064: A Phase 1b, Randomized, Open-Label Study to Evaluate the Pharmacokinetics, Pharmacodynamics & Safety of Vadadustat in Hemodialysis Patients With Anemia Associated With Chronic Kidney Disease

Statement of Purpose: Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor in late-stage development for the treatment of anemia associated with chronic kidney disease (CKD). It is approved in Japan for the treatment of patients with non–dialysis-dependent CKD and dialysis-dependent CKD (DD-CKD) it is under regulatory review in the US and EU. Vadadustat is administered once daily at a recommended starting dose of 300 mg, with dose titration (150-600 mg) to maintain hemoglobin in target range. The purpose of this study was to assess the pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability of higher daily doses of vadadustat (600, 750 and 900 mg) in patients with DD-CKD anemia. An active control group maintained existing treatment with intravenous (IV) darbepoetin alfa or epoetin alfa.

Description of Methods & Materials: This was a Phase 1b, randomized, open-label, active-control study. Patients with DD-CKD received fixed-dose daily treatment with vadadustat for 10 days or the active erythropoiesis-stimulating agent (ESA) comparator. Eligible patients (N=44) were randomized in a 2:2:2:1 ratio to vadadustat 600, 750 or 900 mg once daily or IV ESA (darbepoetin alfa, n=1; epoetin alfa, n=6), respectively. For patients randomized to vadadustat, study duration also included a minimum 5-day (epoetin alfa) or 9-day (darbepoetin alfa) ESA washout period prior to dosing on Day 1. Blood samples for the vadadustat and ESA groups were collected at different time points for PK and PD and exploratory biomarker analyses on Days 1 and 8.

Data & Results: There was a dose-proportional increase in vadadustat exposure as well as a 1.39- to 1.84-fold increase in vadadustat AUC, on Day 8 relative to Day 1. The median T_max ranged between 2.0 to 3.0 hours and the mean elimination half-life ranged from 9.9 to 12.6 h on Day 1 across all doses with no apparent trend vs dose. There was a dose-related increase in endogenous erythropoietin (EPO) concentration on Day 1 and Day 8; the maximum observed EPO concentration ranged from 53.3 to 115 mIU/mL on Day 1. All vadadustat dose groups showed an approximately 2-fold increase in mean reticulocyte count starting on Day 5, which continued to rise through the final on-treatment assessment on Day 10. Mean hemoglobin levels did not increase in any treatment group over the 10-day treatment period, which was expected given the short treatment duration. Vadadustat oral administration at these elevated doses was generally well tolerated, and the frequency of treatment-emergent adverse events was comparable across the 3 vadadustat dose groups.

Interpretation, Conclusion or Significance: This study investigated elevated doses of vadadustat in the target patient population (DD-CKD). Overall, vadadustat exhibited dose-proportional PK across all doses and induced a dose-related increase in EPO concentration, which was consistent to previous studies These results characterized exposure, biomarker response, and safety of vadadustat at doses of 600, 750 and 900 mg, contributing to the design of modified dosing regimens for further investigation in Phase 3.

Disclosures: PNG, DW and KD are all employees of Akebia Therapeutics Inc, and may hold stock in the company.