GPR84, a novel target for the development of therapies for IBD
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1 GPR84, a novel target for the development of therapies for IBD Sonia Dupont 1, Frédéric Labéguère 1, Roland Blanqué 1, Steve de Vos 2, Philippe Clément- Lacroix 1, Isabelle Parent 1, Corinne Saccomani 1, Luc Nelles 2, Annick Hagers 2, Céline Cottereaux 1, Didier Merciris 1, Marie-Christine Ceccotti 1, Cécile Belleville Da Costa 1, Stephen Fletcher, Reginald Brys 2 1 GALAPAGOS, Romainville, France, 2 GALAPAGOS, Mechelen, Belgium UEG Week 214 Abstract OP October 214 Copyright 214 Galapagos NV
2 GPR84, a novel target for the development of therapies for IBD Disclosures All authors are employees of Galapagos 2
3 GPR84 for IBD therapy Compelling evidence: GPR84 as a target in IBD GLPG125, a clinical candidate active in IBD model 3
4 GPR84 Novel target in inflammation Class A GPCR, Gi coupled Ligands: MCFA (9-14 carbon chain length), DIM, Embelin, 6-OAU Limited knowledge on biological role: T cell: increased IL4 production in activated KO cells (Venkataraman et al., 25) Macrophage: MCFA potentiate LPS-induced IL12 secretion (Wang et al., 26) Neutrophil & macrophage: 6-OAU induces chemotaxis and accumulation of PMNs & macrophages in air pouch model (Suzuki et al., 213) Expression strongly increased in RASFs upon cytokine treatment & in paws of animals subjected to CIA (GLPG own data) Early data suggest a potential role in inflammation for GPR84 4
5 Role in IBD Expression in relevant cell types/tissues Cell type / tissue Basal expression Induced expression Human dendritic cells No 5-3 -fold by LPS Human/rat neutrophils Medium * 3 -fold by LPS Human macrophages Low * 3-1 -fold by LPS Human T-cells Medium No induction by LPS Human intestinal epithelial cells (differentiated Caco-2) No No induction by LPS Human whole blood Medium ~1-fold by LPS Mouse colon Low Induced in DSS model Human colon Low Under evaluation GPR84 fold induction DSS model intact diseased n=58 n=49 RT-qPCR data; *: induced by cell incubation; meta-analysis, p<.1 Student t-test versus intact Expression in neutrophils and macrophages, not epithelial cells Strong induction in diseased conditions 5
6 Role in IBD Regulation of neutrophil chemotaxis RLU ( ATP-levels ) ng/ml 15 ng/ml 7.5 ng/ml 3.75 ng/ml 2 µm 6.66 µm 2.22 µm.74 µm 2 mm 1 mm.5 mm.25 mm IL-8 Embelin Capric acid veh RLU (ATP levels) µM Cpd X 1µM Cpd A 1µM Cpd B Vehicle Embelin 5µM Capric SD ac h IL-8.5mM 1ng/ml hc5a 33ng/ml fmlp 8nM Cpd A, Cpd B= GPR84 antagonist Cpd X = negative ctrl Embelin- (but not IL-8-, C5a- and fmlp-) induced chemotaxis is blocked by GPR84 antagonists Rat macrophage chemotaxis: induced by GPR84 agonists, blocked by GPR84 antagonists (not shown) GPR84 regulates biology of primary human cells involved in IBD pathogenesis 6
7 IBD model Chronic mouse colitis model: setup Experimental design (Wirtz et al., 27) BALB/c mouse, 3 cycles 5 days DSS 4% +2 days H 2 Disease activity index (DAI) [from to 12] composed of : weight loss [-4] stool consistency [-4] rectal bleeding [-4] Histology score (Nishitani et al., 29) Immunohistochemistry DAI score Intact Diseased * * DSS H2 DSS H2 DSS Days * p<.5, ** p<.1, p<.1 Student t-test versus intact 7
8 Efficacy in IBD Efficacy of GLPG125 in a chronic colitis model (1) Mouse IBD model (DSS, chronic setting, po qd dosing) Disease Activity Index AUC AUC of DAI score (expressed as % of diseased) Intact n=3 Diseased n=3 GLPG125 n=9 GLPG125 n=29 GLPG125 n=1 cyclosporin n=2 sulfasalazine sulfazalazine n=1 cyclosporin 2mg/kg/day n=2 Intact Diseased 1mg/kg/day GLPG125 3mg/kg/day GLPG125 1mg/kg/day GLPG125 2mg/kg/day cyclosporin 25mg/kg/day sulfazalazine sulfazalazine n=1 1mg/kg/day 3mg/kg/day 1mg/kg/day Intact n=3 Diseased n=3 GLPG125 1mg/kg/day n=9 GLPG125 3mg/kg/day n=29 GLPG125 1mg/kg/day n=1 sulfasalazine 25mg/kg/day GLPG125 efficacy in mouse DSS model similar to cyclosporin and sulfasalazine Minimal efficacy dose established at 3mg/kg po qd 8 Meta analysis of 3 independent experiments p<.1 Tukey s multi-comparison test versus Diseased
9 Efficacy in IBD Efficacy of GLPG125 in a chronic colitis model (2) Histological analysis Mouse IBD model (DSS, chronic setting, po qd dosing) Colon lesion score (% of Diseased) Lesion score ** 9 Neutrophil density Meta analysis of 3 independent experiments ** p<.1, p<.1 Tukey s multi-comparison test versus Diseased Significant efficacy in mouse DSS model, prevents colon lesion and neutrophil infiltration, effect similar to cyclosporin and sulfasalazine Neutrophil density (nb/mm2)
10 GPR84 for IBD therapy GLPG125 ready to be tested in patients GPR84 inhibition prevents neutrophil and macrophage chemotaxis induced by specific triggers Medicinal chemistry delivered GPR84 antagonist GLPG125 First in vivo efficacy data ever with GPR84 inhibitor: GPR84 inhibition prevents disease progression in chronic mouse IBD model Phase 1 data on poster P341: «Human safety, pharmacokinetics and pharmacodynamics of the GPR84 antagonist GLPG125, a potential new approach to treat IBD» GLPG125 expected to enter Phase 2 patient studies in IBD Slides available online on 1
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