Safety, pharmacokinetics and pharmacodynamics of GLPG0974, a potent and selective FFA2 antagonist, in healthy male subjects

Abstract

AimsFree fatty acids (FFA) can act as direct signalling molecules through activation of several membrane‐bound G‐protein coupled receptors. The FFA2 receptor (known as GPR43) is activated by short chain fatty acids (SCFA) such as acetate and has been shown to play a major role in SCFA‐induced neutrophil activation and migration and to contribute in the development and control of inflammation. GLPG0974 is a potent and selective antagonist of the human FFA2. The main objectives of the two phase 1 trials were to characterize the safety, tolerability, pharmacokinetics and pharmacodynamics of GLPG0974.MethodsTwo consecutive randomized, double‐blind, placebo‐controlled, single centre trials in healthy subjects were performed. In the first, GLPG0974 was administered as single doses up to 250 mg and in the second, multiple daily doses up to 400 mg for 14 days were evaluated. Non‐compartmental analysis was used to determine GLPG0974 pharmacokinetics while target engagement was investigated through the inhibition of neutrophils in acetate‐simulated whole blood samples using surface expression of CD11b activated epitope as a marker of neutrophil activation.ResultsThe investigation of safety/tolerability and pharmacokinetics in the early development phase showed that GLPG0974 was safe and well tolerated up to a daily dose of 400 mg. GLPG0974 showed good and dose proportional exposure up to 400 mg daily as well as a substantial and sustained inhibition of acetate‐stimulated neutrophil activation.ConclusionBased on these results, a proof‐of‐concept study was initiated to evaluate the safety, tolerability and efficacy of GLPG0974 in patients with mild to moderate ulcerative colitis.

Functional selective ATP receptor signaling controlled by the free fatty acid receptor 2 through a novel allosteric modulation mechanism

“…However, the effect of the FFA2R antagonist CATPB that separately inhibits the activity mediated not only by propionate but also by Cmp58 suggests that the binding sites for the 2 FFA2R-interacting compounds are very close and possibly overlap. This suggestion is supported by the results with another structurally unrelated FFA2R antagonist (GLPG0974 (30)) that has an inhibitory profile identical to that of CATPB.…”

Protective Effects of Short-Chain Fatty Acids on Endothelial Dysfunction Induced by Angiotensin II

“…During this time, the rings were incubated with acetate (10 mM), propionate (10 mM), or butyrate (5 mM), and in the last 6 h in AngII-free condition (control rings) or under AngII (1 µM)-stimulated condition serum-free Medium 199. In some experiments, rings were coincubated for 24 h with the antagonist of GPR-43 receptor, GLPG0974 (GLPG) (Namour et al, 2016) (Bio-Techne R&D Systems, S.LU, Madrid, Spain) (0.1 µM), or with β-hydroxybutyrate (SHB), a ketone body and antagonist of GPR-41 (5 mM) (Kimura et al, 2011) (Sigma-Aldrich). After the incubation period, rings were mounted in organ chambers filled with Krebs solution (2 mM CaCl 2 , 1.2 mM KH 2 PO 4 , 118 mM NaCl, 25 mM NaHCO 3 , 4.75 mM KCl, 1.2 mM MgSO 4 and 11 mM glucose) at 37 • C and gassed with 95% O 2 and 5% CO 2 (Sanchez et al, 2007).…”

Review article: novel oral‐targeted therapies in inflammatory bowel disease

“…Knockout mice studies suggest FFA2 has important roles in controlling inflammation . GLPG0974 (Galapagos NV, Mechelen, Belgium) is a selective antagonist of FFA2 and was shown to be safe and tolerable in healthy subjects . A randomised, exploratory, double‐blind, phase II trial evaluating the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of GLPG0974 in UC has been completed and results are awaited…”