Safety and pharmacology of a soluble epoxide hydrolase inhibitor

Aims: COPD and vascular dysfunction share an etiological basis with cigarette smoking. s.EH is a critical enzyme in the metabolism of epoxyeicosatrienoic acids (EETs). s.EH inhibition may increase EETs release from endothelial cells, and thus improve EETs-regulated vascular function. We report a Phase I study with the oral s.EH inhibitor GSK2256294 (96294). Methods: Single escalating doses of 96294 or placebo were administered in a randomized crossover design to healthy subjects, and once daily repeat doses of 96294 (6 or 18 mg) or placebo for 14d to obese smokers. Data were collected on safety, pharmacokinetics, enzyme inhibition, forearm blood flow (FBF) and serum biomarkers. Results: 57 subjects were randomized. The most frequent AEs were headache and contact dermatitis. No clinically significant differences in ECG, vital signs or laboratory parameters were noted. Plasma concentrations of 96294 increased with single doses between 2-20mg, with a half-life ranging from 25-42.7 hours. Inhibition of s.EH enzyme activity was dose-dependent, from 41.9% (2 mg; -51.8,77.7) to 99.8% (20 mg; 99.3,100.0). A trend to increased FBF in response to bradykinin was seen in obese smokers, most notably at a dose of 18 mg/d, with no change in stimulated tPA or PAI1 release or response to nitroprusside. The mean value of serum VEGF on Day 15 in subjects receiving 18 mg/d (33.0 pg/mL [24.1, 45.3]) was lower than that in placebo (45.8 pg/mL [31.4, 66.7]). Conclusions: GSK2256294 was well-tolerated and demonstrated sustained inhibition of s.EH enzyme activity. These data support further investigation in patients with endothelial dysfunction, such as COPD. Funding: GSK (SEH114068; NCT01762774) and the TSB (ERICA Consortium).