FO015AKB-6548, A NOVEL HYPOXIA-INDUCIBLE FACTOR PROLYL-HYDROXYLASE INHIBITOR (HIF-PHI) FOR THE TREATMENT OF ANEMIA IN PATIENTS WITH CHRONIC KIDNEY DISEASE NOT ON DIALYSIS (ND-CKD)

Abstract

Introduction and Aims: AKB‐6548 is a novel, once‐daily, oral HIF‐PHI that preferentially stabilizes HIF‐2α. Earlier studies in ND‐CKD patients have shown AKB‐6548 produces physiologic increases in erythropoietin, enhances iron mobilization, and produces a dose dependent increase in hemoglobin (Hb).We now report the results of a Phase 2b trial of AKB‐6548 for the treatment of anemia in ND‐CKD. Methods: A randomized, double‐blind, multi‐center placebo‐controlled study was conducted to assess the efficacy and safety of AKB‐6548 over 20 weeks of dosing in subjects with CKD stages 3‐5 with anemia. 210 subjects were enrolled into one of 3 groups: (1) ESA naïve with Hb ≤10.5 g/dL, (2) previously treated with ESA with Hb ≤10.5 g/dL, or (3) actively treated with ESA with Hb ≥9.5 and ≤12.0 g/dL and randomized 2:1 (132 AKB‐6548 and 78 placebo) to once daily AKB‐6548 (450mg) or placebo. The primary endpoint was the percent of subjects with either a mean Hb of ≥11.0 g/dL or an increase in Hb by ≥1.2 g/dL from baseline. A protocol‐defined dose adjustment algorithm was used to achieve the primary endpoint and to minimize Hb excursions ≥13 g/dL. Subjects could receive ESA or RBC transfusion rescue for worsening anemia. Results: The mean age was 66 years, ∼75% of subjects had diabetes and the mean eGFR was 25 mL/min/1.73m2. 54.9% of AKB‐6548 treated subjects compared to 10.3% of placebo treated subjects met the primary endpoint (p=0.0001). 4.4% of subjects in the AKB 6548 group had a Hb excursion ≥13.0 g/dL vs. 0 in the placebo group. Group 3 placebo treated subjects experienced a decline in the mean Hb within the first 2 weeks, whereas subjects randomized to AKB‐6548 maintained a stable Hb throughout the study, supporting the 450 mg once daily starting dose for patients converting from ESAs to AKB‐6548. Increases in Hb in the AKB‐6548 group were associated with an increase in reticulocytes and TIBC, and a decrease in serum hepcidin and ferritin. AKB‐6548 was generally well tolerated and adverse events were balanced between treatment groups (74.6% vs. 73.6%). Serious adverse events occurred in 23.9% and 15.3% of the AKB‐6548 and placebo treated subjects, respectively, with the most common being renal‐related. The initiation of dialysis was similar between treatment groups (AKB‐6548 8.0% vs. placebo 9.7%). 3 vs. 0 deaths occurred in AKB‐6548 and placebo treated subjects, respectively. Conclusions: AKB‐6548, a novel HIF‐PHI being developed for the treatment of anemia of CKD, achieved the desired outcomes of raising and maintaining Hb, while minimizing Hb excursions ≥13 g/dL, and increasing iron mobilization. The results of this Phase 2b study support advancement into Phase 3 to further evaluate the efficacy and safety of AKB‐6548 for the treatment of anemia in ND‐CKD patients.