Potential of nintedanib in treatment of progressive fibrosing interstitial lung diseases

European Respiratory Journal

Volumn 54, Issue 3, 2019, Pages

  Wollin, Lutz ^a   Distler, Jörg H W ^b   Redente, Elizabeth F ^c   Riches, David W H ^c,d   Stowasser, Susanne ^a   Schlenker Herceg, Rozsa ^e   Maher, Toby M ^f,g   Kolb, Martin ^h  

^a BOEHRINGER INGELHEIM PHARMA GMBH AND CO KG   (Germany)

^b UNIVERSITY HOSPITAL ERLANGEN   (Germany)

^c DEPARTMENT OF MEDICINE   (United States)

^d UNIVERSITY OF COLORADO SCHOOL OF MEDICINE   (United States)

^e BOEHRINGER INGELHEIM PHARMACEUTICALS INC   (United States)

^f NATIONAL HEART AND LUNG INSTITUTE   (United Kingdom)

^g ROYAL BROMPTON HOSPITAL   (United Kingdom)

^h MCMASTER UNIVERSITY   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

BLEOMYCIN; NINTEDANIB; OVALBUMIN; PLACEBO; SILICON DIOXIDE; ZYMOSAN; ANTIINFLAMMATORY AGENT; INDOLE DERIVATIVE; PROTEIN KINASE INHIBITOR;

AIRWAY REMODELING; ALLERGY; ANTIFIBROTIC ACTIVITY; ANTIINFLAMMATORY ACTIVITY; BLEOMYCIN-INDUCED PULMONARY FIBROSIS; CHRONIC HYPERSENSITIVITY PNEUMONITIS; DISEASE COURSE; DISEASE MODEL; DRUG EFFICACY; DRUG MECHANISM; DRUG SAFETY; DRUG TARGETING; ENVIRONMENTAL FACTOR; FORCED VITAL CAPACITY; HEART MUSCLE FIBROSIS; HUMAN; IN VITRO STUDY; INTERSTITIAL PNEUMONIA; LUNG BLOOD VESSEL; LUNG FIBROSIS; MOUSE MODEL; NONHUMAN; PATHOGENESIS; PHENOTYPE; REVIEW; SILICA-INDUCED PULMONARY FIBROSIS; SKIN FIBROSIS; VASCULAR LESION; ZYMOSAN-INDUCED ARTHRITIS; ANIMAL; COMPLICATION; DISEASE EXACERBATION; DRUG EFFECT; EXTRACELLULAR MATRIX; FIBROBLAST; FIBROSING ALVEOLITIS; FIBROSIS; INTERSTITIAL LUNG DISEASE; LUNG; METABOLISM; MOUSE; PATHOPHYSIOLOGY; SYSTEMIC SCLEROSIS;

ANIMALS; ANTI-INFLAMMATORY AGENTS; BLEOMYCIN; DISEASE MODELS, ANIMAL; DISEASE PROGRESSION; EXTRACELLULAR MATRIX; FIBROBLASTS; FIBROSIS; HUMANS; IDIOPATHIC PULMONARY FIBROSIS; INDOLES; LUNG; LUNG DISEASES, INTERSTITIAL; MICE; PHENOTYPE; PROTEIN KINASE INHIBITORS; PULMONARY FIBROSIS; SCLERODERMA, SYSTEMIC;

EID: 85071130469     PISSN: 09031936     EISSN: 13993003     Source Type: Journal    
DOI: 10.1183/13993003.00161-2019     Document Type: Review

References (65)

1. Travis WD, Costabel U, Hansell DM, et al. An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med 2013; 188: 733-748.
2. Raghu G, Remy-Jardin M, Myers JL, et al. Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ ALAT clinical practice guideline. Am J Respir Crit Care Med 2018; 198: e44-e68.
3. Wells AU, Brown KK, Flaherty KR, et al. What's in a name? That which we call IPF, by any other name would act the same. Eur Respir J 2018; 51: 1800692.
4. Jegal Y, Kim DS, Shim TS, et al. Physiology is a stronger predictor of survival than pathology in fibrotic interstitial pneumonia. Am J Respir Crit Care Med 2005; 171: 639-644.
5. Zamora-Legoff JA, Krause ML, Crowson CS, et al. Progressive decline of lung function in rheumatoid arthritis-associated interstitial lung disease. Arthritis Rheumatol 2017; 69: 542-549.
6. Moore OA, Goh N, Corte T, et al. Extent of disease on high-resolution computed tomography lung is a predictor of decline and mortality in systemic sclerosis-related interstitial lung disease. Rheumatology 2013; 52: 155-160.
7. Fernández Pérez ER, Swigris JJ, Forssén AV, et al. Identifying an inciting antigen is associated with improved survival in patients with chronic hypersensitivity pneumonitis. Chest 2013; 144: 1644-1651.
8. Kirkil G, Lower EE, Baughman RP. Predictors of mortality in pulmonary sarcoidosis. Chest 2018; 153: 105-113.
9. Leung CC, Yu IT, Chen W. Silicosis. Lancet 2012; 379: 2008-2018.
10. Ryerson CJ, Urbania TH, Richeldi L, et al. Prevalence and prognosis of unclassifiable interstitial lung disease. Eur Respir J 2013; 42: 750-757.
11. Cottin V, Wollin L, Fischer A, et al. Fibrosing interstitial lung diseases: knowns and unknowns. Eur Respir Rev 2019; 28: 180100.
12. Maher TM, Wuyts W. Management of fibrosing interstitial lung diseases. Adv Ther 2019; 36: 1518-1531.
13. Strieter RM, Mehrad B. New mechanisms of pulmonary fibrosis. Chest 2009; 136: 1364-1370.
14. Maher TM, Wells AU, Laurent GJ. Idiopathic pulmonary fibrosis: multiple causes and multiple mechanisms? Eur Respir J 2007; 30: 835-839.
15. Altorok N, Wang Y, Kahaleh B. Endothelial dysfunction in systemic sclerosis. Curr Opin Rheumatol 2014; 26: 615-620.
16. Bagnato G, Harari S. Cellular interactions in the pathogenesis of interstitial lung diseases. Eur Respir Rev 2015; 24: 102-114.
17. Andersson-Sjöland A, de Alba CG, Nihlberg K, et al. Fibrocytes are a potential source of lung fibroblasts in idiopathic pulmonary fibrosis. Int J Biochem Cell Biol 2008; 40: 2129-2140.
18. Willis BC, du Bois RM, Borok Z. Epithelial origin of myofibroblasts during fibrosis in the lung. Proc Am Thorac Soc 2006; 3: 377-382.
19. Hung C, Linn G, Chow YH, et al. Role of lung pericytes and resident fibroblasts in the pathogenesis of pulmonary fibrosis. Am J Respir Crit Care Med 2013; 188: 820-830.
20. Fernandez IE, Eickelberg O. New cellular and molecular mechanisms of lung injury and fibrosis in idiopathic pulmonary fibrosis. Lancet 2012; 380: 680-688.
21. Huang X, Yang N, Fiore VF, et al. Matrix stiffness-induced myofibroblast differentiation is mediated by intrinsic mechanotransduction. Am J Respir Cell Mol Biol 2012; 47: 340-348.
22. Mross K, Stefanic M, Gmehling D, et al. Phase I study of the angiogenesis inhibitor BIBF 1120 in patients with advanced solid tumors. Clin Cancer Res 2010; 16: 311-319.
23. Eisen T, Shparyk Y, Macleod N, et al. Effect of small angiokinase inhibitor nintedanib (BIBF 1120) on QT interval in patients with previously untreated, advanced renal cell cancer in an open-label, phase II study. Invest New Drugs 2013; 31: 1283-1293.
24. Hilberg F, Roth GJ, Krssak M, et al. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res 2008; 68: 4774-4782.
25. Hilberg F, Tontsch-Grunt U, Baum A, et al. Triple angiokinase inhibitor nintedanib directly inhibits tumor cell growth and induces tumor shrinkage via blocking oncogenic receptor tyrosine kinases. J Pharmacol Exp Ther 2018; 364: 494-503.
26. Cope AP, Schulze-Koops H, Aringer M. The central role of T cells in rheumatoid arthritis. Clin Exp Rheumatol 2007; 25: S4-S11.
27. O'Reilly S, Hügle T, van Laar JM. T cells in systemic sclerosis: a reappraisal. Rheumatology 2012; 51: 1540-1549.
28. Barber EK, Dasgupta JD, Schlossman SF, et al. The CD4 and CD8 antigens are coupled to a protein-tyrosine kinase (p56lck) that phosphorylates the CD3 complex. Proc Natl Acad Sci USA 1989; 86: 3277-3281.
29. Straus DB, Weiss A. Genetic evidence for the involvement of the lck tyrosine kinase in signal transduction through the T cell antigen receptor. Cell 1992; 70: 585-593.
30. Duplay P, Thome M, Hervé F, et al. p56lck interacts via its Src homology 2 domain with the ZAP-70 kinase. J Exp Med 1994; 179: 1163-1172.
31. Weiss A, Littman DR. Signal transduction by lymphocyte antigen receptors. Cell 1994; 76: 263-274.
32. Wollin L, Ostermann A, Williams C. Nintedanib inhibits pro-fibrotic mediators from T cells with relevance to connective tissue disease-associated interstitial lung disease. Eur Respir J 2017; 50: Suppl. 61, PA903.
33. Prasse A, Probst C, Bargagli E, et al. Serum CC-chemokine ligand 18 concentration predicts outcome in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2009; 179: 717-723.
34. Schupp JC, Binder H, Jäger B, et al. Macrophage activation in acute exacerbation of idiopathic pulmonary fibrosis. PLoS One 2015; 10: e0116775.
35. Hoffmann-Vold AM, Tennøe AH, Garen T, et al. High level of chemokine CCL18 is associated with pulmonary function deterioration, lung fibrosis progression, and reduced survival in systemic sclerosis. Chest 2016; 150: 299-306.
36. van Lieshout AW, Fransen J, Flendrie M, et al. Circulating levels of the chemokine CCL18 but not CXCL16 are elevated and correlate with disease activity in rheumatoid arthritis. Ann Rheum Dis 2007; 66: 1334-1338.
37. Tandon K, Herrmann FE, Ayaub E, et al. Nintedanib attenuates the polarization of profibrotic macrophages through the inhibition of tyrosine phosphorylation on CSF1 receptor. Am J Respir Crit Care Med 2017; 195: A2397.
38. Bellamri N, Morzadec C, Joannes A, et al. Alteration of human macrophage phenotypes by the anti-fibrotic drug nintedanib. Int Immunopharmacol 2019; 72: 112-123.
39. Huang J, Maier C, Zhang Y, et al. Nintedanib inhibits macrophage activation and ameliorates vascular and fibrotic manifestations in the Fra2 mouse model of systemic sclerosis. Ann Rheum Dis 2017; 76: 1941-1948.
40. Maharaj S, Shimbori C, Kolb M. Fibrocytes in pulmonary fibrosis: a brief synopsis. Eur Respir Rev 2013; 22: 552-557.
41. Sato S, Shinohara S, Hayashi S, et al. Anti-fibrotic efficacy of nintedanib in pulmonary fibrosis via the inhibition of fibrocyte activity. Respir Res 2017; 18: 172.
42. Hostettler KE, Zhong J, Papakonstantinou E, et al. Anti-fibrotic effects of nintedanib in lung fibroblasts derived from patients with idiopathic pulmonary fibrosis. Respir Res 2014; 15: 157.
43. Wollin L, Wex E, Pautsch A, et al. Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis. Eur Respir J 2015; 45: 1434-1445.
44. Schuett J, Ostermann AM, Wollin L. The effect of nintedanib compared to pirfenidone on serum-stimulated proliferation of human primary lung fibroblasts at clinically relevant concentrations. Am J Respir Crit Care Med 2015; 191: A4940.
45. Wollin L, Ostermann A, Wex E, et al. Nintedanib attenuates motility of lung fibroblasts from patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2014; 189: A2008.
46. Wollin L, Schuett J, Ostermann AM, et al. The effect of nintedanib on platelet derived growth factor-stimulated contraction of human primary lung fibroblasts. Am J Respir Crit Care Med 2016; 193: A2384.
47. Huang J, Beyer C, Palumbo-Zerr K, et al. Nintedanib inhibits fibroblast activation and ameliorates fibrosis in preclinical models of systemic sclerosis. Ann Rheum Dis 2016; 75: 883-890.
48. Wollin L, Maillet I, Quesniaux V, 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.
49. Sava P, Ramanathan A, Dobronyi A, et al. Human pericytes adopt myofibroblast properties in the microenvironment of the IPF lung. JCI Insight 2017; 2: e96352.
50. Ebina M, Shimizukawa M, Shibata N, et al. Heterogeneous increase in CD34-positive alveolar capillaries in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2004; 169: 1203-1208.
51. Renzoni EA. Neovascularization in idiopathic pulmonary fibrosis: too much or too little? Am J Respir Crit Care Med 2004; 169: 1179-1180.
52. Rol N, de Raaf MA, Sun X, et al. Nintedanib improves cardiac fibrosis but leaves pulmonary vascular remodeling unaltered in experimental pulmonary hypertension. Cardiovasc Res 2019; 115: 432-439.
53. Ackermann M, Kim YO, Wagner WL, et al. Effects of nintedanib on the microvascular architecture in a lung fibrosis model. Angiogenesis 2017; 20: 359-372.
54. Lee HY, Hur J, Kim IK, et al. Effect of nintedanib on airway inflammation and remodeling in a murine chronic asthma model. Exp Lung Res 2017; 43: 187-196.
55. Redente EF, Aguilar MA, Black BP, et al. Nintedanib reduces pulmonary fibrosis in a model of rheumatoid arthritis-associated interstitial lung disease. Am J Physiol Lung Cell Mol Physiol 2018; 314: L998-L1009.
56. De Ruysscher D, Granton PV, Lieuwes NG, et al. Nintedanib reduces radiation-induced microscopic lung fibrosis but this cannot be monitored by CT imaging: a preclinical study with a high precision image-guided irradiator. Radiother Oncol 2017; 124: 482-487.
57. Kim HY, Kim MS, Kim SH, et al. Protective effects of nintedanib against polyhexamethylene guanidine phosphate-induced lung fibrosis in mice. Molecules 2018; 23: E1974.
58. Liu F, Wang L, Qi H, et al. Nintedanib, a triple tyrosine kinase inhibitor, attenuates renal fibrosis in chronic kidney disease. Clin Sci 2017; 131: 2125-2143.
59. Öztürk Akcora B, Storm G, Prakash J, et al. Tyrosine kinase inhibitor BIBF1120 ameliorates inflammation, angiogenesis and fibrosis in CCl4-induced liver fibrogenesis mouse model. Sci Rep 2017; 7: 44545.
60. Piñol-Jurado P, Suárez-Calvet X, Fernández-Simón E, et al. Nintedanib decreases muscle fibrosis and improves muscle function in a murine model of dystrophinopathy. Cell Death Dis 2018; 9: 776.
61. Richeldi L, Costabel U, Selman M, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med 2011; 365: 1079-1087.
62. Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 2014; 370: 2071-2082.
63. Distler O, Highland KB, Gahlemann M, et al. Nintedanib for systemic sclerosis-associated interstitial lung disease. N Engl J Med 2019; 380: 2518-2528.
64. Flaherty KR, Brown KK, Wells AU, et al. Design of the PF-ILD trial: a double-blind, randomised, placebo-controlled phase III trial of nintedanib in patients with progressive fibrosing interstitial lung disease. BMJ Open Respir Res 2017; 4: e000212.
65. Oldham JM, Adegunsoye A, Valenzi E, et al. Characterisation of patients with interstitial pneumonia with autoimmune features. Eur Respir J 2016; 47: 1767-1775.