Pharmacokinetics and Pharmacodynamics of KT‐474, a Novel Selective Interleukin‐1 Receptor–Associated Kinase 4 (IRAK4) Degrader, in Healthy Adults

ABSTRACT Interleukin‐1 receptor–associated kinase 4 (IRAK4), a key component of the Myddosome complex, mediates signaling through toll‐like and interleukin‐1 receptors. KT‐474, a heterobifunctional IRAK4 degrader, was evaluated in a randomized, double‐blind, placebo‐controlled Phase 1 trial (NCT04772885) in single (25, 75, 150, 300, 600, 1000, and 1600 mg) and multiple (25, 50, 100, and 200 mg once daily [QD] for 14 days; or 200 mg twice weekly) ascending doses in healthy subjects. The pharmacokinetics of KT‐474 and its diastereomers, the pharmacodynamics of KT‐474, and the effect of food on KT‐474 pharmacokinetics and the pharmacokinetic–pharmacodynamic analysis are presented as additional analyses to supplement the Ackerman et al. publication. KT‐474 showed delayed absorption and prolonged elimination. Plasma exposure increased less than dose‐proportionally, with single‐dose exposure plateauing after the 1000 mg dose. Steady state was achieved after 7 days of daily dosing and resulted in a 3‐ to 4‐fold accumulation in exposure. A significant food effect was observed at the 600 mg dose, with exposure increasing up to 2.57‐fold when KT‐474 was administered with a high‐fat meal. Urinary excretion of KT‐474 was < 1%. KT‐474 demonstrated robust IRAK4 degradation in blood, with mean reductions of up to 98% observed at the 50–200 mg QD doses, as well as inhibition of ex vivo induction of a broad array of cytokines and chemokines by stimulants lipopolysaccharides and R848. Analysis of the relationship between plasma KT‐474 concentration and IRAK4 reduction in blood indicated that plasma concentrations of 4.1–5.3 ng/mL would yield 80% IRAK4 reductions.