SP309SAFETY AND EFFICACY OF MOLIDUSTAT IN ERYTHROPOIESIS STIMULATING AGENTS (ESA) PRE-TREATED ANAEMIC PATIENTS WITH CHRONIC KIDNEY DISEASE NOT ON DIALYSIS (CKD-ND)

Abstract

Introduction and Aims: Molidustat is a novel, oral hypoxia‐inducible factor prolyl‐hydroxylase inhibitor (HIF‐PHI) which is in development for the treatment of CKD anaemia. This randomized, open‐label, active comparator controlled phase 2b study investigated the efficacy and safety of once daily administration of titrated dosages of molidustat in anaemic CKD‐ND patients already on darbepoetin treatment. Methods: 124 stage 3‐5 CKD‐ND subjects with Hb 9.0 ‐ 12.0 g/dL on stable darbepoetin treatment and adequate iron status (transferrin saturation ≥20% or ferritin level ≥ 100 μg/L) were equally randomized to 3 fixed starting dosages of molidustat (25, 50 or 75 mg) or darbepoetin for 16 weeks. Dosages were adjusted based on the subject's Hb and tolerability of the prior dose at weeks 4, 8 and 12. Planned molidustat doses included 15, 25, 50, 75, 100, and 150 mg. The mean Hb in evaluation period (week 12 to 16) was compared to baseline. Results: 92 patients were randomized to molidustat and 32 to darbepoetin. 78.3% of subjects on molidustat (by starting dose: 25mg: 70%, 50mg: 83.3% and 75mg: 81.3%) and 84.4% of subjects on darbepoetin completed the 16 week trial period. Mean Hb at baseline was 10.75 g/dL (+/‐ 0.72 g/dL SD) in molidustat treated subjects and 10.85 g/dL (+/‐ 0.68 g/dL SD) in darbepoetin treated subjects. Mean change in Hb to evaluation period was in molidustat groups +0.46 g/dL (+/‐ 0.9 g/dL SD) and +0.18 g/dL (+/‐ 0.78 g/ dL SD) on darbepoetin. One patient on darbepoetin received rescue treatment with red blood cell transfusion being due to worsening anaemia. Treatment emergent adverse events (TEAE) were reported in 69.6% of molidustat treated subjects and in 53.1% of subjects on darbepoetin. Most frequent TEAEs on molidustat and darbepoetin were infections (18.5% and 21.9%, respectively) and vascular disorders (20.7 and 15.6%, respectively). Serious TEAEs (TESAE) occurred in 20.7% and 18.8% of molidustat and darbepoetin treated subjects, respectively. Most frequent TESAEs were renal and urinary disorders (9.8% on molidustat and 3.1% on darbepoetin) and infections (2.2% on molidustat and 9.4% on darbepoetin). There was no significant difference in decline of kidney function between both treatment groups as assessed by eGFR. There were 2 deaths (1 on each treatment) and 1 stroke (on darbepoetin), but no myocardial infarction, unstable angina, deep vein thrombosis or pulmonary embolism were reported. Conclusions: Molidustat was generally well‐tolerated and maintained CKD‐ND patients in the Hb target range after switching from stable darbepoetin pre‐treatment. Rates and origin of TESAEs were consistent with events described in a non‐dialysis CKD patient population. The results support the further development of molidustat for the treatment of renal anaemia.