Late Breaking Abstract - BBT-877, a Potent Autotaxin Inhibitor in Clinical Development to Treat Idiopathic Pulmonary Fibrosis

Abstract

Idiopathic Pulmonary Fibrosis (IPF) is a progressive, irreversible and fatal lung disease with unmet medical needs. Autotaxin (ATX) is an extracellular enzyme involved in the generation of lysophosphatidic acid (LPA). Preclinical and clinical data have suggested the ATX – LPA – LPA receptor (LPAR) axis plays a pivotal role in the pathogenesis and the progression of IPF. BBT-877 is an orally available small molecule inhibitor against ATX. In ex vivo enzymatic assays using human plasma, IC50 of BBT-877 was measured 6.5 – 6.9 nM (LPA 18:2) whereas that of GLPG1690 was measured 75 – 132 nM. To determine in vivo anti-fibrotic efficacy of BBT-877, bleomycin was intranasally administrated in mice at day 0, and BBT-877 was administrated orally twice a day from day 7 to 21. The BBT-877 treatment showed anti-fibrotic efficacy as revealed by significantly reduced body weight loss, lung weight and Ashcroft score as well as collagen content compared to the vehicle-treated group. During phase 1 clinical trial with 80 healthy volunteers, in which 50 – 800 mg (SAD) and 200 – 800 mg QD or 100 – 200 mg BID for two weeks (MAD) doses were administrated, only mild adverse events were noted. Pharmacokinetic analysis revealed the dose-proportional increase in systemic exposure with elimination half-life of 12hr. The decrease of plasma LPA level was maintained at 80% or higher for 24hr when 400 mg BBT-877 was administrated. Taken together, nonclinical data suggest BBT-877 is a potent, selective, and potentially best-in-class ATX inhibitor. Phase 1 clinical data demonstrate BBT-877 is a safe and well-tolerated drug with excellent pharmacokinetic-pharmacodynamic profiles.