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.

MO542MOLIDUSTAT FOR ANAEMIA IN JAPANESE PATIENTS UNDERGOING PERITONEAL DIALYSIS: A SINGLE ARM, OPEN-LABEL, PHASE 3 STUDY

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Tadao Akizawa ◽  
Kiyoshi Nobori ◽  
Yoshimi Matsuda ◽  
Kentaro Taki ◽  
Yasuhiro Hayashi ◽  
...  
Keyword(s):  
Peritoneal Dialysis ◽  
Japanese Patients ◽  
Target Range ◽  
Renal Anaemia ◽  
Open Label ◽  
Phase 3 ◽  
Once Daily ◽  
Evaluation Period ◽  
Maintenance Haemodialysis ◽  
Rescue Treatment

Abstract Background and Aims Erythropoiesis-stimulating agents (ESA) are the standard of care for anaemia due to chronic kidney disease (renal anaemia). Molidustat, a novel hypoxia-inducible factor prolyl hydroxylase (HIF–PH) inhibitor for the treatment of renal anaemia, could offer an alternative to ESAs. Molidustat was evaluated in the “molidustat once daily improves renal anaemia by inducing erythropoietin (MIYABI) program”, comprising five phase 3 studies. The present study investigated the safety and efficacy of molidustat in Japanese patients with renal anaemia undergoing peritoneal dialysis (PD) and previously treated with ESAs or not. Method This was a 36-week, open-label, single-arm, phase 3 study in Japanese patients ≥20 years with renal anaemia undergoing PD and not expected to start maintenance haemodialysis. Molidustat was administered once daily at a starting dose of 75 mg. Doses were titrated every 4 weeks based on the patient’s haemoglobin (Hb) response to the previous dose during visits to maintain the Hb level within the target range of ≥ 11.0 g/dL to &lt; 13.0 g/dL (Japanese guidelines). The primary efficacy outcome was the responder rate, defined as the proportion of patients who meet all of the following criteria: (1) mean Hb level during the evaluation period in the target range from week 30 to week 36; (2) ≥50% of Hb values within the target range during the evaluation period; (3) no rescue treatment before the end of the evaluation period. Other outcomes included mean Hb level during the evaluation period and its change from baseline, Hb level at each visit and the number of treatment-emergent adverse events (TEAEs). Results Overall, 51 patients received molidustat (49 ESA-treated; 2 ESA-untreated) and 36 (70.6%) completed treatment. Mean age was 63.3 years, mean body weight was 62.4 kg and 62.7% were male. Mean baseline Hb level was 11.19 g/dL and mean duration of peritoneal dialysis was 2.8 years. Over the study period, mean treatment duration was 200.8 days with a mean dosage of 93.8 mg/day. The responder rate (95% confidence interval [CI]) during the evaluation period was 54.9% (40.3, 68.9). The proportions of patients meeting criterion (1), (2) or (3) were 54.9%, 58.8% and 92.2%, respectively. The mean (95% CI) for mean Hb level during the evaluation period was 11.18 (10.83, 11.54) g/dL and the mean (95% CI) for the change in mean Hb level during the evaluation period from baseline was 0.00 (–0.41, 0.41) g/dL. Mean Hb level stayed in the target range from week 12–36. Of the 15 patients who did not complete treatment, 9 discontinued because of a TEAE, 4 initiated rescue treatment and 2 progressed to maintenance haemodialysis. Overall, 98.0% of patients experienced ≥1 TEAE during the study; most TEAEs were mild (49.0%) or moderate (37.3%) in intensity. The most common TEAEs were nasopharyngitis (35.3%), constipation and medical device site infection (11.8% each). No deaths were reported, and major adverse cardiovascular events occurred in 2.0% of patients. Conclusion In this phase 3, single-arm, open-label study, over 70% of patients completed the study and more than half of the patients met the responder criteria. Molidustat maintained Hb in the prespecified range (≥ 11.0 g/dL to &lt; 13.0 g/dL) and was well-tolerated over the 36 weeks of treatment. Molidustat offers a potential alternative to ESAs in patients with renal anaemia undergoing PD.

scholarly journals P1868TO INVESTIGATE THE EFFICACY AND SAFETY OF MOLIDUSTAT IN NON-DIALYSIS PATIENTS WITH RENAL ANEMIA WHO ARE TREATED WITH ERYTHROPOIESIS-STIMULATING AGENTS: MIYABI ND-M

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

Abstract Background and Aims Treatment with subcutaneous erythropoiesis-stimulating agent (ESA) is the standard of care for renal anemia in non-dialysis patients. A hypoxia-inducible factor prolyl-hydroxylase (HF-PH) inhibitor is an oral medication and might be a new treatment option of renal anemia. Molidustat mimics the physiological response to hypoxia, thereby stimulating endogenous EPO production by the kidneys. The phase III program entitled MolIdustat once dailY improves renal Anemia By Inducing EPO (MIYABI) was conducted in Japan. Method MIYABI Non-Dialysis- Maintenance (ND-M) 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 treated with ESAs. A starting dose was in accordance with previous ESA dose and study drug doses were titrated regularly with the aim of 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 1.0 g/dL. Safety variables included adverse events. Prespecified primary analysis results up to 36 weeks are presented here. Results 82 patients were treated with MO, starting doses were 25 mg for 27 patients and 50 mg in 55 patients. 82 patients were treated with DA, starting doses were in accordance with previous ESA dose and interval. The mean of baseline Hb values were 11.31 g/dL and 11.27 g/dL in the MO and DA group, respectively. For the mean Hb values during the evaluation period in MO, the mean was 11.67 g/dL (95%CI; 11.48, 11.85) and the mean Hb values of 66 patients (80.5%) were within the target range. As the primary efficacy variables (the changes from baseline of mean Hb values during the evaluation period), the means were 0.35 g/dL (95%CI; 0.12, 0.58) and 0.26 g/dL (95%CI; 0.04, 0.48) in the MO and DA group, respectively. The LS mean difference was 0.13 (95%CI; -0.15, 0.40), therefore the non-inferiority of MO to DA was established. The mean (SD) doses during the study period were 52.16 (32.58) mg/day of MO and 21.33 (12.33) μg/week of DA. AEs were experienced in 87.8% of patients in the MO group and 89.0% of patients in the DA group up to 36 weeks. The most common AEs occurred ≥ 5% of patients in any group were nasopharyngitis (29.3% and 30.5%, respectively) and worsening of chronic kidney disease (12.2% and 7.3%, respectively). Conclusion 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 anemia treated with ESAs. The MO showed no new safety concern but further longitudinal investigation will be needed.

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.

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 Efficacy and safety of secukinumab in Japanese patients with active ankylosing spondylitis: 24-week results from an open-label phase 3 study (MEASURE 2-J)

2019 ◽  
Vol 30 (1) ◽  
pp. 132-140 ◽  
Author(s):  
Mitsumasa Kishimoto ◽  
Atsuo Taniguchi ◽  
Ayako Fujishige ◽  
Shuhei Kaneko ◽  
Sibylle Haemmerle ◽  
...  
Keyword(s):  
Ankylosing Spondylitis ◽  
Japanese Patients ◽  
Efficacy And Safety ◽  
Open Label ◽  
Phase 3 ◽  
Open Label Phase

scholarly journals Efficacy and safety of sofosbuvir–velpatasvir with or without ribavirin in HCV-infected Japanese patients with decompensated cirrhosis: an open-label phase 3 trial

2018 ◽  
Vol 54 (1) ◽  
pp. 87-95 ◽  
Author(s):  
Tetsuo Takehara ◽  
Naoya Sakamoto ◽  
Shuhei Nishiguchi ◽  
Fusao Ikeda ◽  
Tomohide Tatsumi ◽  
...  
Keyword(s):  
Japanese Patients ◽  
Decompensated Cirrhosis ◽  
Efficacy And Safety ◽  
Open Label ◽  
Phase 3 ◽  
Open Label Phase

scholarly journals Effects of Molidustat in the Treatment of Anemia in CKD

2018 ◽  
Vol 14 (1) ◽  
pp. 28-39 ◽  
Author(s):  
Iain C. Macdougall ◽  
Tadao Akizawa ◽  
Jeffrey S. Berns ◽  
Thomas Bernhardt ◽  
Thilo Krueger
Keyword(s):  
Oral Treatment ◽  
Hypoxia Inducible Factor ◽  
Mean Value ◽  
Fixed Dose ◽  
Target Range ◽  
Efficacy And Safety ◽  
Open Label ◽  
Once Daily ◽  
Endogenous Erythropoietin ◽  
Dose Trial

Background and objectivesThe efficacy and safety of molidustat, a hypoxia-inducible factor-prolyl hydroxylase inhibitor, have been evaluated in three 16-week, phase 2b studies in patients with CKD and anemia who are not on dialysis (DaIly orAL treatment increasing endOGenoUs Erythropoietin [DIALOGUE] 1 and 2) and in those who are on dialysis (DIALOGUE 4).Design, setting, participants, & measurementsDIALOGUE 1 was a placebo-controlled, fixed-dose trial (25, 50, and 75 mg once daily; 25 and 50 mg twice daily). DIALOGUE 2 and 4 were open-label, variable-dose trials, in which treatment was switched from darbepoetin (DIAGLOGUE 2) or epoetin (DIALOGUE 4) to molidustat or continued with the original agents. Starting molidustat ranged between 25–75 and 25–150 mg daily in DIAGLOGUE 2 and 4, respectively, and could be titrated to maintain hemoglobin levels within predefined target ranges. The primary end point was the change in hemoglobin level between baseline and the mean value from the last 4 weeks of the treatment period.ResultsIn DIAGLOGUE 1 (n=121), molidustat treatment was associated with estimated increases in mean hemoglobin levels of 1.4–2.0 g/dl. In DIAGLOGUE 2 (n=124), hemoglobin levels were maintained within the target range after switching to molidustat, with an estimated difference in mean change in hemoglobin levels between molidustat and darbepoetin treatments of up to 0.6 g/dl. In DIAGLOGUE 4 (n=199), hemoglobin levels were maintained within the target range after switching to molidustat 75 and 150 mg, with estimated differences in mean change between molidustat and epoetin treatment of −0.1 and 0.4 g/dl. Molidustat was generally well tolerated, and most adverse events were mild or moderate in severity.ConclusionsThe overall phase 2 efficacy and safety profile of molidustat in patients with CKD and anemia enables the progression of its development into phase 3.

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