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Pharmacological Profile and Efficacy of GLPG1690, a Novel Autotaxin Inhibitor for the Treatment of Idiopathic Pulmonary Fibrosis

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…). GLPG1690 is a novel potent ATX inhibitor that successfully completed clinical Phase 1 evaluations, in which sustained target engagement was shown. Recently, a role for the ATX/LPA axis in lung fibrosis was reported, prompting us to evaluate GLPG1690 in this pathology. Aims & objectives To characterize the pharmacological profile of GLPG1690, a novel ATX inhibitor, as well as its efficacy in lung fibrosis induced by bleomycin in mice. 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. Lung weight, Ashcroft score and collagen content were used as a measure for efficacy in a mouse bleomycin model for idiopathic pulmonary fibrosis (IPF) run in prophylactic and therapeutic setting. LPA levels were determined in plasma and bronchoalveolar lavage fluid (BALF) of control and GLPG1690-treated animals. Results GLPG1690 was shown to be a potent inhibitor of mouse and human ATX (IC50 values of 224 and 131 nM, respectively). Similar potency was observed ex vivo in human and rodent plasma. In GLPG1690-treated mice, an inverse relationship was shown between LPA and GLPG1690 plasma levels reflecting in vivo target engagement. In a prophylactic mouse bleomycin-induced lung fibrosis model, GLPG1690 dosed at 30 mg/kg bid p.o. was significantly superior to pirfenidone (50 mg/kg b.i.d., p.o.) on both Ashcroft score and collagen content readouts. An increase of various LPA species was observed in BALF of bleomycin-treated animals. This increase was reversed by GLPG1690 treatment for short LPA species (C16 to C20 but not for longer species (C22:5 and C22:6). In therapeutic setting, GLPG1690 dosed at 30 mg/kg bid p.o. displayed significant efficacy whereas effects of pirfenidone (50 mg/kg bid p.o.) were not statistically significant. Conclusion GLPG1690, a potent and selective ATX inhibitor, displayed high efficacy in a preclinical model for IPF, pointing to a novel therapeutic area for this target. Taking this information in combination with results from a phase 1 study in healthy subjects showing an excellent safety profile, good pharmacokinetics and a solid LPA biomarker response, Galapagos has decided to initiate an exploratory phase 2a study in IPF patients early 2016.

ATX inhibitor

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