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 -0.1 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.

Keywords: Darbepoetin alfa; EPO protein; Epoetin Alfa; Humans; Prolyl Hydroxylases; Prolyl-Hydroxylase Inhibitors; Pyrazoles; Renal Insufficiency, Chronic; Triazoles; anemia; chronic kidney disease; erythropoietin; hemoglobin; human; hypoxia; molidustat; renal dialysis.

Graphical abstract

Figure 1.

Patient disposition. mITT, modified intention-to-treat set; SAF, safety analysis set.

Figure 1.

Patient disposition. mITT, modified intention-to-treat set; SAF, safety analysis set.

Figure 1.

Patient disposition. mITT, modified intention-to-treat set; SAF, safety analysis set.

Figure 2.

Molidustat was able to correct (DIALOGUE 1) and maintain Hb levels within a pre-specified range (DIALOGUE 2 and 4 [75 and 150 mg starting dose groups only]). Observed case data from modified intention-to-treat populations. Baseline was defined as the average of all values before dosing with the first study agent. Dashed lines indicate target ranges. In DIALOGUE 2 and DIALOGUE 4, the doses of all drugs could be titrated up or down in a stepwise manner to maintain hemoglobin levels within predefined target ranges. Error bars indicate SEM. Bsl, baseline; Eva, evaluation period; Hb, hemoglobin.