1. PFF Teal = 0+160+175 MAIN COLORS PFF Green = 120+162+47 Light Green = 193+216+47 Red = 242+102+73 HIGHLIGHT COLORS Light Grey = 220+220+210 Dark Grey = 100+98+76 Black = 0+0+0 APPROVED DRUGS FOR IPF: SHOULD THEY BE STUDIED FOR NON-IPF PULMONARY FIBROSIS? KEVIN K. BROWN, MD CLINICAL CARE: NEW AND EVOLVING TREATMENT STRATEGIES NOVEMBER 14, 2015

2. Yes

3. Questions to consider: 1. Are we treating a single disease, a syndrome or a pathologic mechanism that manifests as progressive pulmonary fibrosis? 2. Is the treatment safe in the population? 3. Is the treatment efficacious in the population?

4. In 2015 the diagnosis of IPF requires: 1. Exclusion of other known causes of interstitial lung disease (e.g., domestic exposures, connective tissue disease, and drug toxicity). 2. The presence of a UIP chest imaging pattern on HRCT in patients not subjected to surgical lung biopsy. 3. Specific combinations of HRCT chest imaging patterns and pathologic patterns in patients who undergo a surgical lung biopsy.

5. Screen failures in the recent Pirfenidone trial

7. Comparison of Selected Inclusion/Exclusion Criteria

8. Not performed UIP Probable UIP Possible UIP Not UIP UIPIPF Not IPF Possible UIP Unclassifiable IPF Some are IPF, some are not Not IPF Inconsist- ent with UIP Unclassifiable Some are IPF, some are not Not IPF Lung Biopsy HRCT Not IPF per guidelines IPF per guidelines ASCEND INPULSIS Courtesy: Hal Collard

9. The Problem with Chest Imaging

10. Trial Design Comparison: ASCEND vs. CAPACITY

13. Measuring Agreement Among Observers Kappa ValueStrength of Agreement < 0Poor 0–0.2Slight 0.2–0.4Fair 0.4–0.6Moderate 0.6–0.8Substantial 0.8–1.0Almost perfect Sackett DL, et al. Clinical Epidemiology: A basic science for clinical medicine; 1991:29. Landis JR, Koch GG. Biometrics. 1977;33:159-174. Clinically useful agreement Actual Agreement Beyond Chance Potential Agreement Beyond Chance Kappa = =

14. Inter-observer Variation among Radiologists Median (range)  w coefficient of agreement IPF0.63 (0.48 – 0.78) NSIP0.51 (0.27 – 0.78) Sarcoidosis0.70 (0.58 – 0.84) Extrinsic allergic alveolitis0.60 (0.36 – 0.78) COP0.49 (0.06 – 0.76) Smoking related ILD0.51 (0.20 – 0.73) Aziz ZA et al, Thorax 2004 For CT diagnosis of pulmonary embolus Kappa = 0.72-0.96 For CT diagnosis of cystic lung disease Kappa =.77-1.0

15. The Presence of Honeycombing on HRCT  = 0.31 (0.16-0.45)  = 0.21 (0.09-0.32) Agreement among experts and study site Agreement among expert readers Lynch et al, Am J Respir Crit Care Med 2005

16. The Presence of Honeycombing on HRCT  = 0.31 (0.16-0.45)  = 0.21 (0.09-0.32) Agreement among experts and study site Agreement among expert readers Lynch et al, Am J Respir Crit Care Med 2005

17. Agreement on the Presence of a UIP Pattern Lynch et al, Am J Respir Crit Care Med 2005  = 0.33 (0.18-0.48) Agreement among expert readers

18. Thomeer M et al, Eur Respir J 2008

19. Weighted Kappa Among HRCT Reviewers Thomeer M et al, Eur Respir J 2008

20. Weighted Kappa Among HRCT Reviewers Thomeer M et al, Eur Respir J 2008

21. The Problem with Pathology

22. Kappa coefficients (k) between lobar and final diagnoses in 48 patients DiagnosisLobar diagnosis (n = 98) Final diagnosis (n = 48) UIP0.40 Moderate0.49 Moderate NSIP0.32 Fair OP0.590.67 HP0.390.35 Sarcoidosis0.760.82 Normal0.07N/A Overall0.39 Fair0.43 Moderate Nicholson AG et al, Thorax. 2004

23. Weighted Kappas Among 2 Pathologists Nicholson AG et al, Thorax. 2004

24. NSIP vs. UIP

26. Jegal. Am J Respir Crit Care Med 2005; 171:639 P=0.007 Kaplan-Meier survival curves of subjects with IPF and fibrotic NSIP

27. FVC change > 10% p=0.01 Flaherty, Am J Resp Crit Care Med, 2003 Change in FVC predicts survival in IPF and NSIP

28. Jegal. Am J Respir Crit Care Med 2005; 171:639 Change in FVC predict survival in IPF and NSIP

29. Baseline Predictors of Survival Jegal et al, Am J Respir Crit Care Med 2005

30. Predictors of Survival at 6 Months Jegal et al, Am J Respir Crit Care Med 2005

31. Predictors of Survival at 6 Months Jegal et al, Am J Respir Crit Care Med 2005

32. IPF vs. Fibrotic HP

33. UIP NSIP CIP or OP Ohtani et al, Thorax 2005 Pathologic Pattern predicts mortality in HP

34. Vourlekis et al, Am J Med 2004 Fibrosis predicts mortality in HP p = 0.0005 median survival 7.1 yrs median survival > 20 yrs

35. Hanak et al, Chest 2008 Presence of CT Fibrosis predicts survival

36. IPF Mortality is related to CT Disease Extent 3 / 8 (38%) 23 / 93 (25%) 17 / 179 (9%) 1 / 35 (3%) Disease Extent Mortality (%) Lynch et all, Am J Respir Crit Care Med 2005

37. Extent of CT Fibrosis predicts survival in HP Hanak et al, Chest 2008

38. Olson et al, Chest 2008

40. Survival is shortened in RA Solomon JJ et al, Resp Med 2013

41. ExRA shortens survival in RA Solomon JJ et al, Resp Med 2013

42. ILD shortens survival in RA Solomon JJ et al, Resp Med 2013

43. Fibrotic ILD shortens survival in RA Solomon JJ et al, Resp Med 2013

44. Survival with RA-UIP is Similar to IPF Solomon JJ et al, Resp Med 2013

45. Moua T et al, Resp Res 2014

46. Strand et al, Chest 2014 Idiopathic Pulmonary Fibrosis (IPF)

47. Connective Tissue Disease-UIP Strand et al, Chest 2014

48. Corte T, et al 2012 Eur Respir 39:661-668

49. Moua T et al, Mayo Clin Proc 2014 Positive serologies in IPF have no impact on mortality

50. Park et al, Chest 2007

51. AE-PF Clinical context and Prognosis Huie et al, Respirology 2010 Underlying Diagnosis IPF CTD-ILD UIP pattern RA UCTD NSIP pattern UCTD SSc Dermatomyositis LIP Drug-induced ILD Unclassified

52. IPF-like IPF Probable IPF Not IPF IP-AF Fibrotic HP fNSIP ARDS Possible IPF Sarcoidosis CTD-ILD

53. The diagnosis of IPF remains a challenge and many IPF patients do not meet our current diagnostic criteria The presence of fibrosis in the setting of IPAF, connective tissue disease, and hypersensitivity pneumonitis is associated a similar clinical course and early mortality It is the presence of progressive pulmonary fibrosis that is the problem The rationale and opportunity to study the safety and efficacy of current IPF therapy in non-IPF pulmonary fibrosis exists and is compelling Summary