Favorable human safety, pharmacokinetics and pharmacodynamics of the autotaxin inhibitor GLPG1690, a potential new treatment in COPD

Introduction: Autotaxin (ATX) is a secreted enzyme with lysophospholipase D activity responsible for the production of the bioactive lipid lysophosphatidic acid (LPA). LPA acts through several LPA receptors which promote among others cell proliferation, survival and muscle contraction. Recently, a role for the ATX/LPA axis was reported in several lung diseases. We identified GLPG1690 as a potent and selective inhibitor of ATX. It has good ADME and pharmacokinetic properties and showed dose-related effects in a mouse tobacco smoke COPD model. Aim and objectives: To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics (PD) of GLPG1690 in healthy subjects. Methods: GLPG1690 was administered as single oral doses (20 up to 1500 mg) or multiple doses (up to 1000 mg for 14 days). Each dose level was evaluated in panels of 8 male healthy subjects, 6 receiving GLPG1690 and 2 placebo. PD was assessed by the measurement of LPA18:2 levels in plasma via LC-MS. Results: GLPG1690 was safe and well tolerated up to a single oral dose of 1500 mg and up to 1000 mg q.d. for 14 days, with no adverse effects on ECGs, vital signs or laboratory parameters. The compound showed good oral bioavailability with a half-life of 5 h and a dose-proportional increase in exposure. GLPG1690 showed concentration-dependent reduction of plasma LPA18:2 levels with a maximum of approximately 90%. At steady state, continuous reduction of LPA18:2 levels of >60% was observed from 0 to 24 h. Conclusion: These data in healthy subjects and the preclinical data generated encourage Galapagos to explore a Phase 2 study design in pulmonary disease.