Molidustat Research Articles

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

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.

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

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.