RATIONALE Idiopathic Pulmonary Fibrosis (IPF) is a progressive, irreversible and fatal lung disease. Its risk factors include age, genetic and environmental/occupational factors. Currently available therapies only slow down disease progression. Autotaxin (ATX) is an extracellular enzyme involved in the hydrolysis of lysophosphatidylcholine (LPC) to form lysophosphatidic acid (LPA). The ATX-LPA-LPA receptor (LPAR) axis has been suggested to play a pivotal role in the pathogenesis and the progression of IPF. Genetic deletion of ATX, LPAR1 and LPAR2 significantly improved the severity of bleomycin-induced pulmonary fibrosis in mouse. Pharmacological inhibition of ATX and LPAR1 reduced lung fibrosis parameters resulted from the bleomycin treatment in mouse. Positive efficacy data were obtained from clinical trials with drugs targeting the ATX-LPAR pathway. METHODS The inhibitory potency of BBT-877, an orally available small molecule inhibitor of ATX, was measured by FS-3 (in vitro) and plasma LPC (ex vivo) assays. Transwell cell migration assay was used to quantify in vitro anti-migratory efficacy of BBT-877. In mouse disease model, bleomycin was intranasally administrated to induce pulmonary fibrosis at day 0, and BBT-877 was given orally twice a day from day 7 to 21. RESULTS In vitro and ex vivo IC 50 of BBT-877 were determined to be 2.4 nM and 6.89 nM (LPA 18:2), respectively. LPA-induced cell migration was effectively inhibited by BBT-877. In vivo anti-fibrotic efficacy of BBT-877 was shown in the mouse model of bleomycin-induced pulmonary fibrosis. BBT-877 did not significantly impair the viability of various cell types even when treated at high concentrations (CC 50 : >100 M). IND-enabling toxicology studies have been completed in the rat and monkey models, with demonstrated good safety profiles and no remarkable findings up to 1000 and 300 mg/kg/day, respectively. CONCLUSION Results of comprehensive in vitro and in vivo studies with BBT-877 demonstrate this compound is a very potent, selective, potentially best-in-class ATX inhibitor with a very favorable safety profile and support further investigation in clinical testing for the treatment of IPF. Phase 1 clinical studies are currently ongoing and will be completed by Aug 2019.
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