Nerandomilast paves the way for novel strategies in IPF drug discovery*

Rationale: It has been over a decade since drugs addressing the growth/migration of scar-forming fibroblasts were launched for idiopathic pulmonary fibrosis (IPF) and beyond. Novel, differentiated therapies must address the complexity of IPF pathobiology by targeting multiple cell types and pathways. Recent positive phase III trials for the preferential PDE4B inhibitor nerandomilast, and accompanying preclinical studies, provide the first definitive evidence that targets which impact cell-types in addition to the fibroblast can be efficacious. Methods/Results: A wide array of patient cells were stimulated with an IPF mediator cocktail to understand effects of nerandomilast on epithelial cell activation; myofibroblast contractility and (de)differentiation; endothelial barrier integrity and immune cell adhesion/infiltration. Nerandomilast significantly reduced release of fibrogenesis biomarkers from small airway epithelial cell cultures, inhibited myofibroblast contractility, accompanied by markers of dedifferentiation toward a more normal fibroblast. Furthermore, nerandomilast significantly reduced microvascular permeability, innate immune cell adhesion and infiltration in a mouse model of acute lung injury. For next generation target finding, we assessed all the above cell populations and more, using spatial multi-omic analyses of human disease samples to characterize pathologic crosstalk between multiple cell-types in disease-associated niches. AI-assisted systems were applied to provide prioritized targets aligned with a particular pathologic niche. Finally, the advances in in vitro co-culture/organoid test systems were explored which are designed to functionally assess and validate these future targets. Conclusions: Nerandomilast’s efficacy in IPF may be attributable to effects on an array of patho- mechanisms in epithelial, endothelial, and immune cells, in addition to fibroblasts. Cutting edge technologies can build on such principles to transform drug discovery strategies. Next generation targets will influence our newly characterized pathologic niches, with the bold aim to not only limit disease but return functionality to the lung. *previously presented at the American Respiratory Society (ATS) congress 2025; ‡presenting on behalf of the authors Publication History Article published online: 04 March 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany