A Phase 1 First‐in‐Human Pharmacokinetic and Pharmacodynamic Study of JNJ‐64264681, a Covalent Inhibitor of Bruton's Tyrosine Kinase

Abstract

AbstractJNJ‐64264681 is an irreversible covalent inhibitor of Bruton's tyrosine kinase. This phase 1, first‐in‐human, 2‐part (single‐ascending dose [SAD]; multiple‐ascending dose [MAD]) study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD; Bruton's tyrosine kinase occupancy [BTKO]) of JNJ‐64264681 oral solution in healthy participants. For SAD (N = 78), 6 increasing doses of JNJ‐64264681 (4–400 mg) or placebo were evaluated in fasted males. The effects of sex, food, and a capsule formulation were evaluated in separate cohorts. For MAD (N = 27), sequential cohorts of male and female participants received 36/100/200 mg JNJ‐64264681 once daily for 10 days. JNJ‐64264681 exposure (peak concentration; area under the concentration‐time curve) was less than dose proportional from 4 mg to 36 mg. Dose‐normalized area under the concentration‐time curves following the 36 mg and 100 mg doses were generally similar. The mean terminal half‐life was 1.6–13.2 hours. With multiple doses, steady state was achieved by day 2. A semimechanistic PK/PD model was developed using the first 5 SAD cohorts’ data to predict %BTKO in MAD cohorts. PK/PD model guided dose‐escalation, and all participants in the 200/400 mg single‐dose cohorts achieved ≥90% BTKO at 4 hours after dosing (peak) with prolonged occupancy. As BTKO data became available from MAD cohorts, it was found that observed BTKO data were consistent with model predictions. JNJ‐64264681 showed no safety signals of concern. Overall, safety, tolerability, PK, BTKO, and PK/PD modeling guided the rationale for dose selection for the subsequent first‐in‐patient lymphoma studies.