This study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple oral doses of enpatoran (formerly named M5049), a new toll‐like receptor (TLR) 7 and 8 dual antagonist, and the effect of food on a single dose in healthy participants. In this single phase 1, randomized (3:1), double‐blind, placebo‐controlled study, 96 participants received single and multiple ascending oral doses of enpatoran. Participants in single‐dose cohorts received one dose of enpatoran (1, 3, 9, 25, 50, 100, or 200 mg) or placebo using a sentinel dosing strategy. Multiple‐dose cohorts received enpatoran (9, 25, or 200 mg once daily, or 25 or 50 mg twice daily) or placebo for 14 days. Safety, tolerability, PK, and PD (ex vivo‐stimulated cytokine secretion) were assessed in both parts. The effect of food was assessed in an open‐label, one‐way crossover study in the 25 mg single‐dose cohort. Single‐ and multiple‐oral doses of enpatoran up to 200 mg were well tolerated and no significant dose‐limiting adverse events or safety signals were observed under fasting or fed conditions. PK parameters were linear and dose‐proportional across the dose range evaluated, with a slightly delayed absorption and lower peak concentration observed at 25 mg with food. Exposure‐dependent inhibition of ex vivo‐stimulated interleukin‐6 secretion was observed, with maximum inhibition at 200 mg. Enpatoran was well tolerated at doses up to 200 mg. Further investigation of enpatoran is warranted as a potential treatment for diseases driven by TLR7/8 overactivation, such as systemic lupus erythematosus and COVID‐19 pneumonia.
