serum phosphorus, but decreased cFGF23. In FC-low group, median changes in cFGF23 from baseline to week 8 were -58.00 RU/mL in CKD and -725.00 RU/mL in non-CKD; in FC-high group, the median changes were -66.00 RU/mL in CKD and -649.50 RU/mL in non-CKD. By week 8, FC treatment normalized PLT in all patients with high PLT at baseline (>35.2 × 104/µL; FC-low: 1 CKD, 8 non-CKD; FC-high: 3 CKD, 8 non-CKD). CONCLUSION: Regardless of CKD status, iron replacement with FC decreased elevated cFGF23 levels and normalized elevated PLT in patients with IDA. CLINICAL TRIAL REGISTRATION NUMBER: jRCT2080223943.

Iron Parameters in Patients Treated with Roxadustat for Anemia of Chronic Kidney Disease.

Roxadustat is a novel agent with a distinct mechanism of action compared to erythropoiesis-stimulating agents (ESAs) and a potentially different combination of effects on iron parameters. This narrative review describes the effects of roxadustat on iron parameters and on hemoglobin levels in the context of iron supplementation in patients with anemia of non-dialysis-dependent (NDD) or dialysis-dependent (DD) chronic kidney disease (CKD). Roxadustat use was associated with a greater reduction in serum ferritin levels than seen with ESAs and an increase in serum iron levels compared to a decrease with ESAs. Decreases in transferrin saturation in patients treated with roxadustat were relatively small and, in the case of patients with NDD CKD, not observed by Week 52. These changes reflect the concomitant increases in both serum iron and total iron-binding capacity. Compared to placebo and an ESA, roxadustat improved iron availability and increased erythropoiesis while requiring less intravenous iron use. Hepcidin levels generally decreased in patients who received roxadustat compared to baseline values in all CKD populations; these decreases appear to be more robust with roxadustat than with an ESA or placebo. The mechanisms behind the effects of roxadustat and ESAs on iron availability and stores and erythropoiesis appear to differ and should be considered holistically when treating anemia of CKD.

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 m2 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 m2/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).

Treatment satisfaction with molidustat in CKD-related anemia in non-dialysis patients: a post-hoc analysis of two clinical trials.

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) are the standard treatment for patients with renal anemia to increase hemoglobin (Hb) levels and reduce the need for blood transfusions. However, treatments targeting high Hb levels require high doses of ESAs administered intravenously, which is associated with an elevated risk of adverse cardiovascular events. Furthermore, there have been some problems such as hemoglobin variability and low achievement of target hemoglobin due to the shorter half-lives of ESAs. Consequently, erythropoietin-promoting medications, such as hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors, have been developed. This study aimed to evaluate changes in the Treatment Satisfaction Questionnaire for Medicine version II (TSQM-II) domain scores relative to baseline in each trial, to assess patient satisfaction with molidustat versus darbepoetin alfa. METHODS: This post-hoc analysis of two clinical trials compared treatment satisfaction with an HIF-PH inhibitor, molidustat, versus a standard ESA, darbepoetin alfa, as part of therapy in patients with non-dialysis chronic kidney disease (CKD) and renal anemia. RESULTS: Exploratory outcome data using the TSQM-II showed that both arms in both trials had enhanced treatment satisfaction over the course of the study period, as well as improvements in most TSQM-II domains at week 24 of treatment. Molidustat was associated with convenience domain scores at multiple time points depending on the trial. More patients were highly satisfied with the convenience of molidustat than that of darbepoetin alfa. Patients treated with molidustat had increased global satisfaction domain scores compared with those treated with darbepoetin alfa; however, the differences in global satisfaction domain scores were not significant. CONCLUSION: These patient-reported satisfaction outcomes support the use of molidustat as a patient-centered treatment option for CKD-related anemia. REGISTRATION OF CLINICAL TRIALS: ClinicalTrials.gov Identifier: NCT03350321 (November 22, 2017). CLINICALTRIALS: gov Identifier: NCT03350347 (November 22, 2017).

Randomized, double-blind, placebo-controlled phase 3 study of bardoxolone methyl in patients with diabetic kidney disease: design and baseline characteristics of the AYAME study.

BACKGROUND: Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD), but currently available treatments do not improve kidney function or prevent the initiation of dialysis/kidney replacement therapy. A previous study demonstrated that bardoxolone methyl improves the estimated glomerular filtration rate (eGFR), but the study was prematurely terminated because of an imbalance in heart failure between treatment groups. The subsequent phase 2 TSUBAKI study demonstrated no incidence of heart failure and an improved eGFR and GFR as determined by inulin clearance in DKD patients. METHODS: This randomized, double-blind, placebo-controlled multicentre phase 3 study was designed to assess the efficacy and safety of bardoxolone methyl in DKD patients with an eGFR ≥15.0-<60.0 ml/min/1.73 m2 and a urinary albumin:creatinine ratio (UACR) ≤3500 mg/g but without risk factors for heart failure. The primary endpoint is the time to onset of a ≥30% decrease in the eGFR or ESKD. Randomized patients (1:1) have been under treatment with once-daily oral bardoxolone methyl (5, 10 or 15 mg by intrapatient dose adjustment) or placebo for at least 3 years. RESULTS: The mean age of the 1013 patients is 65.9 years, 21.5% are female, the mean eGFR is 37.84 ml/min/1.73 m2 and the median UACR is 351.80 mg/g. CONCLUSIONS: Appropriate patients are enrolled in this study. This study will investigate the long-term efficacy and safety of bardoxolone methyl in DKD patients covering a wider range of eGFR (≥15.0-<60.0 ml/min/1.73 m2) and albuminuria (≤3500 mg/g) compared with previous studies.

Hyporesponsiveness to erythropoiesis-stimulating agent in non-dialysis-dependent CKD patients: The BRIGHTEN study.

Among non-dialysis-dependent chronic kidney disease (ND-CKD) patients, a low hematopoietic response to erythropoiesis-stimulating agents (ESAs) is a predictor for poor renal and cardiovascular outcome. To assess the method for evaluating hyporesponsiveness to ESA in patients with ND-CKD, a multicenter, prospective, observational study of 1,980 adult patients with ND-CKD with renal anemia was conducted. Darbepoetin alfa (DA) and iron supplement administrations were provided according to the recommendation of the attached document and the guidelines of JSDT (Japanese Society of Dialysis and Transplantation). The primary outcomes were progression of renal dysfunction and major adverse cardiovascular events. ESA responsiveness was assessed using pre-defined candidate formulae. During the mean follow-up period of 96 weeks, renal and cardiovascular disease (CVD) events occurred in 683 (39.6%) and 174 (10.1%) of 1,724 patients, respectively. Among pre-set candidate formulae, the one expressed by dividing the dose of DA by Hb level at the 12-week DA treatment was statistically significant in predicting renal (hazard ratio [HR], 1.449; 95% confidence interval [CI], 1.231-1.705; P<0.0001) and CVD events (HR, 1.719; 95% CI, 1.239-2.386; P = 0.0010). The optimum cut-off values for both events were close to 5.2. In conclusion, hyporesponsiveness to ESA in ND-CKD cases, which is associated with a risk for renal and CVD events, may be evaluated practicably as the dose of DA divided by the Hb level at the 12-week DA treatment, and the cut-off value of this index is 5.2. A search for the causes of poor response and measures for them should be recommended in such patients. Trial registration: ClinicalTrials. gov Identifier: NCT02136563; UMIN Clinical Trial Registry Identifier: UMIN000013464.

Safety of daprodustat in patients with anemia of chronic kidney disease: A pooled analysis of phase 3 studies in Japan.

INTRODUCTION: Daprodustat is an approved treatment for anemia of chronic kidney disease (CKD) in Japan. METHODS: This post hoc analysis evaluated pooled safety data for daprodustat from 3 phase 3 Japanese studies in dialysis-dependent and nondialysis patients with anemia of CKD. RESULTS: Median drug exposure duration was 365 days for both daprodustat (N = 369) and injectable erythropoiesis-stimulating agent (ESA, N = 285). The incidence per 100 patient-years of on-therapy adverse events (AEs) was 363.1 and 306.4 in the daprodustat and ESA groups, respectively. The incidence per 100 patient-years of thromboembolic and retinal events were 5.55 and 6.91 (daprodustat) and 6.28 and 7.46 (ESA), respectively. Cardiovascular and malignancy events were similar between groups, although analysis of these were limited by sample size and study duration. CONCLUSION: The safety of daprodustat was comparable to ESA in this pooled analysis, although further large-scale research is needed to evaluate long-term risks including cardiovascular and malignancy events.

Treatment of anemia associated with chronic kidney disease with the HIF prolyl hydroxylase inhibitor enarodustat: A review of the evidence.

Enarodustat, a newly developed hypoxia-inducible factor prolyl hydroxylase inhibitor, is used in clinical practice in Japan. Several clinical studies showed that enarodustat corrected and maintained hemoglobin (Hb) levels by stimulating endogenous erythropoietin production and improving iron utilization in anemic patients with chronic kidney disease, regardless of whether they were on dialysis. In addition, Phase III comparative studies demonstrated that enarodustat was noninferior to darbepoetin alfa in controlling Hb levels. Furthermore, enarodustat was well tolerated during the treatment. Enarodustat is currently being developed in the Republic of Korea and China and is expected to be developed worldwide. This article reviews the data on enarodustat, including the findings from preclinical studies, pharmacokinetics/pharmacodynamics, and efficacy and safety results of clinical studies.

Estimating the causal effect of transient anemia status on renal and cardiovascular outcomes in community-dwelling patients in Japan at the beginning of impaired renal function using marginal structural modeling.

BACKGROUND: Anemia status may be transient. Causal associations between changes in anemia status over time and adverse outcome development are not well characterized in community-dwelling subjects at the beginning of impaired kidney function. METHODS: This retrospective cohort study used annual health checkup and medical and pharmacy claims data from the JMDC between January 2005 and June 2019. Community-dwelling subjects in Japan with a pre-index estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 followed by a subsequent eGFR < 60 mL/min/1.73 m2 (index) were included. The composite renal outcome was ≥ 30% eGFR reduction over 3 years from baseline, serum creatinine doubling, progression to chronic dialysis, kidney transplantation, or eGFR < 15 mL/min/1.73 m2. The composite cardiovascular outcome was fatal and non-fatal unstable angina, myocardial infarction, heart failure, or cerebrovascular event. Time-dependent anemia risk was evaluated using Breslow's estimator and marginal structural Cox models (MSM). RESULTS: In 32,870 included subjects, 1,396 had anemia at baseline. Adverse outcome incidence was higher in the baseline anemic group, but absolute differences in renal and cardiovascular outcomes between groups were diminished after adjusting for baseline characteristics. In MSM, time-dependent anemia status was associated with higher risk of renal (hazard ratio [95% confidence interval]; 2.6 [1.7-3.8]) and cardiovascular (1.6 [1.2-2.2]) outcomes and mortality (2.8 [1.8-4.3]). Absolute differences in survival probabilities were retained over time but were clinically marginal (1.1-2.7% over 6 years). CONCLUSIONS: Even in subjects at the very early stage of impaired kidney function, early detection and treatment of anemia may help reduce the development of negative sequelae.

Molidustat for the treatment of anemia in Japanese patients undergoing peritoneal dialysis: a single-arm, open-label, phase 3 study.

This 36-week, open-label, single-arm, phase 3 study investigated the safety and efficacy of molidustat in Japanese patients with renal anemia undergoing peritoneal dialysis. Molidustat was titrated every 4 weeks to maintain Hb levels within the target range (≥11.0 and <13.0 g/dL). The primary efficacy outcome was the responder rate, defined as the proportion of patients who met all of the following criteria: (1) mean Hb levels in the target range during the evaluation period (Weeks 30-36); (2) ≥50% of Hb values within the target range during the evaluation period; and (3) no rescue treatment before the end of the evaluation period. Overall, 51 patients received molidustat. The responder rate (95% CI) during the evaluation period was 54.9% (40.3, 68.9). Overall, 98.0% of patients experienced at least 1 adverse event during the study. No deaths were reported. Molidustat maintained Hb levels in the prespecified range in more than half of the patients and was well tolerated.

[The effect of ferric citrate hydrate as an iron replacement therapy in Japanese patients with iron deficiency anemia].

Patients with iron deficiency anemia (IDA) need to take oral iron preparations, which serve as the first-line treatment in IDA, for several months in order to replenish body iron stores after the improvement of anemia. However, existing oral iron preparations have concerns regarding its long-term use due to side effects, such as gastrointestinal symptoms. Previous clinical studies have shown that ferric citrate hydrate (FC) exhibits sufficient therapeutic efficacy in patients with IDA and lowers the risks of nausea and vomiting in comparison with existing oral iron preparations. In this study, we evaluated the efficacy and safety of FC administration at doses of 500 and 1,000 mg/day for up to 24 weeks as iron replacement therapy in patients with IDA. The results of this study showed that both the doses of FC improved anemia and iron-deficiency conditions and led to sufficient iron replacement response in most patients with IDA. No safety concerns were identified. Therefore, FC is expected to be a novel oral iron preparation for patients with IDA.

Factors Affecting Doses of Roxadustat Versus Darbepoetin Alfa for Anemia in Nondialysis Patients.

INTRODUCTION: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for treating anemia of chronic kidney disease (CKD). This post hoc analysis of a Japanese, open-label, partially randomized, phase 3 study in nondialysis-dependent (NDD) CKD patients treated with traditional erythropoiesis-stimulating agents (ESAs) evaluated dosing trends of roxadustat and darbepoetin alfa (DA) required to maintain target hemoglobin concentrations in patients with risk factors associated with ESA hyporesponsiveness. METHODS: Patients enrolled in the 1517-CL-0310 study (NCT02988973) that demonstrated noninferiority of roxadustat to DA for change in average hemoglobin levels of week 18-24 from baseline who had used human recombinant erythropoietin or DA before conversion and who were randomized to either roxadustat or DA were included. The endpoints were the average allocated dose of roxadustat and DA per administration in the last 6 weeks (AAD/6W), assessed by subgroups known to be associated with ESA hyporesponsiveness. The analysis of variance was performed by the treatment group to test the influence of subgroup factors on the AAD/6W of study drug. The ratios between the mean AAD/6W in each subgroup category and the within-arm mean AAD/6W were calculated. RESULTS: Two hundred and sixty-two patients were randomized to either the roxadustat or DA comparative group and received treatment (roxadustat, n = 131; DA, n = 131). Higher mean (standard deviation) doses of both roxadustat (63.15 [24.84] mg) and DA (47.33 [29.79] µg) were required in the highest ESA resistance index (≥6.8) quartile (p = 0.003 and p < 0.001, respectively). Patients with adequate iron repletion had the lowest doses for both roxadustat (45.54 [18.01] mg) and DA (28.13 [20.98] µg). High-sensitivity C-reactive protein ≥28.57 nmol/L and the estimated glomerular filtration rate <15 mL/min/1.73 m2 were associated with requiring higher DA but not roxadustat doses. DISCUSSION/CONCLUSION: The roxadustat dose required to maintain target hemoglobin in NDD patients in Japan with anemia of CKD relative to DA dose may not be impacted by low-grade inflammation. Roxadustat may be beneficial for ESA-hyporesponsive NDD CKD patients.

Molidustat for Renal Anemia in Nondialysis Patients Previously Treated with Erythropoiesis-Stimulating Agents: A Randomized, Open-Label, Phase 3 Study.

INTRODUCTION: Erythropoiesis-stimulating agents (ESAs) are the current standard of care for anemia due to chronic kidney disease (CKD) in patients not undergoing dialysis. Molidustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, is being investigated as an alternative treatment for renal anemia. Molidustat was evaluated in five phase 3 studies, the molidustat once daily improves renal anemia by inducing erythropoietin (MIYABI) program. The present study investigated the safety and efficacy of molidustat in Japanese patients with renal anemia not undergoing dialysis and previously treated with ESAs. METHODS: This was a 52-week, active-controlled, randomized (1:1), open-label, parallel-group, multicenter, phase 3 study in Japanese patients with anemia due to CKD (stages 3-5). Molidustat was initiated at 25 mg or 50 mg once daily according to previous ESA dose. The ESA darbepoetin alfa (darbepoetin) was initiated at a starting dose in accordance with the previous ESA dose and injected subcutaneously once every 2 or 4 weeks. Doses were regularly titrated to maintain hemoglobin (Hb) levels in the target range of 11.0-13.0 g/dL. The primary efficacy outcome was the mean Hb level and its change from baseline during the evaluation period (weeks 30-36). The safety outcomes included evaluation of all adverse events. RESULTS: In total, 164 patients were randomized to receive molidustat (n = 82) or darbepoetin (n = 82). Baseline characteristics were well balanced. Mean (standard deviation) Hb levels at baseline were 11.31 (0.68) g/dL for molidustat and 11.27 (0.64) g/dL for darbepoetin. The mean (95% confidence interval [CI]) for mean Hb levels during the evaluation period for molidustat (11.67 [11.48-11.85] g/dL) and darbepoetin (11.53 [11.31-11.74] g/dL) was within the target range. Based on a noninferiority margin of 1.0 g/dL, molidustat was noninferior to darbepoetin regarding the change in mean Hb level during the evaluation period from baseline, with a least squares mean (95% CI) difference (molidustat-darbepoetin) of 0.13 (-0.15, 0.40) g/dL. The proportion of patients who reported at least 1 treatment-emergent adverse event (TEAE) was 92.7% for molidustat and 96.3% for darbepoetin. TEAEs leading to death were reported in 2 patients (2.4%) in the molidustat group and none in the darbepoetin group; serious TEAEs were reported in 32.9% and 26.8% of patients, respectively. DISCUSSION/CONCLUSION: Molidustat was noninferior to darbepoetin and maintained Hb levels in the prespecified target range in patients with renal anemia not undergoing dialysis and previously treated with ESA. Molidustat was well tolerated, and no new safety signal was observed.

Factors affecting the doses of roxadustat vs darbepoetin alfa for anemia treatment in hemodialysis patients.

Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of anemia in chronic kidney disease (CKD). Emerging evidence suggests that roxadustat may be beneficial for patients who inadequately respond to erythropoiesis-stimulating agents (ESAs). This post-hoc analysis of a Japanese, double-blind, randomized, phase 3 study in hemodialysis-dependent CKD patients treated with traditional ESAs assessed the impact of factors associated with ESA hyporesponsiveness on roxadustat and darbepoetin alfa (DA) doses required to maintain target hemoglobin. Endpoints included mean of average doses of roxadustat and DA per administration in the last 6 weeks (AAD/6W) by prior ESA-resistance index (ERI), iron repletion (transferrin saturation; ferritin), and high-sensitivity C-reactive protein (hs-CRP). Of 415 enrolled patients, 303 were randomized (roxadustat, n = 151; DA, n = 152). Weight-adjusted AAD/6W increased with increasing ERI for roxadustat (ERI <3.3, 0.89 mg/kg; ERI ≥8.4, 1.51 mg/kg) and DA (ERI <3.3, 0.26 µg/kg; ERI ≥8.4, 0.91 µg/kg); the weight-adjusted AAD/6W relative to within-arm mean AAD/6W showed a trend toward increased DA doses for the ERI ≥8.4 category (P = .089). AAD/6W remained stable for roxadustat but increased for DA with decreasing baseline iron repletion markers. The relationship between roxadustat doses and end of treatment (EoT) hs-CRP was not significant (estimated slope, -0.494; P = .814); a trend toward increased DA doses was observed with increasing EoT hs-CRP (estimated slope, 2.973; P = .075). Roxadustat doses required to maintain target hemoglobin appear to be less affected by factors that underlie ESA hyporesponsiveness, relative to DA; roxadustat may be beneficial for patients hyporesponsive to ESAs.

Safety and efficacy of etelcalcetide, an intravenous calcimimetic, for up to 52 weeks in hemodialysis patients with secondary hyperparathyroidism: results of a post-marketing surveillance in Japan.

BACKGROUND: Etelcalcetide is a second-generation calcimimetic for the management of secondary hyperparathyroidism (SHPT) in patients on dialysis. We performed a post-marketing surveillance (PMS) to obtain information on the safety and efficacy of etelcalcetide in clinical practice in Japan. METHODS: This PMS enrolled SHPT patients who started initial treatment with etelcalcetide between April 1, 2017 and February 28, 2018 in Japan. Safety [adverse drug reactions (ADRs)] and efficacy [serum intact parathyroid hormone (iPTH), corrected calcium (cCa), phosphorous (P), and alkaline phosphatase (ALP)] were recorded for up to 52 weeks or until treatment discontinuation. Treatment decisions were at the physician's discretion. RESULTS: Of 1226 patients enrolled across 282 centers, safety and efficacy data were available for 1195 and 1192, respectively, while 933 continued treatment to Week 52. The starting dose was 5 mg in 82.0% of patients. There were 218 ADRs in 169 patients (14.1%). Metabolism and nutrition disorders (8.8%), adverse laboratory test results (1.8%), and gastrointestinal disorders (1.6%) were the most frequent classes of ADRs. Hypocalcemia-related ADRs occurred in 104 patients (8.7%). The percentage of patients with iPTH levels within the target range (60-240 pg/mL) steadily increased from 19.5% at Week 0 to 64.1% at Week 52 or last dose. cCa, P, and ALP levels remained well controlled. CONCLUSION: This was the first real-world, large-scale, long-term observational PMS of etelcalcetide in Japan. We did not observe any new safety concerns. Etelcalcetide was associated with clinically relevant improvements in serum iPTH and maintenance of serum cCa, P, and ALP levels.

Efficacy and Safety of Daprodustat Compared with Darbepoetin Alfa in Japanese Hemodialysis Patients with Anemia: A Randomized, Double-Blind, Phase 3 Trial.

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 µg 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.

Phase 3, Randomized, Double-Blind, Active-Comparator (Darbepoetin Alfa) Study of Oral Roxadustat in CKD Patients with Anemia on Hemodialysis in Japan.

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 (∆Hb18-24). 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 (n=151) or darbepoetin alfa (n=152). The difference between roxadustat and darbepoetin alfa in ∆Hb18-24 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).

A Phase 3, Multicenter, Randomized, Two-Arm, Open-Label Study of Intermittent Oral Dosing of Roxadustat for the Treatment of Anemia in Japanese Erythropoiesis-Stimulating Agent-Naïve Chronic Kidney Disease Patients Not on Dialysis.

INTRODUCTION: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved for the treatment of anemia in Japan for patients with dialysis-dependent (DD) chronic kidney disease (CKD). OBJECTIVE: Multicenter, randomized, open-label, noncomparative, phase 3 study to evaluate roxadustat for anemia of non-dialysis-dependent (NDD) CKD in Japan. METHODS: Erythropoiesis stimulating agent (ESA)-naïve NDD-CKD patients were randomized to roxadustat (initial dose, 50 or 70 mg 3 times weekly), titrated to maintain hemoglobin (Hb) within 10.0-12.0 g/dL, for ≤24 weeks. Patients with either transferrin saturation of ≥5% or serum ferritin of ≥30 ng/mL during the screening period were eligible. Endpoints included response rate (proportion of patients achieving Hb ≥10.0 or ≥10.5 g/dL and Hb increase ≥1.0 g/dL from baseline) at end of treatment; average Hb (weeks 18-24); change of average Hb from baseline to weeks 18-24; maintenance rate (proportion of patients achieving Hb 10.0-12.0 g/dL at weeks 18-24); rate of rise (RoR) of Hb from weeks 0-4, discontinuation, or dose adjustment. Adverse events were monitored throughout the study. RESULTS: Of 135 patients who provided informed consent, 100 were randomized and 99 received roxadustat (50 mg, n = 49; 70 mg, n = 50). The mean (SD) dose of roxadustat per intake at week 22 was 36.3 (22.7) mg in the roxadustat 50 mg group and 36.8 (16.0) mg in the roxadustat 70 mg group. Prior medications included oral iron therapy (20.2%) and intravenous iron therapy (1.0%). Overall response rate (95% CI) was 97.0% (91.4, 99.4; Hb ≥10.0 g/dL) and 94.9% (88.6, 98.3; Hb ≥10.5 g/dL). Mean (SD) Hb (weeks 18-24) was 11.17 (0.62) g/dL. Mean (SD) change of Hb from baseline (weeks 18-24) was 1.34 (0.86) g/dL. Maintenance rate (95% CI) was 88.8% (80.3, 94.5) among patients with ≥1 Hb measurement during weeks 18-24. Mean (SD) RoR of Hb was 0.291 (0.197) g/dL/week (50 mg) and 0.373 (0.235) g/dL/week (70 mg). Nasopharyngitis and hypertension were the most common adverse events. CONCLUSION: Roxadustat increased and maintained Hb in ESA-naïve, partially iron-depleted NDD-CKD patients with anemia.

Darbepoetin Alfa in Patients with Advanced CKD without Diabetes: 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 m2. 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 m2, 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; P=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; P=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; P=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.

Oral roxadustat three times weekly in ESA-naïve and ESA-converted patients with anemia of chronic kidney disease on hemodialysis: Results from two phase 3 studies.

Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor approved in China for anemia of dialysis-dependent chronic kidney disease (CKD). Japanese hemodialysis patients with anemia of CKD previously naïve to, or converted from, erythropoiesis-stimulating agents (ESAs) were enrolled in two open-label, noncomparative studies of titrated oral roxadustat administered three times weekly. ESA-naïve patients (n = 75) were randomized to roxadustat (initial dose, 50 or 70 mg) for 24 weeks; ESA-converted patients (n = 164) were assigned to roxadustat (initial dose, 70 or 100 mg based on prior ESA dose) for 52 weeks. Efficacy outcomes included average hemoglobin (Hb, weeks 18-24 or 46-52), change of Hb from baseline to weeks 18 to 24 (ΔHb18-24 ) or weeks 46 to 52 (ΔHb46-52 ), and maintenance rate (proportion of patients who achieved average Hb of 10.0-12.0 g/dL for weeks 18-24 or weeks 46-52). Treatment-emergent adverse events (TEAEs) were monitored. Mean (SD) Hb was 10.93 (0.79) g/dL (weeks 18-24) (ESA-Naïve Study), and 10.93 (0.69; weeks 18-24) g/dL and 11.11 (0.67; weeks 46-52) g/dL (ESA-Converted Study). Mean (SD) ΔHb18-24 was 2.26 (1.02) g/dL (ESA-Naïve Study) and -0.03 (0.90) g/dL (ESA-Converted Study); mean (SD) ΔHb46-52 was 0.12 (0.83) g/dL (ESA-Converted Study). The overall maintenance rate was 73.0% (54/74) (ESA-Naïve Study) (weeks 18-24), and 79.1% (129/163; weeks 18-24) and 71.2% (116/163; weeks 46-52) (ESA-Converted Study). Nasopharyngitis was the most common TEAE. Two deaths, considered unrelated to roxadustat, occurred in the ESA-Converted Study. Roxadustat effectively corrected and maintained Hb, regardless of previous ESA treatment, in Japanese anemic CKD patients on hemodialysis.