Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease characterised by fibrosis of the lung parenchyma and loss of lung function. Although the pathogenic pathways involved in IPF have not been fully elucidated, IPF is believed to be caused by repetitive alveolar epithelial cell injury and dysregulated repair, in which there is uncontrolled proliferation of lung fibroblasts and differentiation of fibroblasts into myofibroblasts, which excessively deposit extracellular matrix (ECM) proteins in the interstitial space. A number of profibrotic mediators including platelet-derived growth factor (PDGF), fibroblast growth factor (FGF) and transforming growth factor-β are believed to play important roles in the pathogenesis of IPF. Nintedanib is a potent small molecule inhibitor of the receptor tyrosine kinases PDGF receptor, FGF receptor and vascular endothelial growth factor receptor. Data from in vitro studies have shown that nintedanib interferes with processes active in fibrosis such as fibroblast proliferation, migration and differentiation, and the secretion of ECM. In addition, nintedanib has shown consistent anti-fibrotic and anti-inflammatory activity in animal models of lung fibrosis. These data provide a strong rationale for the clinical efficacy of nintedanib in patients with IPF, which has recently been demonstrated in phase III clinical trials.

Effect of Nintedanib in Subgroups of Idiopathic Pulmonary Fibrosis by Diagnostic Criteria

“…Nintedanib is an intracellular inhibitor of tyrosine kinases (8) that has been approved for the treatment of IPF in several countries and regions, including the United States (9), Europe (10), and Japan, and it has received a conditional recommendation for use in the latest international clinical practice guideline for the treatment of IPF (11). The two replicate, randomized, placebo-controlled phase III INPULSIS trials investigated the efficacy and safety of nintedanib 150 mg twice daily in patients with IPF (12).…”

Idiopathic pulmonary fibrosis: a holistic approach to disease management in the antifibrotic age

“…This pathway is thought to be involved in the development of fibrosis and its inhibition leads to a reduction in profibrotic mediators (15). Nintedanib is also licensed for the treatment of advanced non-small cell lung cancer.…”

Recommendations for the management of idiopathic pulmonary fibrosis in South Africa: a position statement of the South African Thoracic Society

“…Thus pirfenidone is currently conditionally recommended therapy by both the ATS and ERS because of the reduction in FVC decline, lowering of mortality and absence of severe side-effects (3). Nintedanib is a potent intracellular multi-target tyrosine kinase inhibitor which binds & blocks the receptors of vascular endothelial growth factor, platelet-derived growth factor and fibroblast growth factor (18). Three multicentre randomised double-blind placebo-controlled trials, the phase II TOMORROW and two phase III INPULSIS trials (19) investigated its efficacy and safety over 1 year in patients with IPF.…”