Effects of Molidustat in the Treatment of Anemia in CKD

Abstract

Background and objectives The 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, & measurements DIALOGUE 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. Results In 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 20.1 and 0.4 g/dl. Molidustat was generally well tolerated, and most adverse events were mild or moderate in severity. Conclusions The overall phase 2 efficacy and safety profile of molidustat in patients with CKD and anemia enables the progression of its development into phase 3.

The Influence of Inflammation on Anemia in CKD Patients

“…Despite the level of kidney function impairment and disturbed hepatic erythropoietin production in included patients, molidustat mainly addresses kidney erythropoietin production [121]. 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].…”

“…Molidustat is another potential alternative to the standard treatment of anemia associated with CKD as it increases erythropoietin production and improves iron availability. 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

“…Molidustat is a HIF-PH inhibitor currently in phase 3 of clinical development for the treatment of anaemia in patients with CKD. Its efficacy and safety profiles were evaluated in the DIALOGUE phase 2 clinical trial programme [10]. Given that common concomitant medication in patients with CKD includes iron and calcium supplementations for anaemia [5], the potential for DDI between molidustat and iron or calcium supplements was investigated.…”

“…In DIALOGUEs 2 and 4, molidustat was given as individual dose titration based on Hb values (starting doses ranged between 25-75 mg and 25-150 mg once daily in DIAGLOGUE 2 and 4, respectively). Molidustat treatment was generally well tolerated and corrected and maintained Hb levels within a pre-specified range in patients previously treated with ESAs and in treatment-naïve patients [10]. In healthy volunteers, molidustat was shown to be rapidly absorbed with a maximum plasma concentration of 1 h after drug intake and to elicit dosedependent increases in endogenous EPO after single increasing doses [12].…”

“…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).…”