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Management of Lung Fibrosis in Humans

Management of Lung Fibrosis in Humans. Kevin K. Brown, MD Professor and Vice Chair, Department of Medicine National Jewish Health Denver, CO USA. Disclosures. Wyeth Genzyme Novartis Biogen / Stromedix Actelion Amgen Centocor Gilead Genentech/Roche Medimmune

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Management of Lung Fibrosis in Humans

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  1. Management of Lung Fibrosis in Humans Kevin K. Brown, MD Professor and Vice Chair, Department of Medicine National Jewish Health Denver, CO USA

  2. Disclosures Wyeth Genzyme Novartis Biogen/Stromedix Actelion Amgen Centocor Gilead Genentech/Roche Medimmune BoehringerIngelheimPromedior Galecto Altitude Pharma VeracyteCelgene FibrogenImmuneWorks Mesoblast Pfizer

  3. The problem

  4. Survival in IPF is short Median survival - 2.8 years King et al, Am J RespirCrit Care Med 2000

  5. Survival in IPF is short Median survival - 2.8 years King et al, Am J RespirCrit Care Med 2000

  6. Quality of life with IPF is poor Martinez TY et al, Chest 2000

  7. Quality of life with IPF is poor Martinez TY et al, Chest 2000

  8. Functional Status in IPF is impaired

  9. Functional Status in IPF is impaired Olson A et al, submitted

  10. The clinical courseis unpredictable

  11. Better Disease severity Worse Time (years)

  12. Recent trial results have been disappointing

  13. Summary of Selected Multi-centered Trials

  14. Summary of Selected Multi-centered Trials

  15. Summary of Selected Multi-centered Trials

  16. Summary of Selected Multi-centered Trials

  17. Summary of Selected Multi-centered Trials

  18. Summary of Selected Multi-centered Trials

  19. Summary of Selected Multi-centered Trials

  20. Summary of Selected Multi-centered Trials

  21. What to do?

  22. The future of therapies

  23. Epithelium Adapted from: Maher, TM, Clin Chest Med 33 (2012) 69–83

  24. Alveolar Space Epithelium Adapted from: Maher, TM, Clin Chest Med 33 (2012) 69–83

  25. Alveolar Space Epithelium Endothelium ▪ ▪ ▪ ▪ ▪ ▪ ▪ Adapted from: Maher, TM, Clin Chest Med 33 (2012) 69–83

  26. Alveolar Space Epithelium Endothelium ▪ ▪ ▪ ▪ ▪ ▪ ▪ Vascular Space Adapted from: Maher, TM, Clin Chest Med 33 (2012) 69–83

  27. Alveolar Space Epithelium Mesenchyme Endothelium ▪ ▪ ▪ ▪ ▪ ▪ ▪ Vascular Space Adapted from: Maher, TM, Clin Chest Med 33 (2012) 69–83

  28. Injury Alveolar Space Epithelium Mesenchyme Endothelium ▪ ▪ ▪ ▪ ▪ ▪ ▪ Vascular Space Adapted from: Maher, TM, Clin Chest Med 33 (2012) 69–83

  29. Injury Alveolar Space Epithelium Mesenchyme Endothelium ▪ ▪ ▪ ▪ ▪ ▪ ▪ Vascular Space Adapted from: Maher, TM, Clin Chest Med 33 (2012) 69–83

  30. Injury Alveolar Space Epithelium Mesenchyme Endothelium ▪ ▪ ▪ ▪ ▪ ▪ ▪ Vascular Space Adapted from: Maher, TM, Clin Chest Med 33 (2012) 69–83

  31. Injury Alveolar Space Epithelium Mesenchyme Endothelium ▪ ▪ ▪ ▪ ▪ ▪ ▪ Vascular Space Adapted from: Maher, TM, Clin Chest Med 33 (2012) 69–83

  32. Injury Alveolar Space Epithelium Mesenchyme Endothelium ▪ ▪ ▪ ▪ ▪ ▪ ▪ Vascular Space Adapted from: Maher, TM, Clin Chest Med 33 (2012) 69–83

  33. inhibition Injury Alveolar Space Epithelium Mesenchyme Endothelium ▪ ▪ ▪ ▪ ▪ ▪ ▪ Vascular Space Adapted from: Maher, TM, Clin Chest Med 33 (2012) 69–83

  34. Antioxidants • NOX4 Inhibitors • Anti-reflux therapy • Antimicrobials • Antivirals inhibition Injury Alveolar Space Epithelium Mesenchyme Endothelium ▪ ▪ ▪ ▪ ▪ ▪ ▪ Vascular Space Adapted from: Maher, TM, Clin Chest Med 33 (2012) 69–83

  35. Antioxidants • NOX4 Inhibitors • Anti-reflux therapy • Antimicrobials • Antivirals inhibition Injury Alveolar Space inhibition Epithelium Mesenchyme Endothelium ▪ ▪ ▪ ▪ ▪ ▪ ▪ Vascular Space Adapted from: Maher, TM, Clin Chest Med 33 (2012) 69–83

  36. Antioxidants • NOX4 Inhibitors • Anti-reflux therapy • Antimicrobials • Antivirals • FXa inhibitors • PAR antagonists inhibition Injury Alveolar Space inhibition Epithelium Mesenchyme Endothelium ▪ ▪ ▪ ▪ ▪ ▪ ▪ Vascular Space Adapted from: Maher, TM, Clin Chest Med 33 (2012) 69–83

  37. Antioxidants • NOX4 Inhibitors • Anti-reflux therapy • Antimicrobials • Antivirals • FXa inhibitors • PAR antagonists inhibition Injury Alveolar Space inhibition stimulation Epithelium Mesenchyme Endothelium ▪ ▪ ▪ ▪ ▪ ▪ ▪ Vascular Space Adapted from: Maher, TM, Clin Chest Med 33 (2012) 69–83

  38. Antioxidants • NOX4 Inhibitors • Anti-reflux therapy • Antimicrobials • Antivirals • FXa inhibitors • PAR antagonists inhibition Injury Alveolar Space inhibition • EP receptor agonists • HGF • KGF • Anti-IL-13 stimulation Epithelium Mesenchyme Endothelium ▪ ▪ ▪ ▪ ▪ ▪ ▪ Vascular Space Adapted from: Maher, TM, Clin Chest Med 33 (2012) 69–83

  39. Antioxidants • NOX4 Inhibitors • Anti-reflux therapy • Antimicrobials • Antivirals • FXa inhibitors • PAR antagonists inhibition Injury Alveolar Space inhibition • EP receptor agonists • HGF • KGF • Anti-IL-13 stimulation Epithelium Mesenchyme inhibition Endothelium ▪ ▪ ▪ ▪ ▪ ▪ ▪ Vascular Space Adapted from: Maher, TM, Clin Chest Med 33 (2012) 69–83

  40. Antioxidants • NOX4 Inhibitors • Anti-reflux therapy • Antimicrobials • Antivirals • FXa inhibitors • PAR antagonists inhibition Injury Alveolar Space inhibition • EP receptor agonists • HGF • KGF • Anti-IL-13 stimulation Epithelium • CTGF inhibition • Kinase inhibitors • Anti-TGFβ • Pirfenidone • Anti-CCL-2 • Anti- αVβ6 • LPA1antagonists • NOX4 inhibitors • EP receptor agonists • LOXL2 inhibitors Mesenchyme inhibition Endothelium ▪ ▪ ▪ ▪ ▪ ▪ ▪ Vascular Space Adapted from: Maher, TM, Clin Chest Med 33 (2012) 69–83

  41. Antioxidants • NOX4 Inhibitors • Anti-reflux therapy • Antimicrobials • Antivirals • FXa inhibitors • PAR antagonists inhibition Injury Alveolar Space inhibition • EP receptor agonists • HGF • KGF • Anti-IL-13 stimulation Epithelium • CTGF inhibition • Kinase inhibitors • Anti-TGFβ • Pirfenidone • Anti-CCL-2 • Anti- αVβ6 • LPA1antagonists • NOX4 inhibitors • EP receptor agonists • LOXL2 inhibitors Mesenchyme inhibition Endothelium ▪ ▪ ▪ ▪ ▪ ▪ ▪ Vascular Space Adapted from: Maher, TM, Clin Chest Med 33 (2012) 69–83

  42. Antioxidants • NOX4 Inhibitors • Anti-reflux therapy • Antimicrobials • Antivirals • FXa inhibitors • PAR antagonists inhibition Injury Alveolar Space inhibition • EP receptor agonists • HGF • KGF • Anti-IL-13 stimulation Epithelium • CTGF inhibition • Kinase inhibitors • Anti-TGFβ • Pirfenidone • Anti-CCL-2 • Anti- αVβ6 • LPA1antagonists • NOX4 inhibitors • EP receptor agonists • LOXL2 inhibitors Mesenchyme inhibition Endothelium ▪ ▪ ▪ ▪ ▪ ▪ ▪ Vascular Space • VEGF inhibition • Sildenafil • Anti-CCL-2 • CXCR4 antagonists Adapted from: Maher, TM, Clin Chest Med 33 (2012) 69–83

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