A First‐In‐Human, Randomized, Placebo‐Controlled Single and Multiple Ascending Dose Study of Izicopan (INF904), A Second‐Generation Oral Small Molecule C5a Receptor Inhibitor, in Healthy Participants

Abstract This was a first‐in‐human, single‐center, Phase 1 study of izicopan (formerly INF904), a potent oral, second‐generation small molecule antagonist of C5aR1, in healthy adults. Participants were randomized to a single oral dose of izicopan 3–240 mg or matched placebo (single ascending dose [SAD]), or multiple doses of izicopan 30 mg once daily (QD), 30 or 90 mg twice daily (BID), or matched placebo, for 14 days (multiple ascending dose [MAD]). In the SAD study, izicopan plasma concentration increased with dose from 3 to 240 mg; the mean maximum plasma concentration (C max ) was 21.5–1216.0 ng/mL, reached at a median time (t max ) of 3.5–6.0 h, followed by a biphasic decline. In the MAD study, a steady state appeared to have been reached within 14 days, and AUC 0‐tau exhibited an accumulation ratio of ∼2‐fold following BID dosing, suggesting an effective half‐life of ∼12 h. In an ex vivo whole blood PD assay, izicopan resulted in >90% blockade of CD11b upregulation by recombinant human C5a across almost all dose cohorts from Days 2–15. Adverse events were mild or moderate in severity. In conclusion, izicopan was safe across all single and multiple doses evaluated. Sufficient izicopan exposure was achieved rapidly to exert >90% blockade of C5a‐C5aR1 signaling.