Pharmacological profile and efficacy of GLPG1690, a novel ATX inhibitor for COPD treatment

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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.

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