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A phase 1 study of single and repeat oral doses of GSK3439171A, a highly selective H-PGDS inhibitor, in healthy adult participants
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  • Thomas Haws,
  • Nilay Thakkar,
  • Summer Goodson,
  • Caroline Sychterz,
  • Nisha George,
  • Rebecca Zhang-Roper,
  • Geo Derimanov,
  • David Neil,
  • Victoria Ballard
Thomas Haws
GlaxoSmithKline
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Nilay Thakkar
GlaxoSmithKline Research and Development
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Summer Goodson
GlaxoSmithKline Research and Development
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Caroline Sychterz
GlaxoSmithKline
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Nisha George
GlaxoSmithKline
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Rebecca Zhang-Roper
GlaxoSmithKline Research and Development
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Geo Derimanov
GlaxoSmithKline
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David Neil
GlaxoSmithKline
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Victoria Ballard
GlaxoSmithKline Research and Development
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Abstract

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.