Research progress of targeted drugs for idiopathic pulmonary fibrosis_West China Medical Journal

Authors：

HAN Xing ^1,2 ,  LUO Fengming ¹

1. Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
2. Department of Emergency, Sichuan Provincial Fourth People’s Hospital, Chengdu, Sichuan 610021, P. R. China;

Corresponding author：

LUO Fengming, Email: fengmingluo@outlook.com

Keywords：

Idiopathic pulmonary fibrosis; Pirfenidone; Nintedanib; Targeted drugs; Progress

DOI：

10.7507/1002-0179.202001101

Video：

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Abstract Full text Figures/Tables Video References Cited by

After pirfenidone and nintedanib showed efficacy, drug treatment for idiopathic pulmonary fibrosis began to focused on anti-fibrosis. Current research on idiopathic pulmonary fibrosis mainly focus on the pathogenesis and therapeutic targets, and more targeted drugs are gradually entering clinical trials. This article summarizes the results of recent studies on the treatment of idiopathic pulmonary fibrosis with pirfenidone and nintedanib alone or in combination by searching the literature, and reviews the mechanism and test results of the new target anti-fibrosis drugs based on molecular biology that are currently undergoing clinical research in various phases, and aims to provide a basis for how to choose drugs to treat idiopathic pulmonary fibrosis.

Citation： HAN Xing, LUO Fengming. Research progress of targeted drugs for idiopathic pulmonary fibrosis. West China Medical Journal, 2020, 35(6): 738-744. doi: 10.7507/1002-0179.202001101 Copy

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2.	Bellaye PS, Kolb M. Why do patients get idiopathic pulmonary fibrosis? Current concepts in the pathogenesis of pulmonary fibrosis. BMC Med, 2015, 13: 176.
3.	陈卓, 胡良安. 特发性肺纤维化发病机制及药物治疗进展. 现代医药卫生, 2016, 32(14): 2175-2178.
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6.	Pourgholamhossein F, Rasooli R, Pournamdari M, et al. Pirfenidone protects against paraquat-induced lung injury and fibrosis in mice by modulation of inflammation, oxidative stress, and gene expression. Food Chem Toxicol, 2017, 112(2): 39-46.
7.	甘文华, 黄凯, 吕紫薇, 等. 吡非尼酮和尼达尼布体外抗肺纤维化作用. 中国药理学通报, 2019, 35(10): 1370-1375.
8.	Sköld CM, Bendstrup E, Myllärniemi M, et al. Treatment of idiopathic pulmonary fibrosis: a position paper from a nordic expert group. J Intern Med, 2017, 281(2): 149-166.
9.	Guzy RD, Li L, Smith C, et al. Pulmonary fibrosis requires cell-autonomous mesenchymal fibroblast growth factor (FGF) signaling. J Biol Chem, 2017, 292(25): 10364-10378.
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18.	梁春联, 章琳, 权晓娟, 等. 吡非尼酮对特发性肺纤维化患者肺功能及血清标志物水平的影响. 实用药物与临床, 2019, 22(12): 1249-1253.
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28.	Richeldi L, Costabel U, Selman M, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med, 2011, 365(12): 1079-1087.
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1. Raghu G, Remy-Jardin M, Myers JL, et al. Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ ALAT clinical practice guideline. AmJ Respir Crit Care Med, 2018, 198(5): e44-e68.
2. Bellaye PS, Kolb M. Why do patients get idiopathic pulmonary fibrosis? Current concepts in the pathogenesis of pulmonary fibrosis. BMC Med, 2015, 13: 176.
3. 陈卓, 胡良安. 特发性肺纤维化发病机制及药物治疗进展. 现代医药卫生, 2016, 32(14): 2175-2178.
4. Kaur A, Mathai SK, Schwartz DA. Genetics in idiopathic pulmonary fibrosis pathogenesis, prognosis, and treatment. Front Med (Lausanne), 2017, 4: 154.
5. Raghu G. Idiopathic pulmonary fibrosis: lessons from clinical trials over the past 25years. Eur Respir J, 2017, 50(4): 1701209.
6. Pourgholamhossein F, Rasooli R, Pournamdari M, et al. Pirfenidone protects against paraquat-induced lung injury and fibrosis in mice by modulation of inflammation, oxidative stress, and gene expression. Food Chem Toxicol, 2017, 112(2): 39-46.
7. 甘文华, 黄凯, 吕紫薇, 等. 吡非尼酮和尼达尼布体外抗肺纤维化作用. 中国药理学通报, 2019, 35(10): 1370-1375.
8. Sköld CM, Bendstrup E, Myllärniemi M, et al. Treatment of idiopathic pulmonary fibrosis: a position paper from a nordic expert group. J Intern Med, 2017, 281(2): 149-166.
9. Guzy RD, Li L, Smith C, et al. Pulmonary fibrosis requires cell-autonomous mesenchymal fibroblast growth factor (FGF) signaling. J Biol Chem, 2017, 292(25): 10364-10378.
10. Molina-Molina M, Machahua-Huamani C, Vicens-Zygmunt V, et al. Anti-fibrotic effects of pirfenidone and rapamycin in primary IPF fibroblasts and human alveolar epithelial cells. BMC Pulm Med, 2018, 18(1): 63.
11. Meier R, Lutz C, Cosín-Roger J, et al. Decreased fibrogenesis after treatment with pirfenidone in a newly developed mouse model of interstinal fibrosis. Infamm Bowel Dis, 2016, 22(3): 569-582.
12. Huang NY, Ding L, Wang J, et al. Pharmacokinetics, safety and tolerability of pirfenidone and its major metabolite after single and multiple oral doses in healthy Chinese subjects under fed conditions. Drug Res (Stuttg), 2013, 63(8): 388-395.
13. Potts J, Yogaratnam D. Pirfenidone: a novel agent for the treatment of idiopathic pulmonary fibrosis. Ann Pharmacother, 2013, 47(3): 361-367.
14. Han X, Li F, Wen Z, et al. Pharmacokinetics, tissue distribution, plasma protein binding, and metabolism study of mefunidone, a novel pirfenidone derivative. Clin Exp Pharmacol Physiol, 2019, 46(5): 465-474.
15. Cottin V, Maher T. Long-term clinical and real-world experience with pirfenidone in the treatment of idiopathic pulmonary fibrosis. Eur Respir Rev, 2015, 24(135): 58-64.
16. Yu J, Ritchie TK, Zhou Z, Ragueneau-Majlessi I. Key findings from preclinical and clinical drug interaction studies presented in new drug and biological license applications approved by the Food and Drug Administration in 2014. Drug Metab Dispos, 2016, 44(1): 83-101.
17. 王粉利, 付伟, 李健, 等. 吡非尼酮治疗特发性肺纤维化的临床效果. 临床医学研究与实践, 2019, 4(9): 32-34.
18. 梁春联, 章琳, 权晓娟, 等. 吡非尼酮对特发性肺纤维化患者肺功能及血清标志物水平的影响. 实用药物与临床, 2019, 22(12): 1249-1253.
19. Cottin V, Koschel D, Günther A, et al. Long-term safety of pirfenidone: results of the prospective, observational PASSPORT study. ERJ Open Res, 2018, 4(4): 00084.
20. Noble PW, Albera C, Bradford WZ, et al. Pirfenidone for idiopathic pulmonary fibrosis: analysis of pooled data from three multinational phase 3 trials. Eur Respir J, 2016, 47(1): 243-253.
21. Aravena C, Labarca G, Venegas C, et al. Correction: pirfenidone for idiopathic pulmonary fibrosis: a systematic review and meta-analysis. PLoS One, 2015, 10(10): e0140288.
22. Margaritopoulos GA, Trachalaki A, Wells AU, et al. Pirfenidone improves survival in IPF: results from a real-life study. BMC Pulm Med, 2018, 18(1): 177.
23. Bando M. Pirfenidone: clinical trials and clinical practice in patients with idiopathic pulmonary fibrosis. Respir Investig, 2016, 54(5): 298-304.
24. King TE Jr, Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med, 2014, 370(22): 2083-2092.
25. Raghu G, Rochwerg B, Zhang Y, et al. An official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis. An update of the 2011 clinical practice guideline. Am J Respir Crit Care Med, 2015, 192(2): e3-e19.
26. Wuyts WA, Dahlqvist C, Slabbynck H, et al. Longitudinal clinical outcomes in a real-world population of patients with idiopathic pulmonary fibrosis: the PROOF registry. Respir Res, 2019, 20(1): 231.
27. Costabel U, Albera C, Glassberg MK, et al. Effect of pirfenidone in patients with more advanced idiopathic pulmonary fibrosis. Respir Res, 2019, 20(1): 55.
28. Richeldi L, Costabel U, Selman M, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med, 2011, 365(12): 1079-1087.
29. Robalo-Cordeiro C, Campos P, Carvalho L, et al. Idiopathic pulmonary fibrosis in the era of antifibrotic therapy: searching for new opportunities grounded in evidence. Rev Port Pneumol (2006), 2017, 23(5): 287-293.
30. Dallinger C, Trommeshauser D, Marzin K, et al. Pharmacokinetic properties of nintedanib in healthy volunteers and patients with advanced cancer. J Clin Pharmacol, 2016, 56(11): 1387-1394.
31. Schmid U, Liesenfeld KH, Fleury A, et al. Population pharmacokinetics of nintedanib, an inhibitor of tyrosine kinases, in patients with non-small cell lung cancer or idiopathic pulmonary fibrosis. Cancer Chemother Pharmacol, 2018, 81(1): 89-101.
32. Wind S, Schmid U, Freiwald M, et al. Clinical pharmacokinetics and pharmacodynamics of nintedanib. Clin Pharmacokinet, 2019, 58(9): 1131-1147.
33. Aiello M, Bertorelli G, Bocchino M, et al. The earlier, the better: impact of early diagnosis on clinical outcome in idiopathic pulmonary fibrosis. Pulm Pharmacol Ther, 2017, 44: 7-15.
34. Wuyts WA, Kolb M, Stowasser S, et al. First data on efficacy and safety of nintedanib in patients with idiopathic pulmonary fibrosis and forced vital capacity of ≤50% of predicted value. Lung, 2016, 194(5): 739-743.
35. Rogliani P, Calzetta L, Cavalli F, et al. Pirfenidone, nintedanib and N-acetylcysteine for the treatment of idiopathic pulmonary fibrosis: a systematic review and meta-analysis. Pulm Pharmacol Ther, 2016, 40: 95-103.
36. Crestani B, Huggins JT, Kaye M, et al. Long-term safety and tolerability of nintedanib in patients with idiopathic pulmonary fibrosis: results from the open-label extension study, INPULSIS-ON. Lancet Respir Med, 2019, 7(1): 60-68.
37. Lancaster L, Crestani B, Hernandez P, et al. Safety and survival data in patients with idiopathic pulmonary fibrosis treated with nintedanib: pooled data from six clinical trials. BMJ Open Respir Res, 2019, 6(1): e000397.
38. Kolb M, Richeldi L, Behr J, et al. Nintedanib in patients with idiopathic pulmonary fibrosis and preserved lung volume. Thorax, 2017, 72(4): 340-346.
39. Loveman E, Copley VR, Scott DA, et al. Comparing new treatments for idiopathic pulmonary fibrosis--a network meta-analysis. BMC Pulm Med, 2015, 15: 37.
40. Albera C, Costabel U, Fagan EA, et al. Efficacy of pirfenidone in patients with idiopathic pulmonary fibrosis with more preserved lung function. Eur Respir J, 2016, 48(3): 843-851.
41. Anderson A, Shifren A, Nathan SD. A safety evaluation of pirfenidone for the treatment of idiopathic pulmonary fibrosis. Expert Opin Drug Saf, 2016, 15(7): 975-982.
42. Ogura T, Taniguchi H, Azuma A, et al. Safety and pharmacokinetics of nintedanib and pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J, 2015, 45(5): 1382-1392.
43. Flaherty K, Fell C, Huggins J, et al. Safety of combined pirfenidone and nintedanib in patients with idiopathic pulmonary fibrosis. Thorax, 2017, 72: A253-A256.
44. Kraljić K, Jelić D, Žiher D, et al. Benzoxaboroles-novel autotaxin inhibitors. Molecules, 2019, 24(19): 3419.
45. Ninou I, Magkrioti C, Aidinis V. Autotaxin in pathophysiology and pulmonary fibrosis. Front Med (Lausanne), 2018, 5: 180.
46. Stoddard NC, Chun J. Promising pharmacological directions in the world of lysophosphatidic acid signaling. Biomol Ther (Seoul), 2015, 23(1): 1-11.
47. van der Aar E, Desrivot J, Dupont S, et al. Safety, pharmacokinetics, and pharmacodynamics of the autotaxin inhibitor GLPG1690 in healthy subjects: phase 1 randomized trials. J Clin Pharmacol, 2019, 59(10): 1366-1378.
48. Maher TM, van der Aar EM, Van de Steen O, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of GLPG1690, a novel autotaxin inhibitor, to treat idiopathic pulmonary fibrosis (FLORA): a phase 2a randomised placebo-controlled trial. Lancet Respir Med, 2018, 6(8): 627-635.
49. Maher TM, Kreuter M, Lederer DJ, et al. Rationale, design and objectives of two phase Ⅲ, randomised, placebo-controlled studies of GLPG1690, a novel autotaxin inhibitor, in idiopathic pulmonary fibrosis (ISABELA 1 and 2). BMJ Open Respir Res, 2019, 6(1): e000422.
50. Palmer SM, Snyder L, Todd JL, et al. Randomized, double-blind, placebo-controlled, phase 2 trial of BMS-986020, a lysophosphatidic acid receptor antagonist for the treatment of idiopathic pulmonary fibrosis. Chest, 2018, 154(5): 1061-1069.
51. Barreto SC, Ray A, Ag Edgar P. Biological characteristics of CCN proteins in tumor development. J BUON, 2016, 21(6): 1359-1367.
52. Cannito S, Novo E, Parola M. Therapeutic pro-fibrogenic signaling pathways in fibroblasts. Adv Drug Deliv Rev, 2017, 121: 57-84.
53. Raghu G, Scholand MB, de Andrade J, et al. FG 3019 anti-connective tissue growth factor monoclonal antibody: results of an open-label clinical trial in idiopathic pulmonary fibrosis. Eur Respir, 2016, 47(5): 1481-1491.
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