Evaluation of Rusfertide, a Hepcidin Mimetic, on Cardiac Repolarization: A Randomized, Placebo- and Positive-Controlled Crossover Thorough QT Study in Healthy Participants

PURPOSE: Rusfertide, a hepcidin mimetic, is in clinical development for the treatment of polycythemia vera. This study evaluated the effect of rusfertide on cardiac repolarization. METHODS: A positive-controlled, randomized, double-blind, crossover study was conducted in healthy adults. Subjects received subcutaneous rusfertide 90 mg, matching subcutaneous placebo, and oral moxifloxacin. Subjects underwent continuous 12-lead Holter recording during each period. A central laboratory extracted up to 10 replicate electrocardiograms (ECGs) at each time point prior to and following treatment, paired with pharmacokinetic sampling. The primary analysis for Fridericia corrected QT interval (QTcF) was a mixed model for repeated measures with change from baseline QTcF (ΔQTcF) as the dependent variable; period, sequence, time, treatment, and time-by-treatment interaction as fixed effects; and baseline QTcF as a covariate. The relationship between rusfertide and metabolite concentrations and change-from-baseline QTcF was quantified using linear mixed-effects modeling. FINDINGS: was 0.04 ms (90% CI: -1.21 to 1.29). Overall, 24 of 60 subjects (40.0%) experienced treatment-emergent adverse events (TEAEs). All TEAEs were mild. TEAEs noted in ≥5% subjects were headache, nausea, injection site erythema, injection site pain, and influenza-like illness. There were no clinically significant changes in clinical laboratory, vital signs, ECG, or physical examination findings. IMPLICATIONS: Rusfertide had no clinically relevant effect on HR, cardiac conduction, or QTc. Rusfertide was well tolerated. An effect on ΔΔQTcF exceeding 10 ms could be excluded within the observed rusfertide plasma concentrations up to approximately 2130 ng/mL.