Background: The anti-inflammatory potential of phosphodiesterase 4 (PDE4) inhibition is well established. Dose limiting nausea and vomiting of PDE4 inhibitors in patients is likely associated to subtype PDE4D inhibition. BI1015550 is a preferential PDE4B inhibitor with suggested improved tolerability in humans.

Aim: To investigate activity of BI1015550 in a therapeutic rat model of bleomycin (bleo)-induced lung fibrosis, transcriptional profiling of lung tissue and confirmation of markers in human in-vitro models.

Methods: Bleo-induced lung fibrosis in rats was treated with BI1015550, 2.5mg/kg, b.i.d. from day 10 - 20. Lung tissue density (µCT) and function was monitored. Lung tissue was analyzed by RNA-Seq (NGS) and OPN protein expression. For comparison, human lung fibroblasts and airway epithelial cells (SAEC) were assayed.

Results: Therapeutic treatment with BI1015550 improved lung volume by 31%, reduced tissue density by 64% and OPN expression by 49%. Transcriptional changes induced by bleo were largely reverted by BI1015550. Rat NGS data were confirmed in human assays where BI1015550 attenuated MMP7 and OPN release in IPF-cocktail stimulated SAEC and reduced myofibroblast aSMA, CTGF and PAI1 protein levels.

Conclusions: Improvement of functional parameters by the preferential PDE4B inhibitor, BI1015550 (lung function and µCT measurement), reversal of fibrosis relevant pathways as demonstrated by NGS, and validated by human in vitro results, suggest a positive impact on fibrotic lung remodeling. These features make BI1015550 a promising clinical candidate for the treatment of fibrotic lung diseases.