Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis.
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.
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany Stefan-lutz.wollin@boehringer-ingelheim.com.
Lutz
L
Wollin
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
Eva
E
Wex
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
Alexander
A
Pautsch
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
Gisela
G
Schnapp
University Hospital Basel, Basel, Switzerland.
Katrin E
KE
Hostettler
Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany.
Susanne
S
Stowasser
McMaster University, Hamilton, ON, Canada.
Martin
M
Kolb
D000818:Animals; D017209:Apoptosis; D001761:Bleomycin / Q000737:chemistry; D002454:Cell Differentiation; D049109:Cell Proliferation; D002986:Clinical Trials as Topic; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D005109:Extracellular Matrix / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology; D005355:Fibrosis; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000188:drug therapy*; D007211:Indoles / Q000737:chemistry / Q000627:therapeutic use*; D008168:Lung / Q000166:cytology / Q000473:pathology; D008171:Lung Diseases / Q000188:drug therapy; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D012822:Silicon Dioxide / Q000737:chemistry; D016212:Transforming Growth Factor beta / Q000378:metabolism
D004791:Enzyme Inhibitors; D007211:Indoles; D010982:Platelet-Derived Growth Factor; D016212:Transforming Growth Factor beta; D001761:Bleomycin; D005346:Fibroblast Growth Factors; D012822:Silicon Dioxide; C530716:nintedanib