Nerandomilast Paves the Way for Novel Strategies in IPF Drug Discovery

Abstract 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. We hypothesize that novel, differentiated therapies must address the complexity of IPF pathobiology by targeting multiple cell types and pathways. Recent positive phase III trial data for the preferential PDE4B inhibitor nerandomilast, and accompanying preclinical mechanism of action studies, provide the first definitive evidence that targets which impact cell-types in addition to the fibroblast can be efficacious in the context of IPF. Objectives: By further defining the multiple mechanisms through which nerandomilast may confer efficacy, can we build on this knowledge by applying novel analytics and state-of-the-art technologies to guide the next generation of pharmacologic interventions for IPF? Methods and Results: We used a wide array of patient cells 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 the release of biomarkers of fibrogenesis from small airway epithelial cell cultures. Myofibroblast contractility was also inhibited, accompanied by markers of dedifferentiation toward a more normal fibroblast. Furthermore, nerandomilast significantly reduced microvascular permeability as well as innate immune cell adhesion and infiltration in an adeno-associated virus-human diphtheria toxin receptor/diphtheria toxin mouse model of acute lung injury. These effects were linked to activated cAMP-associated pathways, G-protein-coupled receptor (GPCR) signaling events, mitogen-activated protein kinase (MAPK) signaling pathways and transforming growth factor beta 1(TGFβ1) signaling. 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. We then applied AI-assisted systems – a gene prioritization algorithm (GPA) and large language model – to provide prioritized targets aligned with a particular pathologic niche. Finally, we explore the advances in in vitro co-culture / organoid test systems which are designed to functionally assess, and thereby help validate these targets of the future. 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.