A randomized study of the safety and pharmacokinetics of GSK3358699, a mononuclear myeloid-targeted bromodomain and extra-terminal domain inhibitor

Abstract

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 of 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 of 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 to 1.1 (GSK3358699) and 2.1 to 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 of GSK3358699 and 1 and 4 hours post-dose following 20-40 mg. Mean predicted percentage inhibition of ex vivo lipopolysaccharide-induced monocyte chemoattractant protein (MCP)-1 reached 75% with 40 mg of GSK3358699. GSK3358699 did not inhibit interleukin (IL)-6 and tumour necrosis factor (TNF). The most common adverse event (AE) was headache. Four AEs of nonsustained 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.

Keywords: GSK3358699; bromodomain and extra-terminal domain; epigenetic reader protein; myeloid; pharmacodynamics; pharmacokinetics.

FIGURE 1

Dosing schematic. In part A of the study, two interlocking cohorts of participants (cohorts 1 and 2) received GSK3358699 in a single ascending‐dose crossover design during three dose‐escalating treatment periods (treatment periods 1‐3). Each participant received a maximum of two single ascending oral doses of GSK3358699 (1, 3, 10, 20, 40 or 30 mg) and one dose of placebo. In treatment period 4, participants were treated with 25 mg of GSK3358699 or placebo followed by an in vivo LPS (cohort 1) or GM‐CSF challenge (cohort 2). Part C of the study was planned to be a repeat‐dose design in sequential cohorts with participants randomized to either 10 mg of GSK3358699 or placebo daily for 14 days. However, the study was terminated during cohort 5 and cohorts 6‐8 were not conducted. GM‐CSF, granulocyte‐macrophage colony‐stimulating factor; LPS, lipopolysaccharide; PBO, placebo; PD, pharmacodynamic; PK, pharmacokinetic

FIGURE 2

Participant disposition for parts A and C of the study. In part A, 23 participants were randomized and 17 completed the study. In part C, 25 patients were randomized and four completed the study (received all 14 doses). Reasons for discontinuation are shown in the diagram. PK, pharmacokinetics. ^aParticipant reached haematological stopping criteria‐low neutrophils

FIGURE 3

Median plasma concentration over time in part A^a of the study (pharmacokinetic population^b). Median plasma concentrations of GSK3358699 (top) and the metabolite GSK3206944 (bottom) over 48 hours following treatment with a single dose of GSK3358699 (1, 3, 10, 20, 30 or 40 mg) are shown on a linear (left) and semilogarithmic scale (right). SD, single dose. ^aPart A was a single ascending‐dose crossover study in two interlocking cohorts. Each participant received a maximum of two single ascending oral doses of GSK3358699 (1, 3, 10, 20, 40 or 30 mg) and one dose of placebo. ^bThe pharmacokinetic population included all participants who received an active dose of the study drug and for whom pharmacokinetic samples were obtained and analysed

FIGURE 4

Median plasma concentration over time on day 1 of part C of the study (pharmacokinetic population^a). Median plasma concentrations of GSK3358699 (top) and the metabolite GSK3206944 (bottom) over 48 hours following treatment with 10 mg of GSK3358699 are shown on a linear (left) and semilogarithmic scale (right). As only two participants had a PK profile for day 14, only a median concentration‐time profile for day 1 is presented. RD, repeat dose. ^aThe pharmacokinetic population included all participants who received an active dose of the study drug and for whom pharmacokinetic samples were obtained and analysed

FIGURE 5

Median GSK3206944 intracellular molar concentration over time (linear and semilog) in (A) part A^a and (B) part C^b, day 1 (pharmacokinetic population^c). The median intracellular molar concentration of the metabolite GSK3206944 in monocytes over 4 hours in participants in part A treated with a single dose of GSK3358699 (10, 20, 35, 30 and 40 mg) are shown on a linear (top left) and semilogarithmic scale (top right). Concentrations were not quantifiable for single doses of 1 and 3 mg in part A. There was no evidence for enhanced intracellular GSK3206944 concentrations on repeat dosing at the 10 mg dose investigated in part C (bottom). SD, single dose. ^aPart A was a single ascending‐dose crossover study in two interlocking cohorts. Each participant received a maximum of two single ascending oral doses of GSK3358699 (1, 3, 10, 20, 40 or 30 mg) and one dose of placebo. ^bIn part C, participants received 10 mg of GSK3358699 or placebo daily for up to 14 days. ^cThe pharmacokinetic population included all participants who received an active dose of the study drug and for whom pharmacokinetic samples were obtained and analysed

FIGURE 6

Mean predicted percentage inhibition of MCP‐1 in part A^a of the study (safety population^b). The mean predicted percentage inhibition of MCP‐1 at 1 hour post‐dose (left) and 4‐hours post dose (right) in participants in part A treated with single doses of GSK3358699 of 1, 3, 10, 20, 30 and 40 mg. ^aPart A was a single ascending‐dose crossover study in two interlocking cohorts. Each participant received a maximum of two single ascending oral doses of GSK3358699 (1, 3, 10, 20, 40 or 30 mg) and one dose of placebo. ^bThe safety population consisted of all randomized participants who received at least one dose of study treatment