First‐in‐Human Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of E6742, a Dual Antagonist of Toll‐like Receptors 7 and 8, in Healthy Volunteers

Abstract The first‐in‐human phase I study for E6742, a dual toll‐like receptor (TLR) 7 and TLR8 antagonist, has been conducted to assess the safety, tolerability, and pharmacokinetics of E6742 in healthy volunteers. In a single ascending dose (SAD) study, 42 subjects received 10–800 mg of E6742 in the fasted state, as well as a 100‐mg cohort in the fed state for evaluating the effect of food. In a multiple ascending dose (MAD) study, 18 subjects received 100–400 mg of E6742 twice daily for 7 days. E6742 was rapidly absorbed with a median t max ranging from 1.50 to 2.50 hours across dose groups under the fasted condition, and eliminated with a median t ½ ranging from 2.37 to 14.4 hours. After multiple oral doses, a steady state was reached by day 7. In the SAD study, dose proportionality was observed for C max , AUC (0‐t) , and AUC (0‐inf) values of E6742 up to 800 mg, but these values were slightly less than dose proportional at 10 mg. In the MAD study, the C max and AUC (0‐12h)ss of E6742 appeared to be almost dose proportionally increased between 100 and 200 mg, while these parameters showed more than a dose proportional increase at 400 mg. In addition to safety and good tolerability, this study demonstrated cytokine concentrations in cultured peripheral blood in response to E6742 were suppressed in a dose‐dependent manner. Further clinical studies targeting systemic lupus erythematosus patients are currently underway.