Randomized, Placebo-Controlled, First-in-Human Study of the Safety, Tolerability, and Pharmacokinetics of Single and Repeat Oral Doses of Novel Antitubercular Drug Candidate, GSK2556286, in Healthy Adults.

This first-in-human study (ClinicalTrials.gov identifier: NCT04472897) evaluated the safety, tolerability, pharmacokinetics, and food effect of single ascending and repeat oral doses of GSK2556286 (GSK286), a novel antitubercular drug candidate with efficacy in animal models of tuberculosis. In part A, 56 participants received single GSK286 doses (25-1000 mg; 10 cohorts) and 19 participants received a placebo. In part B, GSK286 and placebo doses were administered once daily for up to 14 days. Cohorts received repeat doses of GSK286 (225 or 650 mg; 13 participants) or placebo (four participants) in part B before the study was placed on hold due to reaching the stopping criterion, defined as clinically significant, non-serious adverse events (AEs) that are considered to be at least possibly related to GSK286 in two or more participants on active treatment. Single GSK286 doses were well tolerated; all reported AEs were mild, apart from moderate AEs in two participants administered GSK286 1000 mg, and there were no serious AEs (SAEs). In part B (repeat dosing), three participants reported moderate AEs, one reported a severe AE, and there were no SAEs. However, four of six participants in the 650 mg repeat dose cohort discontinued treatment due to the AEs (at least one) of headache, photophobia, fatigue, nausea, and vomiting. There was high intraindividual variability in the pharmacokinetics of GSK286 in both parts of the study, and the effect of food in modulating this variability was unclear. The combination of unexpected pharmacokinetic variability and exposure-related AEs led to termination of the study.