MP418VADADUSTAT DOES NOT PROLONG CORRECTED QT INTERVAL IN A THOROUGH QTC STUDY IN HEALTHY SUBJECTS

Abstract

INTRODUCTION AND AIMS: Vadadustat is a hypoxia‐inducible factor prolylhydroxylase inhibitor under investigation for the treatment of anemia associated with chronic kidney disease (CKD). Regulatory guidance ICH E14 recommends assessing the proarrhythmic potential of new clinical entities by thorough electrocardiographic (ECG) assessment of QT interval. Patients with CKD are at high risk of arrhythmic cardiovascular events, frequently exhibit cardiac repolarization abnormalities, and are exposed to electrolyte shifts. Arrhythmic risk is particularly high in patients with endstage renal disease treated with hemodialysis. Preclinical studies have shown no effect of vadadustat on QT interval. Here, the effect of vadadustat on cardiac repolarization was assessed in a thorough QT study in healthy human subjects (NCT02062203). METHODS: In this single‐center, randomized, placebo‐ and active‐controlled, fourperiod crossover study, 50 healthy adults received a single oral dose of vadadustat (600 mg or 1200 mg) or placebo in a blinded fashion or an open‐label oral dose of moxifloxacin 400 mg (positive control). All doses were administered under fasting conditions. All subjects were in normal sinus rhythm. Twelve‐lead ECGs were extracted from continuous recordings at baseline (predose) and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours postdose. Blood samples were collected for pharmacokinetic assessments following ECG extractions. Cardiac repolarization was assessed from QT interval corrected for heart rate with Fridericia's formula (QTcF); change from baseline QTcF (DQTcF) was analyzed with a linear mixed‐effects model. The primary endpoint was the placeboadjusted DQTcF (DDQTcF). Other analyses included assessment of DDQTcF using exposure‐response relationship, QTcF and DQTcF outliers, vadadustat pharmacokinetics, and adverse events (AEs). RESULTS: Of 50 subjects enrolled (mean age 38.5 years; 52% female), 47 completed the study. The maximum mean DDQTcF was 1.2 ms (two‐sided 90% confidence interval [CI]: ≥1.2 to 3.5) at 24 hours after dosing with vadadustat 600 mg and 3.3 ms (two‐sided 90% CI: 1.0‐5.7) at 8 hours after dosing with vadadustat 1200 mg. Concentration‐QTc analysis similarly demonstrated a small DDQTcF within the studied range of plasma concentrations of vadadustat, with the upper bound of the two‐sided 90% CI clearly below 10 ms. The slope of the relationship between plasma concentration of vadadustat and DDQTcF was 0.0233 ms/lg/mL (two‐sided 90% CI: 0.004‐0.043). No subjects with QTcF >460 ms or DQTcF >30 ms were observed in the vadadustat groups. Assay sensitivity was demonstrated by post‐moxifloxacin DDQTcF >10 ms with the lower bound of the two‐sided 90% CI >5 ms at all 3 predefined time points (2, 3, and 4 hours; maximum mean [SE] DDQTcF: 13.1 [1.1] ms at 3 hours). At least 1 AE was reported in 23 (46%) subjects; all AEs were mild. The most common (≥5%) AEs in the vadadustat groups were nausea, diarrhea, abdominal pain, and headache. There were no deaths or serious AEs. CONCLUSIONS: Consistent with preclinical studies, single oral therapeutic (600 mg) and supratherapeutic (1200 mg) doses of vadadustat did not significantly affect cardiac repolarization in healthy subjects.