P146 Staying in the flow: PDE4B inhibitor nerandomilast (BI 1015550) improves features of vascular dysfunction in lung fibrosis in vitro and in vivo

The role of vascular dysfunction in the pathogenesis of pulmonary fibrosis has only recently emerged as an important contributor to the progression of disease. Several aspects such as increased vascular permeability and coagulation, increased immune cell infiltration and loss of endothelial specialisation have been discussed as pathological features in pulmonary fibrosis. The antifibrotic and anti-inflammatory potential of phosphodiesterase 4 (PDE4) inhibition for the pharmacological management of lung fibrosis is well established pre-clinically, but has failed so far to translate to patients due to dose-limiting nausea and vomiting, which is likely associated with subtype PDE4D inhibition. Nerandomilast (BI 1015550) is a novel preferential PDE4B inhibitor with suggested improved tolerability in humans. We investigated the activity and molecular mode of action of nerandomilast in disease-relevant 3D models of endothelial injury in vitro and validated results in a therapeutic rat model of bleomycin-induced lung fibrosis.

Human lung microvascular endothelial cells were cultured in microfluidic chips to form functional tubes. After inducing fibrotic changes by stimulation with an idiopathic pulmonary fibrosis-relevant cytokine cocktail, functional and molecular readouts were performed to analyse the effect of treatment with nerandomilast. Bleo-induced lung fibrosis in rats was treated with nerandomilast (2.5mg/kg twice daily from Day 10-20) and lung tissue was analysed by RNA sequencing (next-generation sequencing [NGS]).

Nerandomilast improves barrier integrity of injured endothelium up to 41% by increasing vasodilator-stimulated phospho-protein phosphorylation. Furthermore, nerandomilast reduces immune cell infiltration into injured endothelium up to 63% by inhibition of vascular cell adhesion molecule 1 and E-selectin. NGS data of a bleomycin rat model confirmed the beneficial effect of therapeutic treatment with nerandomilast on markers of vascular dysfunction in vivo.

Nerandomilast shows beneficial effects on several features of vascular dysfunction in vitro, which was confirmed in a therapeutic in vivo model of lung fibrosis. In the context of the existing preclinical and clinical data (Phase I and II studies), nerandomilast proves to be a promising candidate for treating patients with pulmonary fibrosis.

D. Reininger: Corporate appointments; Boehringer Ingelheim. F. Wolf: Corporate appointments; Boehringer Ingelheim (past). C. Mayr: Corporate appointments; Boehringer Ingelheim. P. Nickolaus: Corporate appointments; Boehringer Ingelheim. F. Hermann: Corporate appointments; Boehringer Ingelheim. Other; Boehringer Ingelheim (intellectual property).