A phase I, first-in-human study investigating the safety, tolerability, and pharmacokinetics of the maturation inhibitor GSK3739937.

We report the safety and pharmacokinetic properties of the HIV-1 maturation inhibitor GSK3739937 (GSK'937) in healthy participants. This was a phase I, first-in-human, double-blind, randomized, placebo-controlled, single- (part 1) and multiple- (part 2) dose escalation study with an additional open-label relative bioavailability and food effect study (part 3). Participants received oral ascending single doses (10-800 mg) in part 1, up to 18 once-daily 25- to 100-mg or 3 once-weekly 500-mg doses in part 2, and single 100-mg doses as powder-in-bottle or tablet (in fed and fasted states) formulations in part 3. Primary and secondary objectives were safety and pharmacokinetic assessments, respectively. Ninety-one participants were enrolled; 38 reported 81 total adverse events (AEs). All AEs in participants receiving GSK'937 were grade 1 or 2 and resolved during the study. Most drug-related AEs were gastrointestinal (14/17, 82%). The terminal phase half-life of GSK'937 was ~3 days for all doses following single and repeat dosing. Geometric mean maximum concentration and total drug exposures exhibited dose-proportional increases during part 1. Accumulation in exposure following repeat dosing was 6- to 7-fold with daily dosing and ~1.7-fold after weekly treatment, as expected due to the long half-life. Bioavailability of GSK'937 after a meal was 1.35- to 1.40-fold greater as a tablet versus powder-in-bottle and >2-fold higher in fed versus fasted states when provided as a tablet. No unexpected or dose-limiting safety events occurred. Pharmacokinetic parameters of long half-life and accumulation of exposure following repeat dosing suggest the potential for weekly oral dosing. ClinicalTrials.gov identifier: NCT04493684.