scholarly journals A Phase 3 Study of Enarodustat (JTZ-951) in Japanese Hemodialysis Patients for Treatment of Anemia in Chronic Kidney Disease: SYMPHONY HD Study

2021 ◽  
pp. 1-9
Author(s):  
Tadao Akizawa ◽  
Masaomi Nangaku ◽  
Takuhiro Yamaguchi ◽  
Ryosuke Koretomo ◽  
Kazuo Maeda ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Binding Capacity ◽  
Hypoxia Inducible Factor ◽  
Intravenous Iron ◽  
Target Range ◽  
Maintenance Hemodialysis ◽  
Phase 3 ◽  
Evaluation Period ◽  
The Mean

<b><i>Introduction:</i></b> Enarodustat (JTZ-951) is a new oral hypoxia-inducible factor-prolyl hydroxylase inhibitor for the treatment of anemia in chronic kidney disease (CKD). We conducted a phase 3 study to compare the efficacy and safety of enarodustat with darbepoetin alfa (DA) in Japanese anemic patients with CKD receiving maintenance hemodialysis. <b><i>Methods:</i></b> Subjects receiving maintenance hemodialysis were randomly assigned at a 1:1 ratio to receive oral enarodustat once daily or intravenous DA every week for 24 weeks with dose adjustment every 4 weeks to maintain hemoglobin (Hb) within a target range (≥10.0 to &#x3c;12.0 g/dL). The primary efficacy endpoint was difference in mean Hb level between arms during the evaluation period defined as weeks 20–24 (noninferiority margin: −1.0 g/dL). Intravenous iron preparations were prohibited during the screening period and during weeks 0–4. <b><i>Results:</i></b> The mean Hb level of each arm during the evaluation period was 10.73 g/dL (95% confidence interval [CI]: 10.56, 10.91) in the enarodustat arm and 10.85 g/dL (95% CI: 10.72, 10.98) in the DA arm. The difference in the mean Hb level between arms was −0.12 g/dL (95% CI: −0.33, 0.10), confirming the noninferiority of enarodustat to DA. The mean Hb level of each arm was maintained within the target range during the treatment period. Increased total iron-binding capacity and serum iron and decreased hepcidin were observed through week 4 in the enarodustat arm albeit after switching from erythropoiesis-stimulating agents. No apparent safety concerns of enarodustat were observed compared with DA. <b><i>Discussion/Conclusion:</i></b> Enarodustat was noninferior to DA for the treatment of anemia in CKD patients receiving maintenance hemodialysis and was generally well tolerated over 24 weeks.

scholarly journals A Placebo-Controlled, Randomized Trial of Enarodustat in Patients with Chronic Kidney Disease Followed by Long-Term Trial

2019 ◽  
Vol 49 (2) ◽  
pp. 165-174 ◽  
Author(s):  
Tadao Akizawa ◽  
Masaomi Nangaku ◽  
Takuhiro Yamaguchi ◽  
Masanobu Arai ◽  
Ryosuke Koretomo ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Binding Capacity ◽  
Hypoxia Inducible Factor ◽  
Target Range ◽  
Adaptive Responses ◽  
Double Blind ◽  
Hypoxic Conditions ◽  
Period 2 ◽  
Term Trial

Background: Enarodustat (JTZ-951) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that mimics adaptive responses to hypoxic conditions and may provide a new therapeutic approach for managing anemia in patients with chronic kidney disease (CKD). We evaluated the efficacy, safety, and maintenance dose of enarodustat in anemic patients with CKD not on dialysis. Methods: Erythropoiesis-stimulating agent (ESA) naïve patients (correction group) and patients on a stable dose of ESA (conversion group) were randomized to receive 2, 4, or 6 mg of enarodustat or placebo once daily for 6 weeks in a double-blind manner (Period 1) followed by 24 weeks of open enarodustat treatment to maintain their hemoglobin (Hb) levels within a target range of 10.0–12.0 g/dL in reference to a dose adjustment algorithm (Period 2). Results: In the correction group, Hb level increase rate per week increased in a dose-response manner. The proportion of subjects in the conversion group who maintained Hb levels within ± 1.0 g/dL of baseline did not differ between each enarodustat arm and placebo arm during Period 1. Over 70% of subjects in both groups maintained Hb levels within the target range at the end of treatment in Period 2. The mean prescribed doses were 3.58 and 3.74 mg/day in the correction group and the conversion group, respectively. Enarodustat was associated with decreases in hepcidin and ferritin and increased total iron-binding capacity and was generally well tolerated. Conclusions: Enarodustat corrects and maintains Hb levels in anemic patients with CKD not on dialysis.

scholarly journals P1866TO INVESTIGATE THE EFFICACY AND SAFETY OF MOLIDUSTAT IN NON-DIALYSIS PATIENTS WITH RENAL ANEMIA WHO ARE NOT TREATED WITH ERYTHROPOIESIS-STIMULATING AGENTS: MIYABI ND-C

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Hiroyasu Yamamoto ◽  
Megumi Taguchi ◽  
Kiyoshi Nobori ◽  
Yoshimi Matsuda ◽  
Kazuma Iekushi ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Renal Anemia ◽  
Target Range ◽  
Primary Efficacy ◽  
Efficacy And Safety ◽  
Dialysis Patients ◽  
Evaluation Period ◽  
Starting Dose ◽  
The Mean

Abstract Background and Aims Anemia is a common complication of chronic kidney disease (CKD). A hypoxia-inducible factor prolyl-hydroxylase (HF-PH) inhibitor is developing as a new treatment option of renal anemia. Molidustat, an oral HIF-PH inhibitor, stimulated endogenous production of erythropoietin and was well tolerated in phase IIb clinical trials. The phase III program entitled MolIdustat once dailY improves renal Anemia By Inducing EPO (MIYABI) was conducted in Japan. Method MIYABI Non-Dialysis-Correction (ND-C) of Hb study (up to 52 weeks, randomized, darbepoetin-controlled, open-label) was conducted to investigate the efficacy and safety of molidustat (MO) in non-dialysis patients with renal anemia who are not treated with erythropoiesis-stimulating agents. Study drug doses were titrated regularly with the aim of correcting and maintaining the patients’ Hb values between the target range (11.0-13.0 g/dL). The primary efficacy variables were the mean Hb values during the evaluation period (30-36 weeks) and its change from baseline to demonstrate the non-inferiority of MO to darbepoetin alfa (DA) using a non-inferiority margin of 1.0g/dL. Safety variables included adverse events (AE). Prespecified primary analysis results up to 36 weeks are presented here. Results 82 patients were treated with a starting dose of 25mg of MO and 79 patients were treated with a starting dose of 30μg/2weeks of DA. The mean of baseline Hb values were 9.84 g/dL and 10.00 g/dL in the MO and DA group, respectively. MO increased the mean Hb values (rate of rise from baseline in Hb values at the first dose change up to 8 weeks: mean: 0.086 g/dL/week (95%CI; 0.047, 0.126)) and achieved the lower limit of target range at 12 weeks. MO maintained Hb values after 12 weeks, and for the mean Hb values during the evaluation period, the mean was 11.28 g/dL (95%CI; 11.07, 11.50). As the primary efficacy variables (the changes from baseline of mean Hb values during the evaluation period), the means were 1.45 g/dL (95%CI; 1.21, 1.68) and 1.70 g/dL (95%CI; 1.47, 1.92) in the MO and DA group, respectively. The LS mean difference was -0.38 (95%CI; -0.67, -0.08), therefore the non-inferiority of MO to DA was established. The mean (SD) doses during the study period were 45.33 (28.88) mg/day of MO and 17.87 (12.49) μg/week of DA. The most common maximum dose of MO was 25 mg (26 patients, 31.7%) followed by 75 mg (16 patients, 19.5%) and 50mg (14 patients, 17.1%). AEs were experienced in 84.1% of patients in the MO group and in 91.1% of patients in the DA group up to 36 weeks. The most common AEs occurred ≥ 5% of patients in any group were nasopharyngitis (20.7% and 25.3%, respectively) and worsening of chronic kidney disease (13.4% and 6.3%, respectively). Conclusion Correction and Maintenance effect of MO on the Hb values was investigated and the non-inferiority of MO to DA was established in non-dialysis patients with untreated anemia. The MO showed no new safety concern but further longitudinal investigation will be needed.

scholarly journals MO541HEMATOLOGIC EFFICACY OF VADADUSTAT FOR ANEMIA IN PATIENTS WITH NON--DIALYSIS-DEPENDENT CHRONIC KIDNEY DISEASE

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Mark Koury ◽  
Pablo E Pergola ◽  
Prabir Roy-Chaudhury ◽  
Youssef Farag ◽  
Dennis Vargo ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Darbepoetin Alfa ◽  
Hypoxia Inducible Factor ◽  
The United States ◽  
Target Range ◽  
Phase 3 ◽  
Two Phase ◽  
Prolyl Hydroxylases ◽  
Safety Outcome

Abstract Background and Aims Vadadustat is a small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylases under development to treat anemia associated with chronic kidney disease (CKD). The vadadustat phase 3 program includes four efficacy and cardiovascular safety outcome trials of vadadustat versus the erythropoiesis-stimulating agent (ESA) darbepoetin alfa. Here we describe detailed results on hematologic efficacy in two phase 3, randomized trials (the PRO2TECT trials) in adult patients with non–dialysis-dependent (NDD) CKD and anemia, in which vadadustat met prespecified noninferiority criteria compared to darbepoetin alfa, with respect to hematologic efficacy (correction/maintenance of hemoglobin [Hb] target concentrations). Method The mean screening Hb level for the ESA-untreated NDD-CKD trial (NCT02648347) had to be &lt;10.0 g/dL, and for the ESA-treated NDD-CKD trial (NCT02680574), the range had to be from 8.0-11.0 g/dL in the United States (US) and from 9.0-12.0 g/dL non-US. In the ESA-untreated trial, patients received no ESA within 8 weeks before randomization; in the ESA-treated trial, patients were maintained on ESA therapy, with ≥1 dose received within 6 weeks prior to or during screening. The vadadustat starting dose was 300 mg/day for all patients, whereas the initial darbepoetin alfa dose depended on each patient’s prior dose or the product label. Both vadadustat and darbepoetin alfa doses were titrated according to prespecified dosing algorithms to achieve target Hb concentrations (US: 10-11 g/dL; non-US: 10-12 g/dL) both during the primary (PEP; weeks 24-36) and secondary (SEP; weeks 40-52) evaluation periods. Herein, we present topline results from the PEP and SEP endpoints, in addition to more detailed erythrocyte parameters. Results A total of 3,476 patients (1751 ESA-untreated and 1725 ESA-treated) were randomized 1:1 to vadadustat or darbepoetin alfa. In both trials, vadadustat was noninferior to darbepoetin alfa with regard to the difference of mean change in Hb concentrations between baseline and PEP, as well as between baseline and SEP. The respective proportions of patients (vadadustat vs. darbepoetin alfa) with an average Hb value within the geography-specific target range in the PEP and SEP were 50.4% versus 50.2% and 43.1% versus 43.5% in the ESA-untreated trial and 60.1% versus 60.7% and 50.7% versus 49.0% in the ESA-treated trial. The proportion of patients (vadadustat vs darbepoetin alfa) who achieved an Hb increase &gt;1.0 g/dL from baseline to week 52 was assessed only for the ESA-untreated trial and was 87.7% (95% CI: 85.4%, 89.8%) for vadadustat versus 88.0% (95% CI: 85.6%, 90.0%) for darbepoetin alfa. Hematologic parameters at time points within the PEP and SEP are presented in Table 1. In both the ESA-untreated and ESA-treated trials, the reticulocyte count trended up from baseline through week 52 for vadadustat and trended down from baseline for darbepoetin alfa. Trends in erythrocyte mean corpuscular volume and erythrocyte mean corpuscular Hb were largely unremarkable by week 52 in both treatment groups. Conclusion Vadadustat demonstrated similar profiles across erythrocyte parameters compared with darbepoetin alfa in the treatment of adults with anemia in CKD not on dialysis, whether ESA-untreated or ESA-treated at study entry.

scholarly journals Peginesatide to Manage Anemia in Chronic Kidney Disease Patients on Peritoneal Dialysis

2015 ◽  
Vol 35 (4) ◽  
pp. 481-489 ◽  
Author(s):  
Raja Zabaneh ◽  
Simon D. Roger ◽  
Mohamed El-Shahawy ◽  
Michael Roppolo ◽  
Grant Runyan ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Adverse Event ◽  
Peritoneal Dialysis ◽  
Kidney Disease ◽  
Common Adverse Event ◽  
Erythropoietin Receptor ◽  
Open Label ◽  
Evaluation Period ◽  
Red Blood Cell Transfusions ◽  
The Mean

♦BackgroundPeginesatide is a novel, synthetic, peptide-based pegylated erythropoiesis-stimulating agent that is designed specifically to stimulate the erythropoietin receptor. The purpose of the present study was to assess, for the first time, the efficacy and safety of peginesatide in chronic kidney disease (CKD) patients receiving peritoneal dialysis (PD) and previously on epoetin treatment.♦MethodsIn this open-label multicenter study, 59 PD patients with CKD were converted from epoetin (alfa or beta) to once-monthly peginesatide. Doses were titrated to maintain hemoglobin levels between 10 g/dL and 12 g/dL during the 25 weeks of the study. The primary endpoint was change from baseline in mean hemoglobin values during the evaluation period (weeks 20 – 25).♦ResultsThe mean hemoglobin value during the evaluation period was 11.3 ± 1.07 g/dL, and the mean change from baseline was 0.10 ± 1.15 g/dL (95% confidence limits: –0.24, 0.44 g/dL). During the evaluation period, most patients maintained hemoglobin levels between 10 g/dL and 12 g/dL (63.0%) and within ±1.0 g/dL of baseline (60.9%). The median weekly epoetin dose at baseline was 96.0 U/kg, and the median starting peginesatide dose was 0.047 mg/kg. Forty-three patients (72.9%) completed the study. Six patients (10.2%) received red blood cell transfusions. The observed adverse event profile was consistent with underlying conditions in the PD patient population. The most common adverse event was peritonitis (20.3%), a complication commonly associated with PD. Four deaths occurred during the study (2 related to septic shock, and 1 each to myocardial ischemia and myasthenia gravis).♦ConclusionsIn this study, once-monthly peginesatide maintained hemoglobin levels in PD patients after conversion from epoetin.

MO539HEMATOLOGIC EFFICACY OF VADADUSTAT FOR ANEMIA IN PATIENTS WITH KIDNEY FAILURE ON DIALYSIS

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Wolfgang Winkelmayer ◽  
James A Tumlin ◽  
Steven Fishbane ◽  
Youssef Farag ◽  
Dennis Vargo ◽  
...  
Keyword(s):  
Darbepoetin Alfa ◽  
Reticulocyte Count ◽  
Hypoxia Inducible Factor ◽  
The United States ◽  
Target Range ◽  
Cardiovascular Safety ◽  
Open Label ◽  
Phase 3 ◽  
Evaluation Period ◽  
Safety Outcome

Abstract Background and Aims Vadadustat is a small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase being developed for treatment of anemia associated with chronic kidney disease (CKD). The vadadustat phase 3 program includes four efficacy and cardiovascular safety outcome trials of vadadustat versus the erythropoiesis-stimulating agent (ESA) darbepoetin alfa. Here we describe detailed results on hematologic efficacy in two of the four phase 3, randomized, open-label, sponsor-blind trials (the INNO2VATE trials) in adult patients with dialysis-dependent (DD) CKD and anemia, where vadadustat met prespecified noninferiority criteria compared with darbepoetin alfa with respect to cardiovascular safety and correction/maintenance of hemoglobin (Hb) target concentrations. Method The mean screening Hb range for the incident DD-CKD trial (NCT02865850) was 8.0-11.0 g/dL; for the prevalent DD-CKD trial (NCT02892149), it was 8.0-11.0 g/dL in the United States (US) and 9.0-12.0 g/dL for non-US. Patients in the incident and prevalent DD-CKD trials had initiated dialysis within &lt;16 weeks with limited or no prior ESA exposure and &gt;12 weeks with established ESA treatment prior to screening, respectively. Vadadustat starting dose was 300 mg/day for all patients, whereas initial darbepoetin alfa dose depended on each patient’s prior dose or product label. Both vadadustat and darbepoetin alfa doses were titrated according to prespecified dosing algorithms to achieve target Hb concentrations (US: 10-11 g/dL; non-US: 10-12 g/dL) during the primary evaluation period (PEP; weeks 24-36) and the secondary evaluation period (SEP; weeks 40-52). Herein, we present topline results from PEP and SEP endpoints, as well as other, more detailed hematologic erythrocyte parameters. Results A total of 3923 patients (369 with incident DD-CKD and 3554 with prevalent DD-CKD) were randomized 1:1 to vadadustat or darbepoetin alfa. Vadadustat was noninferior to darbepoetin alfa in achieving target-range Hb concentrations (primary efficacy endpoint) among patients who were new to, or established on, dialysis. The respective proportions of patients (vadadustat vs. darbepoetin alfa) with an average Hb value within the geography-specific target range in the PEP and SEP were 43.6% versus 56.9% and 39.8% versus 41.0% in the incident trial and 49.2% versus 53.2% and 44.3% versus 50.9% in the prevalent dialysis trial. The proportion of patients who achieved an Hb increase &gt;1.0 g/dL from baseline to week 52 was assessed only for the incident trial and was 84.0% (95% CI: 77.8%, 89.0%) for vadadustat versus 89.9% (95% CI: 84.7%, 93.8%) for darbepoetin alfa. Hematologic erythrocyte parameters at time points within the PEP and SEP are presented in Table 1. In the incident trial, reticulocyte count was slightly increased from baseline at 28 and 52 weeks for vadadustat, whereas for darbepoetin alfa, reticulocyte count was slightly decreased or unchanged in both trials. Erythrocyte mean corpuscular volume and erythrocyte mean corpuscular Hb showed increases by week 52 for both groups. Conclusion Vadadustat demonstrated similar profiles across erythrocyte parameters compared with darbepoetin alfa in the treatment of anemia associated with CKD in adults in both incident dialysis and prevalent dialysis settings.

scholarly journals Long-Term Efficacy and Safety of Molidustat for Anemia in Chronic Kidney Disease: DIALOGUE Extension Studies

2019 ◽  
Vol 49 (4) ◽  
pp. 271-280 ◽  
Author(s):  
Tadao Akizawa ◽  
Iain C. Macdougall ◽  
Jeffrey S. Berns ◽  
Thomas Bernhardt ◽  
Gerald Staedtler ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Hypoxia Inducible Factor ◽  
Efficacy And Safety ◽  
Open Label ◽  
Multicenter Studies ◽  
Parallel Group ◽  
The Mean ◽  
Term Management

Background: Molidustat, a novel hypoxia-inducible factor-prolyl hydroxylase inhibitor, is being investigated for the treatment of anemia associated with chronic kidney disease (CKD). The efficacy and safety of molidustat were recently evaluated in three 16-week phase 2b studies. Here, we report the results of two long-term extension studies of molidustat. Methods: Both studies were parallel-group, open-label, multicenter studies of ≤36 months’ duration, in patients with anemia due to CKD, and included an erythropoiesis-stimulating agent as active control. One study enrolled patients not receiving dialysis (n = 164), and the other enrolled patients receiving hemodialysis (n = 88). The primary efficacy variable for both studies was change in blood hemoglobin (Hb) level from baseline to each post-baseline visit, and safety outcomes included adverse events (AEs). Results: In patients not on dialysis, the mean ± SD Hb concentrations at baseline were 11.28 ± 0.55 g/dL for molidustat and 11.08 ± 0.51 g/dL for darbepoetin. The mean ± SD blood Hb concentrations throughout the study (defined as mean of each patient’s overall study Hb levels) were 11.10 ± 0.508 and 10.98 ± 0.571 g/dL in patients treated with molidustat and darbepoetin, respectively. Similar proportions of patients reported at least one AE in the molidustat (85.6%) and darbepoetin (85.7%) groups. In patients on dialysis, mean ± SD Hb levels at baseline were 10.40 ± 0.70 and 10.52 ± 0.53 g/dL in the molidustat and epoetin groups, respectively. The mean ± SD blood Hb concentrations during the study were 10.37 ± 0.56 g/dL in the molidustat group and 10.52 ± 0.47 g/dL in the epoetin group. Proportions of patients who reported at least one AE were 91.2% in the molidustat group and 93.3% in the epoetin group. Conclusions: Molidustat was well tolerated for up to 36 months and appears to be an effective alternative to darbepoetin and epoetin in the long-term management of anemia associated with CKD.

scholarly journals Safety and Efficacy of Antiviral Therapy of Chronic Hepatitis C in Chronic Kidney Disease and Hemodialysis Patients

2021 ◽  
Vol 3 (1) ◽  
pp. 160-164
Author(s):  
W. Fadili ◽  
A. Ait Errami ◽  
S. Zaoui ◽  
K. Elkassimi ◽  
N. ElBouhi ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Hepatitis C ◽  
Kidney Disease ◽  
Antiviral Therapy ◽  
Treatment Success ◽  
Virologic Response ◽  
Limited Resources ◽  
Maintenance Hemodialysis ◽  
Viral Hepatitis C ◽  
The Mean

Background and Aims: To assess the efficacy and tolerability of sofosbuvir-based antiviral therapy for viral hepatitis C (HCV) patients with chronic kidney disease and on maintenance hemodialysis. Methods: We retrospectively reviewed all treated patients with HCV from January 2015 to November 2020. They were treated either with standard Interferon/Ribavirin or with Sofosbuvir combined to Daclatasvir or to Ledipasvir. We evaluated the sustained virologic response at 12 weeks (SVR12). Data were analyzed using SPSS 20.00. Results: Out of 61 patients, the mean age of our patients was 56,8±12,56 years and 42,6% were males. Six patients had eGFR< 60 ml/mn/1,73 m2 (9,8%) and 26 patients were on maintenance hemodialysis (42,6%). The majority had genotype 1 and overall SVR12 was 70,1% with a rate of 75% in the Sofosbuvir-regimen subgroup. The adverse events were minor. On multivariate analysis, genotype, viral load and rapid virologic response were independent factors that significantly predicted treatment success. Conclusion: Sofosbuvir-based regimen appears to be safe and efficious in patients with chronic kidney disease and on maintenance hemodialysis, especially in countries with limited resources.

scholarly journals Efficacy and Safety of Molidustat for Anemia in ESA-Naive Nondialysis Patients: A Randomized, Phase 3 Trial

2021 ◽  
pp. 1-13
Author(s):  
Hiroyasu Yamamoto ◽  
Kiyoshi Nobori ◽  
Yoshimi Matsuda ◽  
Yasuhiro Hayashi ◽  
Takanori Hayasaki ◽  
...  
Keyword(s):  
Japanese Patients ◽  
Renal Anemia ◽  
Target Range ◽  
Efficacy And Safety ◽  
Open Label ◽  
Phase 3 ◽  
Once Daily ◽  
Evaluation Period ◽  
The Mean ◽  
Change In Mean

<b><i>Introduction:</i></b> Molidustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that predominantly induces renal production of erythropoietin (EPO). Molidustat was evaluated for the treatment of anemia associated with chronic kidney disease (CKD) in the “Molidustat Once Daily Improves Renal Anemia by Inducing EPO” (MIYABI) program, which comprises 5 phase 3 clinical trials. The present MIYABI Non-Dialysis Correction (ND-C) study investigated the efficacy and safety of molidustat in Japanese patients with renal anemia who were not undergoing dialysis and were not receiving erythropoiesis-stimulating agent (ESA) treatment. <b><i>Methods:</i></b> This was a 52-week, randomized (1:1), open-label, active-control, parallel-group, multicenter, phase 3 study in Japanese patients with renal anemia associated with CKD (stages 3–5). Molidustat or the ESA darbepoetin alfa (hereinafter referred to as darbepoetin) were initiated at 25 mg once daily or 30 μg every 2 weeks, respectively, and doses were regularly titrated to correct and to maintain hemoglobin (Hb) levels in the target range of ≥11.0 g/dL and &#x3c;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. <b><i>Results:</i></b> In total, 162 patients were randomized to receive molidustat (<i>n</i> = 82) or darbepoetin (<i>n</i> = 80). Baseline characteristics were generally well balanced between treatment groups. The mean (standard deviation) Hb levels at baseline were 9.84 (0.64) g/dL for molidustat and 10.00 (0.61) g/dL for darbepoetin. The mean (95% confidence interval [CI]) for mean Hb levels during the evaluation period for molidustat (11.28 [11.07, 11.50] g/dL) and darbepoetin (11.70 [11.50, 11.90] g/dL) was within the target range. Based on a noninferiority margin of 1.0 g/dL, molidustat was noninferior to darbepoetin in the change in mean Hb level during the evaluation period from baseline; the least-squares mean (95% CI) difference (molidustat-darbepoetin) was −0.38 (−0.67, −0.08) g/dL. The proportion of patients who reported at least 1 treatment-emergent adverse event (TEAE) was 93.9% for molidustat and 93.7% for darbepoetin. Most TEAEs were mild (54.9% for molidustat and 63.3% for darbepoetin) or moderate (22.0% for molidustat and 22.8% for darbepoetin) in intensity. There were 3 deaths in the molidustat group and 1 in the darbepoetin group. <b><i>Discussion/Conclusion:</i></b> In the MIYABI ND-C study, molidustat appeared to be an efficacious and generally well-tolerated alternative to darbepoetin for the treatment of renal anemia in Japanese patients who were not undergoing dialysis and were not receiving ESA treatment.

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

2021 ◽  
pp. 1-10
Author(s):  
Hiroyasu Yamamoto ◽  
Kiyoshi Nobori ◽  
Yoshimi Matsuda ◽  
Yasuhiro Hayashi ◽  
Takanori Hayasaki ◽  
...  
Keyword(s):  
Japanese Patients ◽  
Renal Anemia ◽  
Target Range ◽  
Open Label ◽  
Phase 3 ◽  
Once Daily ◽  
Evaluation Period ◽  
Erythropoiesis Stimulating Agents ◽  
Previously Treated ◽  
The Mean

<b><i>Introduction:</i></b> 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. <b><i>Methods:</i></b> 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. <b><i>Results:</i></b> In total, 164 patients were randomized to receive molidustat (<i>n</i> = 82) or darbepoetin (<i>n</i> = 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. <b><i>Discussion/Conclusion:</i></b> 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.

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