Arginase inhibitor AZD8965: A novel therapeutic approach for idiopathic pulmonary fibrosis

Idiopathic Pulmonary Fibrosis (IPF) is a fatal and rapidly progressing lung disease with high unmet need. It is characterized by excessive matrix deposition, leading to severe lung function decline. Arginase expression and arginine metabolism has been shown to be dysregulated in pulmonary fibrosis. The critical role of arginase activity in collagen production, through ornithine production and proline biosynthesis, positions it as an attractive target for IPF treatment. This study investigated the efficacy of the novel, highly potent, and selective arginase inhibitor, AZD8965, currently in Ph1 in healthy volunteers, in reducing collagen production in models of IPF. In human lung tissue treated with pro-fibrotic cocktail, AZD8965 demonstrated a dose-dependent reduction in arginase activity, accompanied by a significant reduction in collagen synthesis. Mechanistically, we could show that altered ornithine concentrations can impact collagen synthesis by human primary lung fibroblasts. Moreover, in two Bleomycin-induced in- vivo mouse models of IPF, we successfully demonstrated the efficacy of AZD8965 to reduce lung ornithine levels (≥66%) and collagen synthesis (≥47%), resulting in an improvement in lung fibrosis endpoints. These findings support our hypothesis that reducing ornithine levels can effectively limit the availability of essential collagen building blocks. Consequently, our arginase inhibitor, AZD8965, emerges as a promising candidate for future monotherapy or combination therapies aimed at enhancing efficacy and tolerability in IPF treatment, with potential applicability extending beyond lung fibrosis.