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

Abstract

Aberrantly controlled activation of the complement system contributes to inflammatory diseases. Safety, tolerability, and pharmacokinetics of singleascending 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 twicedaily 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.

Multiple‐ascending doses of ACT‐1014‐6470, an oral complement factor 5a receptor 1 (C5a1 receptor) antagonist: Tolerability, pharmacokinetics and target engagement

“…For multiple‐dose administration of ACT‐1014‐6470, a twice daily (b.i.d.) dosing regimen was chosen based on the PK data in the SAD study 14 . A rapid distribution phase was observed for ACT‐1014‐6470, leading to approximately 70% of overall exposure covered within 12 h after administration.…”

“…dosing. A treatment duration of 4.5 days and a starting dose of 30 mg were selected based on steady‐state exposure predictions from single‐dose PK data 14 . The predicted area under the plasma concentration–time curve during a dosing interval (AUC τ ) at 30 mg resulted in safety margins to the no‐observed‐adverse‐effect level in animals of 5.2.…”

“…from Day 1 to the morning of Day 5. Based on the effect of food on ACT‐1014‐6470 exposure in the SAD study, 14 the compound was administered 30 minutes after consumption of a standardized breakfast or dinner (700–800 kcal). After the last dose, subjects were observed for 120 h and, if appropriate based on their medical condition, discharged on Day 10.…”

“…ACT‐1014‐6470, a potent, selective, orally available C5a 1 receptor antagonist, could fill this treatment gap 14 . The low‐molecular weight compound concentration‐dependently inhibits C5a‐mediated C5a 1 receptor signalling in vitro.…”

“…The time to maximum plasma concentration (t max ) was 3 h and the terminal half‐life (t ½ ) 30–46 h, while exposure increased slightly more than dose‐proportionally. Administration under fed compared to fasted conditions increased ACT‐1014‐6470 exposure by >100% 14 . This manuscript reports the safety, tolerability, pharmacokinetics (PK) and target engagement data of multiple‐ascending doses (MADs) of ACT‐1014‐6470 in healthy male and female subjects.…”