Safety, Pharmacokinetics and Pharmacodynamics of GLPG0974, a Potent and Selective FFA2 Antagonist, in Healthy Male Subjects

Overview

Journal Br J Clin Pharmacol

Specialty Pharmacology

Date 2016 Feb 9

PMID 26852904

Citations 19

Authors

Florence Namour

Rene Galien

Tim Van Kaem

Annegret Van der Aa

Frederic Vanhoutte

Johan Beetens

Gerben Vant Klooster

Affiliations

Soon will be listed here.

Abstract

Aims: Free 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.

Methods: Two 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.

Results: The 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.

Conclusion: Based 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.

Citing Articles

Akkermansia muciniphila and its metabolite propionic acid maintains neuronal mitochondrial division and autophagy homeostasis during Alzheimer's disease pathologic process via GPR41 and GPR43.

Wang Z, Wang C, Yuan B, Liu L, Zhang H, Zhu M Microbiome. 2025; 13(1):16.

PMID: 39833898 PMC: 11744907. DOI: 10.1186/s40168-024-02001-w.

Development of a yeast-based sensor platform for evaluation of ligands recognized by the human free fatty acid 2 receptor.

Clausen Lind A, De Castro Gomes D, Bisquert R, Alcaraz R, Martensson J, Sundqvist M FEMS Yeast Res. 2025; 25.

PMID: 39824656 PMC: 11781196. DOI: 10.1093/femsyr/foaf001.

Trans-vaccenic acid reprograms CD8 T cells and anti-tumour immunity.

Fan H, Xia S, Xiang J, Li Y, Ross M, Lim S Nature. 2023; 623(7989):1034-1043.

PMID: 37993715 PMC: 10686835. DOI: 10.1038/s41586-023-06749-3.

Selectivity, efficacy and safety of JAKinibs: new evidence for a still evolving story.

Bonelli M, Kerschbaumer A, Kastrati K, Ghoreschi K, Gadina M, Heinz L Ann Rheum Dis. 2023; 83(2):139-160.

PMID: 37923366 PMC: 10850682. DOI: 10.1136/ard-2023-223850.

Discovery of Potent Tetrazole Free Fatty Acid Receptor 2 Antagonists.

Valentini A, Schultz-Knudsen K, Hansen A, Tsakoumagkou A, Jenkins L, Christensen H J Med Chem. 2023; 66(9):6105-6121.

PMID: 37129317 PMC: 10547238. DOI: 10.1021/acs.jmedchem.2c01935.

References

Kim M, Kang S, Park J, Yanagisawa M, Kim C . Short-chain fatty acids activate GPR41 and GPR43 on intestinal epithelial cells to promote inflammatory responses in mice. Gastroenterology. 2013; 145(2):396-406.e1-10. DOI: 10.1053/j.gastro.2013.04.056. View

Tolhurst G, Heffron H, Lam Y, Parker H, Habib A, Diakogiannaki E . Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes. 2011; 61(2):364-71. PMC: 3266401. DOI: 10.2337/db11-1019. View

Brown A, Goldsworthy S, Barnes A, Eilert M, Tcheang L, Daniels D . The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J Biol Chem. 2002; 278(13):11312-9. DOI: 10.1074/jbc.M211609200. View

Sina C, Gavrilova O, Forster M, Till A, Derer S, Hildebrand F . G protein-coupled receptor 43 is essential for neutrophil recruitment during intestinal inflammation. J Immunol. 2009; 183(11):7514-22. DOI: 10.4049/jimmunol.0900063. View

Hong Y, Nishimura Y, Hishikawa D, Tsuzuki H, Miyahara H, Gotoh C . Acetate and propionate short chain fatty acids stimulate adipogenesis via GPCR43. Endocrinology. 2005; 146(12):5092-9. DOI: 10.1210/en.2005-0545. View

Pizzonero M, Dupont S, Babel M, Beaumont S, Bienvenu N, Blanque R . Discovery and optimization of an azetidine chemical series as a free fatty acid receptor 2 (FFA2) antagonist: from hit to clinic. J Med Chem. 2014; 57(23):10044-57. DOI: 10.1021/jm5012885. View

Tazoe H, Otomo Y, Kaji I, Tanaka R, Karaki S, Kuwahara A . Roles of short-chain fatty acids receptors, GPR41 and GPR43 on colonic functions. J Physiol Pharmacol. 2008; 59 Suppl 2:251-62. View

Maslowski K, Vieira A, Ng A, Kranich J, Sierro F, Yu D . Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature. 2009; 461(7268):1282-6. PMC: 3256734. DOI: 10.1038/nature08530. View

Cummings J, Pomare E, Branch W, Naylor C, Macfarlane G . Short chain fatty acids in human large intestine, portal, hepatic and venous blood. Gut. 1987; 28(10):1221-7. PMC: 1433442. DOI: 10.1136/gut.28.10.1221. View

10.

Witko-Sarsat V, Rieu P, Descamps-Latscha B, Lesavre P, Halbwachs-Mecarelli L . Neutrophils: molecules, functions and pathophysiological aspects. Lab Invest. 2000; 80(5):617-53. DOI: 10.1038/labinvest.3780067. View

11.

Vinolo M, Ferguson G, Kulkarni S, Damoulakis G, Anderson K, Bohlooly-Y M . SCFAs induce mouse neutrophil chemotaxis through the GPR43 receptor. PLoS One. 2011; 6(6):e21205. PMC: 3115979. DOI: 10.1371/journal.pone.0021205. View

12.

Nilsson N, Kotarsky K, Owman C, Olde B . Identification of a free fatty acid receptor, FFA2R, expressed on leukocytes and activated by short-chain fatty acids. Biochem Biophys Res Commun. 2003; 303(4):1047-52. DOI: 10.1016/s0006-291x(03)00488-1. View

13.

Cavaglieri C, Nishiyama A, Fernandes L, Curi R, Miles E, Calder P . Differential effects of short-chain fatty acids on proliferation and production of pro- and anti-inflammatory cytokines by cultured lymphocytes. Life Sci. 2003; 73(13):1683-90. DOI: 10.1016/s0024-3205(03)00490-9. View

14.

Namour F, Galien R, Van Kaem T, Van der Aa A, Vanhoutte F, Beetens J . Safety, pharmacokinetics and pharmacodynamics of GLPG0974, a potent and selective FFA2 antagonist, in healthy male subjects. Br J Clin Pharmacol. 2016; 82(1):139-48. PMC: 4917808. DOI: 10.1111/bcp.12900. View

15.

Orr Y, Taylor J, Cartland S, Bannon P, Geczy C, Kritharides L . Conformational activation of CD11b without shedding of L-selectin on circulating human neutrophils. J Leukoc Biol. 2007; 82(5):1115-25. DOI: 10.1189/jlb.0906545. View

16.

Niederman R, Zhang J, KASHKET S . Short-chain carboxylic-acid-stimulated, PMN-mediated gingival inflammation. Crit Rev Oral Biol Med. 1997; 8(3):269-90. DOI: 10.1177/10454411970080030301. View

17.

Zarbock A, Ley K . Neutrophil adhesion and activation under flow. Microcirculation. 2008; 16(1):31-42. PMC: 2851240. DOI: 10.1080/10739680802350104. View

18.

Ge H, Li X, Weiszmann J, Wang P, Baribault H, Chen J . Activation of G protein-coupled receptor 43 in adipocytes leads to inhibition of lipolysis and suppression of plasma free fatty acids. Endocrinology. 2008; 149(9):4519-26. DOI: 10.1210/en.2008-0059. View

19.

Kimura I, Ozawa K, Inoue D, Imamura T, Kimura K, Maeda T . The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43. Nat Commun. 2013; 4:1829. PMC: 3674247. DOI: 10.1038/ncomms2852. View

20.

Bjursell M, Admyre T, Goransson M, Marley A, Smith D, Oscarsson J . Improved glucose control and reduced body fat mass in free fatty acid receptor 2-deficient mice fed a high-fat diet. Am J Physiol Endocrinol Metab. 2010; 300(1):E211-20. DOI: 10.1152/ajpendo.00229.2010. View