A Randomized Study of the Safety and Pharmacokinetics of GSK3358699, a Mononuclear Myeloid-Targeted Bromodomain and Extra-Terminal Domain Inhibitor

AIMS GSK3358699 is a mononuclear myeloid-targeted bromodomain and extra-terminal domain (BET) family inhibitor which demonstrates immunomodulatory effects in vitro. This phase 1, randomized, first-in-human study evaluated the safety, pharmacokinetics, and pharmacodynamics of GSK3358699 in healthy male participants (NCT03426995). METHODS Part A (N=23) included three dose-escalating periods of 1-40 mg GSK3358699 or placebo in two cohorts in a single ascending-dose crossover design. Part C (N=25) was planned as an initial dose of 10 mg GSK3358699 or placebo daily for 14 days followed by selected doses in four sequential cohorts. RESULTS In part A, exposure to GSK3358699 and its metabolite GSK3206944 generally increased with increasing doses. The median initial half-life ranged from 0.7-1.1 (GSK3358699) and 2.1-2.9 (GSK3206944) hours after a single dose of 1-40 mg. GSK3206944 concentrations in monocytes were quantifiable at 1-hour post-dose following 10 mg GSK3358699 and 1 and 4 hours post-dose following 20-40 mg. Mean predicted percent inhibition of ex vivo lipopolysaccharide (LPS)-induced MCP-1 reached 75% with 40 mg GSK3358699. GSK3358699 did not inhibit IL-6 and TNF. The most common adverse event (AE) was headache. Four AEs of non-sustained ventricular tachycardia were observed across parts A and C. One serious AE of atrial fibrillation (part C) required hospitalization. CONCLUSIONS Single doses of GSK3358699 are generally well tolerated with significant metabolite concentrations detected in target cells. A complete assessment of pharmacodynamics was limited by assay variability. A causal relationship could not be excluded for cardiac-related AEs, resulting in an inability to identify a suitable repeat-dose regimen and study termination.