FP660PHARMACOKINETICS AND PHARMACODYNAMICS OF LEXAPTEPID, A NOVEL ANTI-HEPCIDIN MOLECULE, IN ESA-RESISTANT HAEMODIALYSIS PATIENTS

Abstract

Introduction and Aims: Hepcidin levels are known to be grossly elevated in haemodialysis patients, and this contributes to ESA‐resistant anaemia. Inhibiting hepcidin may therefore improve resistance to ESA therapy and anaemia. We therefore studied the pharmacokinetics (PK) and pharmacodynamics of lexaptepid, a novel anti‐hepcidin L‐RNA aptamer (Spiegelmer®), in a small cohort of chronic haemodialysis patients with ESA‐resistant anaemia. Methods: This was a single‐blind, placebo‐controlled crossover trial with a single intravenous dose of both lexaptepid (1.2 mg/kg) and placebo at the end of a routine dialysis session, with a 1‐week washout period. Blood samples were taken at 3, 6, 9, 12, 18, and 24 hours post‐dosing, and then at 2, 4, 7, 14, and 28 days, for measurement of lexaptepid levels, hepcidin, iron, TIBC, ferritin, TSAT, Hb, RBC, MCH, retics, CHr, % HRC, and sTfR. Safety and adverse events were recorded. Results: Nine patients, 3 M; 6 F, mean age 58 ± 10 (SD) years, were enrolled. Eight patients completed the study as scheduled; one patient, who discontinued early for an unrelated adverse event, was replaced. Compared to healthy subjects, the dialysis patients in this study showed a similar early elimination until about 8 to 12 h post‐dose (t1/2α 4.9 vs. 4.1 h) but an approximately 2‐fold higher terminal elimination half‐life (t1/2β 52.0 vs. 22.4 h) and a systemic clearance reduced by half. This resulted in a 2‐times higher systemic exposure for the dialysis patients compared to healthy subjects (AUC0‐96: 55.6 vs. 29.5 h). The simulation of these data to repeated, twice‐weekly administrations indicates that Cmax in dialysis patients should not exceed Cmax in healthy subjects (Table). Baseline serum iron levels were similar prior to placebo (7.7±2.5 μM) and lexaptepid administration (7.4±2.5 μM). Three hours after lexaptepid administration, serum iron started to increase, reaching peak levels at 12 hours that were 69% higher than baseline; no significant changes were evident following placebo injection (Figure). There were no treatment‐related adverse events or other safety concerns in this study. Conclusions: This study is the first to examine an anti‐hepcidin strategy in haemodialysis patients. The PK data suggest that the elimination of lexaptepid is slower than in healthy controls, but dose adjustments may not be necessary for repeated administration. Compared to placebo, there were significant increases in serum iron concentrations following lexaptepid administration, consistent with its anti‐hepcidin action. This molecule merits further assessment in ESA‐resistant anaemia. (Figure Presented).