First‐in‐human study with ACT‐1014‐6470, a novel oral complement factor 5a receptor 1 (C5aR1) antagonist, supported by pharmacokinetic predictions from animals to patients

Aberrantly controlled activation of the complement system contributes to inflammatory diseases. Safety, tolerability, and pharmacokinetics of single‐ascending doses of ACT‐1014‐6470, a novel orally available complement factor 5a receptor 1 antagonist, were assessed in a randomized, double‐blind, placebo‐controlled Phase 1 study. Six ACT‐1014‐6470 doses (0.5–200 mg) were selected after predictions from a Complex Dedrick plot. In each group, ACT‐1014‐6470 or matching placebo was administered to six and two healthy male individuals under fed conditions, respectively, including a cross‐over part with 10 mg administered also under fasted conditions. Pharmacokinetic blood sampling and safety assessments (adverse events, clinical laboratory, vital signs, 12‐lead electrocardiogram, and QT telemetry) were performed. ACT‐1014‐6470 was absorbed with a time to maximum plasma concentration ( t max ) of 3 h across dose levels and eliminated with a terminal half‐life of 30–46 h at doses ≥ 2.5 mg. Exposure increased approximately dose proportionally. Under fed compared to fasted conditions, ACT‐1014‐6470 exposure was 2.2‐fold higher and t max delayed by 1.5 h. Pharmacokinetic modelling predicted that twice‐daily oral administration is warranted in a subsequent multiple‐dose study. No clinically relevant findings were observed in safety assessments. ACT‐1014‐6470 was well tolerated at all doses and could provide a novel therapy with more patient‐friendly administration route compared to biologicals.