A phase 1 study of single and repeat oral doses of GSK3439171A, a highly
selective H-PGDS inhibitor, in healthy adult participants
Aim: Prostaglandin D2 (PGD2) is implicated in the pathophysiology of
inflammatory diseases. GSK3439171A is a potent, reversible, and highly
selective azetidine urea inhibitor of haematopoietic prostaglandin D
synthase (H-PGDS, a key promoter of PGD2 production in several
inflammatory cell types). Based on favourable preclinical data, we
performed a first-time-in-human study to assess the safety,
tolerability, pharmacokinetics, and pharmacodynamics of GSK3439171A, and
the effect of food on these parameters. Methods: This was a phase 1,
randomized, double-blind, placebo-controlled, dose-escalation study.
Single and repeat oral doses of GSK3439171A were administered to healthy
males aged 18–65 years. Levels of inflammatory markers including
tetranor-prostaglandin D metabolite (tPGDM) were measured in urine
samples. Results: Sixty-six participants were enrolled, with 57
receiving GSK3439171A. Single doses (5–180 mg) and repeat once-daily
doses (5 and 11 mg for 14 days; 40 mg for 7 days) were administered.
Seven participants (12%) had adverse events (AEs) related to study
drug, mainly drug hypersensitivity (n=4 [7%]; non-serious,
transient skin rash). There were no serious AEs (SAEs) or clinically
significant changes in vital signs, electrocardiogram, or laboratory
parameters. Dose-proportional increases in Cmax and AUC(0–inf) were
observed, and the geometric mean half-life of GSK3439171A was up to 12
hours. Results were similar when GSK3439171A was taken with or without
food. No consistent suppression of tPGDM levels was observed.
Conclusion: GSK3439171A was well tolerated in healthy participants and
there were no SAEs. Selective inhibition of H-PGDS offers therapeutic
potential for muscle-related disorders (e.g. Duchenne Muscular
Dystrophy) and muscular recovery following injury.