Nintedanib Inhibits Pulmonary Fibrosis Development in Aged Mice but Does Not Reverse Age-Dependent Established Fibrosis

Rationale: Idiopathic pulmonary fibrosis (IPF) is the most severe and deadly form of lung fibrosis. IPF is widely regarded as a disease of aging, as it disproportionately affects the elderly population. Nintedanib, a receptor tyrosine kinase inhibitor, is one of two FDA-approved treatments for IPF. Although numerous pre-clinical studies demonstrating the efficacy of nintedanib in young animals, nintedanib is almost exclusively prescribed to elderly patients. To date, no studies have specifically evaluated whether aging impacts the efficacy of nintedanib. Methods: We evaluated the efficacy of nintedanib in both young (2 month) and old (18 month) mice. Lung fibrosis was induced by intratracheal administration of bleomycin. Nintedanib (60 mg/kg) or vehicle was administered daily by oral gavage during the development of fibrosis (10-21 days post-injury). We also evaluated the efficacy of nintedanib in an aging model of persistent fibrosis, where treatment was administered during the established fibrotic phase (3w-6w post-injury). Lung fibrosis was assessed by histopathology, quantitative biochemical assays for whole lung collagen, organ and systemic measurements, and lung functional testing. Results: Young and aged mice demonstrated similar severity of fibrosis in response to injury. Nintedanib treatment inhibiting the development of fibrosis in both young and aged mice to the same extent, indicating that aging does not impact the efficacy of nintedanib. However, nintedanib treatment demonstrated no efficacy for rapidly resolving age-dependent established fibrosis during this 3-week treatment period. Conclusions: This study is the first to demonstrate that aging does not impact the efficacy of nintedanib in terms of its ability to inhibit the development of fibrosis. Given that nintedanib is predominantly administered to elderly patients, this is reassuring from a clinical standpoint, as these studies suggest that age alone does not impact the efficacy of nintedanib for inhibiting the development of de novo lung fibrosis. Our studies indicate that nintedanib failed to rapidly promote the resolution of age-dependent established lung fibrosis during this 3-week treatment period. However, it is possible that increased treatment duration of nintedanib may be required in order to more rigorously evaluate its efficacy for reversal of established fibrosis. Funding: Boehringer Ingelheim Pharma GmbH & Co. KG.