PT  - JOURNAL ARTICLE
AU  - Roland Blanque
AU  - Nicolas Desroy
AU  - Sonia Dupont
AU  - Céline Cottereaux
AU  - Alain Monjardet
AU  - Emanuelle Wakselman
AU  - Wendy Laenen
AU  - Vince Russell
AU  - Ellen Van der Aar
AU  - Reginald Brys
AU  - Bertrand Heckmann
TI  - Pharmacological profile and efficacy of GLPG1690, a novel ATX inhibitor for COPD treatment
AID  - 10.1183/13993003.congress-2015.PA2129
DP  - 2015 Sep 01
TA  - European Respiratory Journal
PG  - PA2129
VI  - 46
IP  - suppl 59
4099  - http://erj.ersjournals.com/content/46/suppl_59/PA2129.short
4100  - http://erj.ersjournals.com/content/46/suppl_59/PA2129.full
SO  - Eur Respir J2015 Sep 01; 46
AB  - Introduction: Autotaxin (ATX), a secreted lysophospholipase, plays a central role in the production of the bioactive lipid lysophosphatidic acid (LPA). LPA signals through multiple LPA receptors to control a range of cell activities (migration, contraction, survival…). Recently, a role for the ATX/LPA axis in asthma and fibrosis were reported, suggesting involvement in additional lung diseases.Aims & objectives: To characterize the pharmacological profile of GLPG1690, a novel ATX inhibitor, as well as its efficacy in COPD.Methods: Biochemical potency was assessed using human and mouse recombinant ATX. Ex vivo potency was determined in plasma by measuring LPA levels (LC-MS) after incubation with GLPG1690. Plasma LPA levels of GLPG1690-treated animals was used as pharmacodynamic marker. Inflammatory cell counts in bronchoalveolar lavage fluid (BALF) were used as a measure for efficacy in a mouse 11-day tobacco smoke (TS) model for COPD.Results: GLPG1690 was shown to be a potent inhibitor of mouse and human ATX (IC50: 100-500 nM range). Similar potency was observed ex vivo in human and rodent plasma. In a therapeutic mouse COPD model, GLPG1690 (3, 10 and 30 mg/kg b.i.d., p.o.), dose-dependently reduced inflammatory cell counts in the BALF to a similar extent as roflumilast (5 mg/kg q.d., p.o.). In GLPG1690-treated mice, an inverse relationship was shown between LPA and GLPG1690 plasma levels.Conclusion: GLPG1690, a potent and selective ATX inhibitor, displays a strong overall developability profile, supporting the progression towards First-in-Human studies. For the first time, efficacy of an ATX inhibitor was shown in a model for COPD, pointing to a novel therapeutic area for this target.