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A1649 - Pharmacodynamics and Pharmacokinetics of the Autotaxin Inhibitor GLPG1690 in the FLORA Trial: A Randomized, Placebo-Controlled, Double Blind Phase IIa Clinical Trial of 12 Weeks in Individuals with Idiopathic Pulmonary Fibrosis
Author Block: S. Dupont1, J. Desrivot1, J. Ralic2, R. Blanqué1, A. Monjardet1, L. Allamassey3, L. Fagard3, J. Padovan2, B. Heckmann1, O. Van de Steen3, E. van der Aar3, A. Fieuw3; 1Galapagos, Romainville, France, 2Fidelta, Zagreb, Croatia, 3Galapagos, Mechelen, Belgium.
Rationale Idiopathic Pulmonary Fibrosis (IPF) is a chronic and progressive disease with a median survival of 2-5 years after diagnosis. Current drugs slow down disease progression; however the need for more effective and better tolerated therapies remains. GLPG1690 is a novel, potent, and selective small-molecule autotaxin (ATX) inhibitor. ATX is the main enzyme responsible of lysophosphatidic acid (LPA) production in blood. Studies in IPF individuals indicated an increase in LPA levels in the bronchoalveolar lavage fluid, an elevation of LPA 22:4 in exhaled breath condensate, and an increase of ATX levels in human fibrotic lung. The current FLORA trial included pharmacokinetics (PK) and pharmacodynamics (PD) as primary objective. Methods 24 IPF patients were to be randomized (3:1) to GLPG1690 600 mg once daily or placebo for 12 weeks of treatment and 2 weeks follow-up. Blood samples were drawn at baseline, 2 weeks after last dosing and pre-dose over the study, as well as on week 4 (predose, 1.5, 4 and 6 hours (h) post-dosing). Pharmacodynamics was monitored using LPA 18:2 plasma levels and analysed using liquid chromatography with tandem mass spectrometric detection (LC-MS/MS). GLPG1690 plasma levels were determined by LC-MS/MS and PK parameters by non-compartmental analysis using Phoenix WinNonlin. Results 23 patients (17 active, 6 placebo) were randomized. At 4 weeks of treatment, a strong reduction of LPA 18:2 plasma levels post dosing, up to 89±1 % in the GLPG1690 arm was observed, with similar reduction at 1.5h and 6h post dosing. The regulation of LPA 18:2 was sustained with 52±9 and 68±6 % reduction at pre-dose on week 4 and 12, respectively. Full reversibility of the effect was observed at the follow-up visit 2 weeks post treatment. At week 4, the median maximum observed plasma concentration (Cmax) of GLPG1690 was 6.06 µg/mL reached at a median tmax of 4 h. The mean area under the plasma concentration time curve for the dosing interval of 24 hours (AUC0-Ʈ) was 55.6 µg.h/mL associated with a trough plasma concentration (CƮ) of 604 ng/mL being around 4-fold higher than the IC50 in human plasma assay for the reduction of LPA 18:2 (143 ng/mL). Conclusion GLPG1690 induced a fast and sustained reduction in LPA 18:2 plasma levels in IPF patients, indicative for target engagement. Similar pharmacodynamic and pharmacokinetic profiles were previously observed in healthy subjects. The PK and the sustainable PD effect of GLPG1690 support once-daily dosing.