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

Abstract

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.

The Influence of Inflammation on Anemia in CKD Patients

“…In this study, patients treated with molidustat starting doses of 75 or 150 mg once daily had lower response rates, spent less time within the target hemoglobin range, and were more likely to have hemoglobin levels above the pre-specified limit in comparison to epoetin group [120,121]. Therefore, it seems that molidustat is an effective alternative to rhEPO and its analogs in the long-term management of anemia associated with CKD [122].…”

“…This HIF-PH inhibitor mimics hypoxia by stabilizing HIF-α subunits and it shows high relative selectivity for the induction of EPO gene expression, predominately in the kidney [120,121]. Molidustat enables the accumulation of HIF, which is then transported to the nucleus where it promotes the transcription of EPO and other hypoxia-inducible genes and thus leading to the elevation of endogenous EPO levels [122].…”

Effects of oral iron and calcium supplement on the pharmacokinetics and pharmacodynamics of molidustat: an oral HIF–PH inhibitor for the treatment of renal anaemia

“…relative percentage changes between -20% and + 25%) recommended by the FDA and the EMA guidelines to claim no interaction [15,16]. However, based on previous data, molidustat was well tolerated over a wide dose range (5-200 mg) and is dosed in phase 2 and 3 based on individual response [10,11]. Consequently, it has been recommended that the intake of oral iron and molidustat should be separated by at least 1 h in the phase 3 clinical trials, which are currently ongoing.…”

“…Molidustat is an orally bioavailable HIF-PH inhibitor being investigated in phase 3 clinical trials in patients with renal anaemia, including patients receiving dialysis treatment [8,9]. The phase 2 DIALOGUE (DaIly orAL treatment increasing endOGenoUs Erythropoietin) programme, which included three studies with a 16week treatment duration and two extension studies, assessed the safety and efficacy of molidustat in different populations of patients with renal anaemia [10,11]. DIALOGUE 1 was a placebo-controlled, fixed-dose trial (25, 50, and 75 mg once daily; 25 and 50 mg twice daily).…”

Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors in Patients with Renal Anemia: A Meta-Analysis of Randomized Trials

“…Group 1 (G1) included patients who went ≥12 weeks without receiving rhEPO, while group 2 (G2) included patients with stable ESA treatment for ≥8 weeks. DIALOGUE studies on molidustat, conducted by Akizawa et al [17, 18], included 3 trials of 3 kinds of people and 2 extensive trials. DIALOGUE 1 (D1) included patients with nondialysis-dependent chronic kidney disease (NDD-CKD) who were not previously treated with ESAs.…”