Molidustat for Japanese Patients With Renal Anemia Receiving Dialysis

Abstract

Introduction: Molidustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor for renal anemia treatment, was evaluated in 5 phase 3 studies (MIYABI program). We report the results of the MIYABI hemodialysis-maintenance study.

Methods: This 52-week, randomized, double-blinded, double-dummy study compared the efficacy and safety of molidustat and darbepoetin in Japanese patients receiving hemodialysis and erythropoiesis-stimulating agents. Molidustat (starting dose: 75 mg/day) and darbepoetin were titrated to maintain hemoglobin (Hb) levels in the target range (≥10.0 and <12.0 g/dl). Primary outcomes were mean Hb level during the evaluation period (weeks 33-36) and its change from baseline. Safety outcomes included adverse events.

Results: Overall, 229 patients were randomized (molidustat, n = 153; darbepoetin, n = 76). Baseline characteristics were well balanced. Mean baseline Hb level was 10.8 g/dl. Mean (95% confidence interval [CI]) for mean Hb levels during the evaluation period were within the target range in both groups (molidustat: 10.63 [10.42-10.84] g/dl; darbepoetin: 10.77 [10.59-10.95] g/dl). Least-squares mean (95% CI) change in mean Hb level during the evaluation period from baseline was -0.14 (-0.37 to 0.09) g/dl for molidustat and -0.07 (-0.30 to 0.16) g/dl for darbepoetin; molidustat was noninferior to darbepoetin (least-squares mean difference [95% CI] [molidustat-darbepoetin]: -0.13 [-0.46 to 0.19] g/dl), based on a noninferiority margin of 1.0 g/dl. In line with published literature, and as expected in this patient population, most participants had ≥1 treatment-emergent adverse event.

Conclusion: Molidustat maintained Hb levels throughout the trial in patients receiving dialysis and previously treated with erythropoiesis-stimulating agents, and was noninferior to darbepoetin.

Keywords: darbepoetin alfa; dialysis; erythropoiesis-stimulating agent; hypoxia-inducible factor prolyl hydroxylase inhibitor; molidustat; renal anemia.

Graphical abstract

Figure 1

Study design. EOF, end of follow-up; EOT, end of treatment; ESA, erythropoiesis-stimulating agent; W, week.

Figure 2

Patient disposition. Screening failure: terminated the study before randomization (for any reason). Completed study: completed both treatments up to week 52 and follow-up.

Figure 3

Mean central Hb levels by visit (full analysis set) during the evaluation period (a) and during the overall treatment period (b). BL, baseline; Hb, hemoglobin.

Figure 4

Mean central Hb levels by visit stratified by previous ESA treatment: (a) darbepoetin alfa, (b) epoetin beta pegol, or (c) epoetin alfa or beta. BL, baseline; ESA, erythropoiesis-stimulating agent; Hb, hemoglobin. BL Hb level is defined as the mean of all Hb levels during the screening period and Hb level at week 0. The number of patients treated with epoetin beta pegol was smaller than that receiving other ESAs, which might have resulted accidentally in bias. (a) At baseline: n = 86 for molidustat and n = 35 for darbepoetin. (b) At baseline: n = 19 for molidustat and n = 9 for darbepoetin. (c) At baseline: n = 48 for molidustat and n = 32 for darbepoetin.

Figure 5

Subgroup analysis of the difference (molidustat – darbepoetin) of changes in mean (95% CI) central Hb level (g/dl) during the evaluation period from baseline (full analysis set). ANCOVA, analysis of covariance; CI, confidence interval; CKD, chronic kidney disease; ESA, erythropoiesis-stimulating agent; Hb, hemoglobin; IxRS, interactive voice/web response system. For the overall population, least-squares mean difference (95% CI) was estimated using ANCOVA. The between-group difference in the response variable (i.e. change from baseline in mean Hb level during the evaluation period) with 2-sided 95% CI was estimated using ANCOVA with treatment group, previous thromboembolic events recorded in IxRS, previous ESA dose group (low/high) recorded in IxRS as fixed effect and baseline central Hb level as covariate. For each subgroup, the 2-sided 95% CI was estimated using t statistics.

Figure 6

Mean (SD) dosage of (a) molidustat and (b) darbepoetin alfa at each visit (full analysis set).