Pharmacodynamic and biomarker analyses
AD
A single dose of KT-474 resulted in rapid, dose-dependent degradation of IRAK4 in PBMCs of HVs in SAD, starting with the lowest dose level of 25 mg and plateauing after 600 mg (Fig. The functional impact of more than 90% IRAK4 degradation in PBMCs was evaluated using an ex vivo TLR stimulation assay on whole blood. At the 1,000-mg and 1,600-mg SAD dose levels, the induction by LPS and R848 of a broad array of cytokines involved in innate immunity, as well as Th1, Th17 and Th2 responses, was inhibited 24–48 h after dose (Extended Data Fig. IRAK4 degradation in PBMCs of patients with HS and patients with AD treated with KT-474 for 28 d was similar to what was achieved in the HV MAD cohorts treated for 14 d, with an IRAK4 nadir of more than 90% and a similar relationship of plasma KT-474 C