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.

Keywords: immunology; inflammation; inhibition; pharmacokinetics‐pharmacodynamics.

FIGURE 1

Mean (±SD) plasma concentration versus time profiles for KT‐474 and its diastereomers, KT‐5481 and KT‐5482, after ascending (a) single and (b) multiple doses of KT‐474. Steady‐state profiles on Day 14 are shown for the multiple dose groups. Concentrations below the limit of quantification (0.150 ng/mL for KT‐474 and 0.200 ng/mL for KT‐5481 and KT‐5482) were replaced with zero for the calculation of summary statistics. The 600 mg fed group contains two subjects from Cohort 5 and six subjects from Cohort 8. BIW, twice weekly dosing; QD, once daily dosing; SD, standard deviation. Note part of the KT‐474 profiles has been adapted from Ackerman et al., 2023, previously published by Nature Medicine under CC BY 4.0 Deed | Attribution 4.0 International | Creative Commons .

FIGURE 2

Mean (±SD) plasma concentration versus time profiles for KT‐474 after administration of a single oral dose of 600 mg KT‐474 (a) and 50 mg KT‐474 (b) in fasted and fed states. In the fed state, the 600 mg dose was administered within 30 min of starting a high‐fat meal, and the 50 mg dose was administered within 30 min of a moderate‐fat meal.

FIGURE 3

Mean (±SE) time course of IRAK4 reduction from baseline (a) and maximum IRAK4 reduction (b) in PBMCs, monocytes, and lymphocytes after single doses of KT‐474 or placebo. PBMC, peripheral blood mononuclear cell; SD, single dose; SE, standard error. * = p < 0.05 compared to placebo.

FIGURE 4

Mean (±SE) time course of IRAK4 reduction from baseline (a) and maximum IRAK4 reduction (b) in PBMCs, monocytes, and lymphocytes after multiple QD or BIW doses of KT‐474. BIW, biweekly; PBMC, peripheral blood mononuclear cell; QD, once daily; SE, standard error. * = p < 0.05 compared to placebo.

FIGURE 5

Mean (±SE) maximum change from baseline in cytokine induction by (a) TLR 4 agonist LPS or (b) TLR 7/8 agonist R848 after multiple dosing in healthy subjects. BIW, twice weekly; LPS, lipopolysaccharide; QD, once daily; SE, standard error; TLR, toll‐like receptor.

FIGURE 6

PK‐PD relationship for IRAK4 degradation in blood (PBMCs, monocytes, and lymphocytes). KT‐474 concentrations required to produce 80% IRAK4 reduction. IC₈₀ was estimated to be 4.1 ng/mL in PBMCs, 5.3 ng/mL in monocytes, and 4.6 ng/mL in lymphocytes. PBMC, peripheral blood mononuclear cell; PD, pharmacodynamic; PK, pharmacokinetic.