Simultaneous inhibition of CTGF and Autotaxin reduces lung fibrosis and improves lung function in mice

IPF is a progressive and lethal disease and phase 2 trials have shown that inhibition of CTGF (Pamrevlumab/FG3019, Fibrogen Inc.) or Autotaxin (Ziretaxestat/GLPG1690 Galapagos Inc.) slow the decline in FVC experienced by IPF patients. Given the stabilization of FVC observed from combining Nintedanib and Pirfenidone, we investigated the potential benefit of combining FG3019 and GLPG1690 in a mouse model of IPF. Mice were subjected to intratracheal dosing of bleomycin to induce lung fibrosis and treated with FG3019 and/or GLPG1690 for 14 days. Changes in bodymass, survival, physiological measurements, plasma, BALF and lung tissue were recorded during the study. The progression of fibrosis was determined by Flexivent, lung hydroxyproline levels, Ashcroft-Hubner histopathological scores, as well as machine learning-based of lung sections or micro CT-scanned lungs respectively. FG3019 prevented the increase in lung hydroxyproline levels caused by bleomycin, while treatment with GLPG1690 did not have this effect. In contrast, GLPG1690 treated mice had better FVC and inspiratory capacity than vehicle controls, while mice receiving FG3019 did not. The combination of FG3019 and GLPG1690 reduced the accumulation of lung hydroxyproline and improved lung function parameters. The Ashcroft-Hubner scores were reduced in mice receiving FG3019 or GLPG1690 as a single treatment, but further reductions were not observed mice treated with FG3019 and GLPG1690. The combination of FG3019 and GLPG1690 treatment demonstrated an enhanced therapeutic efficacy by conferring the independent and parallel benefits of the single agents on experimental lung fibrosis endpoints.