TY - JOUR T1 - Late Breaking Abstract - PK/PD assessment of an oral, selective aVß6/aVß1 integrin dual antagonist, PLN-74809, for the treatment of idiopathic pulmonary fibrosis JF - European Respiratory Journal JO - Eur Respir J DO - 10.1183/13993003.congress-2019.PA1298 VL - 54 IS - suppl 63 SP - PA1298 AU - Scott Turner AU - Eve Irene Lepist AU - Fernando Rock AU - Martin Decaris AU - Johanna Schaub AU - Chun Chen AU - Eduard Gorina AU - Eric Lefebvre Y1 - 2019/09/28 UR - http://erj.ersjournals.com/content/54/suppl_63/PA1298.abstract N2 - Integrins αVβ6 and αVβ1 are cell surface proteins that bind to and activate latent TGF-β, resulting in SMAD phosphorylation and pro-fibrotic gene expression. In IPF, both integrins are upregulated in the lung and are thought to play a role in the development and propagation of fibrosis. We have identified an orally available small molecule inhibitor with equal potency towards αVβ6 and αVβ1 that prevents integrin-mediated activation of TGF-β.PLN-74809 has a ligand binding IC50 < 10 nM for both murine and human αVβ6 and αVβ1, and an IC50 against TGF-β activation of <200 nM, with high selectivity relative to other integrins. Phase 1 studies of PLN-74809 in healthy volunteers have demonstrated good oral bioavailability and tolerability with a t1/2 supportive of once daily dosing.Inhibition of αVβ6-mediated TGF-β activation in the lung by can be detected through measurement of SMAD phosphorylation in alveolar macrophages. We administered inhibitors of αVβ6 to healthy and bleomycin-injured mice, healthy cynomolgus monkeys, and healthy volunteers to establish their pharmacokinetic/pharmacodynamic relationship. In healthy and fibrotic animals, oral dosing with PLN-74809 resulted in a time- and dose-dependent inhibition of SMAD phosphorylation in alveolar macrophages and lung tissue reflecting a reduction in TGF-β signaling.In healthy volunteers administered PLN-74809 40 mg QD for 7 days, BAL macrophage SMAD phosphorylation was suppressed by approximately half, demonstrative of in vivo pharmacological activity. These clinical pharmacodynamic data inform planned Phase 2a studies of PLN-74809 in IPF patients.FootnotesCite this article as: European Respiratory Journal 2019; 54: Suppl. 63, PA1298.This is an ERS International Congress abstract. No full-text version is available. Further material to accompany this abstract may be available at www.ers-education.org (ERS member access only). ER -