1. IPF Pathophysiology and Nintedanib Mode of Action
Slidekit
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2. Wound repair in healthy lungs
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3. In healthy lungs, alveolar epithelial cells form part of
the alveolar-capillary barrier.1
Alveolar epithelium
Interstitial space
Strieter RM, et al. Chest. 2009;136:
Gordon SB, et al. Br Med Bull. 2002;61:45-61.
Clarke DL, et al. Fibrogenesis Tissue Repair. 2013;6:20.
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4. On the inner surface of the alveolus, macrophages serve as a first-line defence against pathogens.2 
Alveolar macrophages
Interstitial space
Strieter RM, et al. Chest. 2009;136:
Gordon SB, et al. Br Med Bull. 2002;61:45-61.
Clarke DL, et al. Fibrogenesis Tissue Repair. 2013;6:20.
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5. Gas exchange takes place across the alveolar-capillary barrier
and the blood is oxygenated.1 
Gas exchange
Strieter RM, et al. Chest. 2009;136:
Gordon SB, et al. Br Med Bull. 2002;61:45-61.
Clarke DL, et al. Fibrogenesis Tissue Repair. 2013;6:20.
references

6. Local fibroblasts play a central role in maintaining normal tissue structure and function, and mediate the wound healing response.3
Fibroblasts
Strieter RM, et al. Chest. 2009;136:
Gordon SB, et al. Br Med Bull. 2002;61:45-61.
Clarke DL, et al. Fibrogenesis Tissue Repair. 2013;6:20.
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7. Damage to the alveolar epithelium initiates the coagulation cascade
Cytokines
Alveolar
damage
Camelo A, et al. Inflamm Pharmacol. 2014;4:173.
Chambers RC. Eur Respir Rev. 2008;17:
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8. Activated platelets from the blood stream release pro-fibrotic factors
including PDGF and TGF-β1…1
Platelets
Camelo A, et al. Inflamm Pharmacol. 2014;4:173.
Chambers RC. Eur Respir Rev. 2008;17:
Clarke DL, et al. Fibrogenesis Tissue Repair. 2013;6:20.
references

9. …and form a loose plug, which is stabilised by long strands of fibrin
Fibrin network
Camelo A, et al. Inflamm Pharmacol. 2014;4:173.
Chambers RC. Eur Respir Rev. 2008;17:
Clarke DL, et al. Fibrogenesis Tissue Repair. 2013;6:20.
references

10. Inflammatory cells are recruited to the site of injury.1,3
Alveolar macrophages
Neutrophils
Camelo A, et al. Inflamm Pharmacol. 2014;4:173.
Chambers RC. Eur Respir Rev. 2008;17:
Clarke DL, et al. Fibrogenesis Tissue Repair. 2013;6:20.
references

11. In this repair response, fibroblasts differentiate into myofibroblasts and begin to remodel the extracellular matrix.1-3
Fibroblasts
Myofibroblasts
Camelo A, et al. Inflamm Pharmacol. 2014;4:173.
Chambers RC. Eur Respir Rev. 2008;17:
Clarke DL, et al. Fibrogenesis Tissue Repair. 2013;6:20.
references

12. 1. Gardner A., et al. Expert Rev Respir Med. 2010;4:647-660.
In the physiologic healing process, these cells normally undergo apoptosis once wound contraction is complete.1
Collagen
1. Gardner A., et al. Expert Rev Respir Med. 2010;4:
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13. Reformed alveolar epithelium Mature extracellular matrix
The provisional extracellular matrix matures and the alveolar epithelium reforms.1 
Reformed alveolar epithelium
Mature extracellular matrix
1. Gardner A., et al. Expert Rev Respir Med. 2010;4:
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14. IPF Mechanism of Disease
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15. Although the pathophysiology of IPF is not yet fully understood…
Alveolar
damage
1. Gardner A., et al. Expert Rev Respir Med. 2010;4:
2. Chambers RC. Eur Respir Rev. 2008;17:
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16. Cytokines (e.g. PDGF, TGF-β1)
…there is evidence that repetitive alveolar injury causes dysregulated wound healing in susceptible individuals.1,2 
Cytokines (e.g. PDGF, TGF-β1)
1. Gardner A., et al. Expert Rev Respir Med. 2010;4:
2. Chambers RC. Eur Respir Rev. 2008;17:
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17. Under the influence of numerous fibrogenic mediators such as PDGF and TGF-β1, myofibroblasts proliferate uncontrolled.1,2
Fibroblasts
Myofibroblasts
Collagen
Chambers RC. Eur Respir Rev. 2008;17:
Hinz B. Proc Am Thorac Soc 2012;9:
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18. Excessive deposition of Permanently impaired epithelium
extracellular matrix in the interstitium creates fibrotic scar tissue.2
Permanently impaired epithelium
Fibrotic tissue
Chambers RC. Eur Respir Rev. 2008;17:
Hinz B. Proc Am Thorac Soc 2012;9:
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19. Excessive deposition of
As a result, the lung tissue stiffens and the gas exchange is impaired.2
Excessive deposition of
extracellular matrix in the interstitium creates fibrotic scar tissue.2
Impaired
gas exchange
Chambers RC. Eur Respir Rev. 2008;17:
Hinz B. Proc Am Thorac Soc 2012;9:
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20. Nintedanib Mode of Action
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21. In IPF, damaged alveolar epithelial cells secrete numerous cytokines
including TGF-β1, FGF, PDGF and TNF-α.1,2
1. Chambers RC. Eur Respir Rev 2008;17:130–137.
2. Gardner A., et al. Expert Rev Respir Med. 2010;4:647–660.
references

22. Receptors located on the fibroblast surface are activated
through those cytokines and induce intracellular signalling.1-3
Cytokines incl. TGF-β1, FGF, PDGF and TNF-α
Tyrosine kinase receptors
Fibroblast cell membrane
Wollin L, et al. J Pharmacol Exp Ther. 2014;349:
Wollin L, et al. Eur Respir J. 2015;45:
Thannickal VJ, et al. J Biol Chem. 2003;278:
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23. Receptors located on the fibroblast surface are activated
through those cytokines and induce intracellular signalling.1-3
Cytokine-receptor-complex
Downstream signalling
Wollin L, et al. J Pharmacol Exp Ther. 2014;349:
Wollin L, et al. Eur Respir J. 2015;45:
Thannickal VJ, et al. J Biol Chem. 2003;278:
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24. receptors specific for PDGF, FGF and VEGF.2
Nintedanib is a tyrosine kinase inhibitor that targets, amongst others,
receptors specific for PDGF, FGF and VEGF.2
Nintedanib
Wollin L, et al. J Pharmacol Exp Ther. 2014;349:
Wollin L, et al. Eur Respir J. 2015;45:
Thannickal VJ, et al. J Biol Chem. 2003;278:
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25. Downstream signalling inhibited
By binding to the intracellular ATP binding pocket, nintedanib can block downstream signalling cascades.2
Nintedanib
Downstream signalling inhibited
Wollin L, et al. J Pharmacol Exp Ther. 2014;349:
Wollin L, et al. Eur Respir J. 2015;45:
Thannickal VJ, et al. J Biol Chem. 2003;278:
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26. Inhibited fibroblasts
By doing this, fibroblast proliferation and TGF-β-induced differentiation into myofibroblasts is inhibited.1,2
Inhibited fibroblasts
Nintedanib
Hostettler KE, et al. Respir Res. 2014;15:157.
Wollin L, et al. Eur Respir J. 2015;45:
Richeldi L, et al. N Engl J Med. 2014;370:
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27. Reduced fibrotic tissue production
Consequently, fibrotic tissue production and inflammatory processes are reduced and disease progression is slowed down.2,3
Reduced fibrotic tissue production
Hostettler KE, et al. Respir Res. 2014;15:157.
Wollin L, et al. Eur Respir J. 2015;45:
Richeldi L, et al. N Engl J Med. 2014;370:
references

28. OFEV® (nintedanib) is indicated in adults for the treatment of
Idiopathic Pulmonary Fibrosis (IPF).
Ofev® Summary of Product Characteristics (abbreviated, January 2016)
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29. Ofev® Summary of Product Characteristics (abbreviated, Jan 28th 2016)
1. Strieter RM., et al. NEw mechanisms of pulmonary fibrosis. Chest 2009;136:1364–1370.
Gordon SB., et al. Macrophage defences against respiratory tract infections The immunology of
childhood respiratory infections. Br Med Bull 2002;61:45–61.
3. Clarke DL., et al. Matrix regulation of idiopathic pulmonary fibrosis: the role of enzymes.
Fibrogenesis Tissue Repair 2013;6:20.
4. Chambers RC. Abnormal wound healing responses in pulmonary fibrosis: focus on coagulation signalling.
Eur Respir Rev 2008;17:130–137.
Camelo A., et al. The epithelium in idiopathic pulmonary fibrosis: breaking the barrier.
Inflamm Pharmacol 2014;4:173.
Gardner A., et al. Lung epithelial wound healing in health and disease.
Expert Rev Respir Med 2010;4:647–660.
7. Hinz B. Mechanical Aspects of Lung Fibrosis. Proc Am Thorac Soc 2012;9:137–147.
8. Gardner A., et al. Lung epithelial wound healing in health and disease. Expert Rev Respir Med 2010;4:647–660.
9. Wollin L., et al. Antifibrotic and Anti-inflammatory Activity of the Tyrosine Kinase Inhibitor Nintedanib in Experimental Models of Lung Fibrosis. J Pharmacol Exp Ther 2014;349:209–220.
Wollin L., et al. Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis.
Eur Respir J 2015;45:1434–1445.
11. Thannickal VJ., et al. Myofibroblast differentiation by transforming growth factor-beta1 is dependent on cell adhesion and integrin signaling via focal adhesion kinase. J Biol Chem 2003;278:12384–12389.
12. Hostettler KE., et al. Anti-fibrotic effects of nintedanib in lung fibroblasts derived from patients with idiopathic pulmonary fibrosis. Respir Res 2014;15:157.
Richeldi L., et al. Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis.
N Engl J Med 2014;370:2071–2082.
Ofev® 100 mg/150 mg soft capsules, for oral use. Active substance: Nintedanib. Qualitative and quantitative composition: One capsule contains 100 mg/150 mg nintedanib (as esilate). Excipient(s) with known effect: Each capsule contains 1.2 mg of soya lecithin. /Each capsule contains 1.8 mg of soya lecithin. List of excipients: Capsule content: Triglycerides, medium-chain; hard fat; lecithin (soya) (E322). Capsule shell: Gelatin, glycerol (85%), titanium dioxide (E171), iron oxide red (E172), iron oxide yellow (E172). Printing ink: Shellac glaze, iron oxide black (E172), propylene glycol (E1520). Indication: Ofev® is indicated in adults for the treatment of Idiopathic Pulmonary Fibrosis (IPF). Contraindications: Hypersensitivity to nintedanib, peanut or soya, or to any of the excipients listed above. Pregnancy and breast feeding: As nintedanib may cause foetal harm also in humans, it must not be used during pregnancy. There is no information on the excretion of nintedanib and its metabolites in human milk. Pre-clinical studies showed that small amounts of nintedanib and its metabolites (≤0.5% of the administered dose) were secreted into milk of lactating rats. A risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with Ofev®. Effects on ability to drive and use machines: Ofev® has minor influence on the ability to drive and use machines. Patients should be advised to be cautious when driving or using machines during treatment with Ofev®. Adverse reactions: Very common: Diarrhoea, nausea, abdominal pain, hepatic enzyme increased. Common: Weight decreased, decreased appetite, epistaxis, vomiting, aspartate aminotransferase (AST) increased, alanine aminotransferase (ALT) increased, gamma-glutamyltransferase (GGT) increased. Uncommon: Hypertension, hyperbilirubinaemia, blood alkaline phosphatase (ALKP) increased. Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01XE31. Mechanism of action: Nintedanib is a small molecule tyrosine kinase inhibitor including the receptors platelet-derived growth factor receptor (PDGFR) α and β, fibroblast growth factor receptor (FGFR) 1-3, and vascular endothelial growth factor receptor (VEGFR) 1-3. Nintedanib binds competitively and blocks the intracellular signalling. Warnings and precautions: See SmPC. Posology: The recommended dose of nintedanib is 150 mg twice daily administered approximately 12 hours apart. The 100-mg twice-daily dose is only recommended to be used in patients who do not tolerate the 150-mg twice-daily dose. Special populations: Elderly patients: Patients ≥75 years may be more likely to require dose reduction to manage adverse effects. Renal impairment: The safety, efficacy, and pharmacokinetics of nintedanib have not been studied in patients with severe renal impairment (<30 mL/min creatinine clearance). Hepatic impairment: Exposure increased in patients with hepatic impairment (Child Pugh A and Child Pugh B).No adjustment of the starting dose is needed for patients with mild hepatic impairment based on clinical data (Child Pugh A). Treatment of patients with moderate (Child Pugh B) and severe (Child Pugh C) hepatic impairment with Ofev® is not recommended. Paediatric population: The safety and efficacy of Ofev® in children aged 0-18 years have not been established. No data are available. Medicinal product subject to restricted medical prescription. Further Information: See SmPC. Distributed by: Boehringer Ingelheim Pharma GmbH & Co. KG, Binger Strasse 173, D Ingelheim am Rhein, Germany.
(Please note that this is the European Version of the abbreviated SmPC that should be adapted based on the local rules of your respective country. Please reach out to the respective unit of Boehringer Ingelheim for a local SmPC.)
references

30. References Strieter RM, et al. Chest. 2009;136:1364-1370.
1. Strieter RM., et al. NEw mechanisms of pulmonary fibrosis. Chest 2009;136:1364–1370.
Gordon SB., et al. Macrophage defences against respiratory tract infections The immunology of
childhood respiratory infections. Br Med Bull 2002;61:45–61.
3. Clarke DL., et al. Matrix regulation of idiopathic pulmonary fibrosis: the role of enzymes.
Fibrogenesis Tissue Repair 2013;6:20.
4. Chambers RC. Abnormal wound healing responses in pulmonary fibrosis: focus on coagulation signalling.
Eur Respir Rev 2008;17:130–137.
Camelo A., et al. The epithelium in idiopathic pulmonary fibrosis: breaking the barrier.
Inflamm Pharmacol 2014;4:173.
Gardner A., et al. Lung epithelial wound healing in health and disease.
Expert Rev Respir Med 2010;4:647–660.
7. Hinz B. Mechanical Aspects of Lung Fibrosis. Proc Am Thorac Soc 2012;9:137–147.
8. Gardner A., et al. Lung epithelial wound healing in health and disease. Expert Rev Respir Med 2010;4:647–660.
9. Wollin L., et al. Antifibrotic and Anti-inflammatory Activity of the Tyrosine Kinase Inhibitor Nintedanib in Experimental Models of Lung Fibrosis. J Pharmacol Exp Ther 2014;349:209–220.
Wollin L., et al. Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis.
Eur Respir J 2015;45:1434–1445.
11. Thannickal VJ., et al. Myofibroblast differentiation by transforming growth factor-beta1 is dependent on cell adhesion and integrin signaling via focal adhesion kinase. J Biol Chem 2003;278:12384–12389.
12. Hostettler KE., et al. Anti-fibrotic effects of nintedanib in lung fibroblasts derived from patients with idiopathic pulmonary fibrosis. Respir Res 2014;15:157.
Richeldi L., et al. Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis.
N Engl J Med 2014;370:2071–2082.
Strieter RM, et al. Chest. 2009;136:
Gordon SB, et al. Br Med Bull. 2002;61:45-61.
Clarke DL, et al. Fibrogenesis Tissue Repair. 2013;6:20.
Chambers RC. Eur Respir Rev. 2008;17:
Camelo A, et al. Inflamm Pharmacol. 2014;4:173.
Hinz B. Proc Am Thorac Soc. 2012;9:
Gardner A, et al. Expert Rev Respir Med. 2010;4:
Wollin L, et al. J Pharmacol Exp Ther. 2014;349:
Wollin L, et al. Eur Respir J. 2015;45:
Thannickal VJ, et al. J Biol Chem. 2003;278:
Hostettler KE, et al. Respir Res. 2014;15:157.
Richeldi L, et al. N Engl J Med 2014;370:
references