Multiple-Dose Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Subcutaneous Rusfertide, a Hepcidin Mimetic, in Healthy Subjects.

Abstract

Rusfertide, a peptide hepcidin mimetic, has shown efficacy in polycythemia vera. This trial investigated the multiple-dose pharmacokinetics, pharmacodynamics, and safety of once-weekly rusfertide 60 mg for 5 weeks in healthy subjects. Subjects were randomized to subcutaneous injection in the abdomen, upper arm, or thigh. Eighteen subjects were enrolled, and 15 completed the study. Geometric mean peak rusfertide plasma concentrations (C_max) following the first dose were 547, 387, and 560 ng/mL following injection in the abdomen, thigh, and arm, respectively (P = .0054). There was no difference between injection sites in the rusfertide area under the plasma concentration-time curve (AUC) following the first dose (P ≥ .179) or in the C_max or AUC during the dosing interval following the last dose (P ≥ .238). Geometric mean accumulation (Dose 5/Dose 1) for AUC and C_max was 1.5 and 1.2, respectively, and similar across injection sites. Mechanism-based decreases in serum iron, transferrin-iron saturation, hemoglobin, and hematocrit were noted following multiple doses. There were no differences between injection sites in the pharmacodynamic effect as measured by change from baseline in hematocrit values. There were no serious adverse events. Treatment-emergent adverse events in 2 or more subjects were injection-site reactions (erythema, induration, pruritus), fatigue, and headache. There were no clinically relevant findings in the safety laboratory parameters, vital signs, electrocardiograms, or physical examination. While a higher incidence of treatment-emergent adverse events was noted in these healthy participants following multiple doses of 60 mg, rusfertide was generally well tolerated. There were no clinically meaningful differences in rusfertide pharmacokinetics or pharmacodynamics between injection sites.