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A promising approach for the treatment of neutrophil-driven disorders
Johan Beetens, PhD, PharmD Development Project Leader, Head Fatty acid activation of G protein-coupled receptors: Basic and clinical perspectives (ASPET meeting, Boston) 22 April 2013
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Presentation outline
• Drug target FFA2
biology and expression
• GLPG0974
pharmacology
initial Phase I clinical data
• Next steps: Proof-of-Concept
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Free Fatty Acid Receptor 2 (FFA2)
• Ligands: short-chain fatty acids (SCFA; C1-C6)
acetate/propionate/butyrate
major source in human body: via fermentation by colonic bacteria
act also via other receptors and enzymes: FFA3, GPR109A, HDAC, PPARγ, COX,…
Mortality due to sepsis ↓ PMN infiltration in colon ↓ MPO & TNFα in colon ↑ TNFα & KC in serum
Chronic DSS colitis
Exaggerated inflammation ↑ Mortality in the 1st week ↑ Histology score ↑ MPO in colon on D42 ↓ effect of oral acetate
Reduced inflammation ↓ PMN infiltration in colon ↓ MPO & TNFα in colon
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GLPG0974 Monkey model for IBD
• Cotton-top tamarin IBD model spontaneous acute and chronic colitis
close similarities to human ulcerative colitis
good response to marketed therapies
but
listed as endangered species, only breeding programs allowed
model no longer available
• Invest in other monkey model of inflammation?
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Neutrophil migration biomarker Activation of CD11b
• CD11b/CD18 (Mac-1) interaction with ICAM-1 mediates firm adhesion
• Conformational change of CD11b (CD11b[AE]) needed for ICAM-1 interaction
total CD11b expression does not per se correlate with adhesion capacity of Mac-1
CD11b[AE] more relevant marker of neutrophil activation in blood than total CD11b
Diamond, 1993; Orr, 2007; Zarbock, 2009;
Sherwood, 2004
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GLPG0974 CD11b[AE] as biomarker in human whole blood
In vitro inhibition of acetate-induced CD11b[AE]
GLPG0974 inhibits acetate-induced CD11b[AE] expression, not IL8-, fMLP-, TNFα or LPS-induced expression
IC50: 483 ± 72 nM
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GLPG0974 single dose FiH study Robust effect on biomarker
Ex vivo inhibition of acetate-induced CD11b[AE]
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0
20
40
60
80
100
0 1 2 3 4 5 6 7 8
% I
nh
ibit
ion
Time post dose (h)
Placebo
30 mg
90 mg
250 mg
Safety: safe & well tolerated up to 250 mg SD PK: good oral bioavailability and dose-proportional exposure PD: dose-dependent response, apparent PK/PD relationship
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GLPG0974 Multiple Ascending Doses Challenges and questions
• Prolonged (up to 24 h) and sustained effect (up to 14 days) on biomarker activity?
• Effect of multiple dosing on exposure?
• Conflicting data on metabolic function (FFA2-/- KO mice)
improved (high-fat diet) or no effect (normal diet) on glucose tolerance, protected from obesity and dislipidemia (HF diet) (Bjursell, 2011)
GLPG0974: conclusions and prospects • Potent and very selective FFA2 antagonist
only active on human and monkey receptor
• Inhibits FFA2-induced activation and migration of neutrophils
• Good PK/PD profile, safe and well-tolerated in volunteers
• First FFA2 antagonist to be evaluated in patients (IBD)
MoA clearly differentiates from existing therapies and new compounds currently in pipeline for IBD
Four-week PoC study ongoing in UC patients in Belgium and Eastern European Union
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Acknowledgements Chemistry Laurent Sanière Mathieu Pizzonero Marielle Babel Jean-Michel Lefrançois Fatoumata Djata Sabrina Kopiejewski Christelle L’ebraly Murielle Manioc Stephane Beaumont Elsa De Lemos Benedetta Crescenzi François Nique Natacha Bienvenu Hélène Jary Laetitia Peltier Florilène Soulas Pierre Deprez Stephen Fletcher
Biology/ADME Sonia Dupont Roland Blanque René Galien Thierry Christophe Katja Conrath Luc Nelles David Craeye Celine Cottereaux Corinne Saccomani Steve De Vos Nicolas Triballeau Philippe Delerive Nick Vandeghinste Emanuelle Wakselman Ellen van der Aar Reginald Brys Dennis Polancec Katarina Oreskovic
Development Gerben van ‘t Klooster Florence Namour Giocondo Lorenzon Christine Guerin Frédéric Vanhoutte Marc De Weer Nicolas Sabourault Annegret Van der AA Tim Van Kaem Bart Franken Luc Meuleneers Piet Wigerinck
External experts Paul Rutgeerts Severine Vermeire Walter Reinisch Brian Feagan Daniel Podolsky Axel Dignass Tim Orchard Martine Devos Graeme Milligan