1. Pulmonary Fibrosis Foundation Summit 2015
Approved Drugs for IPF: Should They be Studied for Non-IPF Pulmonary Fibrosis?
Pulmonary Fibrosis Foundation Summit 2015
November 14, 2015
Washington, DC
Kevin K. Brown, MD
Professor and Vice Chair
Department of Medicine
National Jewish Health
Denver, CO

2. CLINICAL CARE: NEW AND EVOLVING TREATMENT STRATEGIES NOVEMBER 14, 2015
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

3. Conflict of Interest Disclosure
Grant monies:
NIH-NHLBI
Foundations:
Pulmonary Fibrosis Foundation
Consultancies: Aeolus, Altitude Pharma, Amgen, Array Biopharma, Astra Zeneca, Bayer, Biogen, Boehringer- Ingelheim, Bristol Myers Squibb, Celgene, Centocor, Eisai, Fibrogen, Galecto, GeNO, Genoa, Gilead, Immuneworkx, MedImmune, Mesoblast, Moerae, Novartis, Pfizer, Promedior, ProMetic, Respironics, Genentech, Sanofi, and Veracyte

4. Yes

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

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

7. Screen failures in the recent Pirfenidone trial

8. Screen failures in the recent Pirfenidone trial

9. Comparison of Selected Inclusion/Exclusion Criteria

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

11. The Problem with Chest Imaging

12. Trial Design Comparison: ASCEND vs. CAPACITY

13. Trial Design Comparison: ASCEND vs. CAPACITY

14. Trial Design Comparison: ASCEND vs. CAPACITY

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

16. Inter-observer Variation among Radiologists
Median (range) kw coefficient of agreement
IPF
0.63 (0.48–0.78)
NSIP
0.51 (0.27–0.78)
Sarcoidosis
0.70 (0.58–0.84)
Extrinsic allergic alveolitis
0.60 (0.36–0.78)
COP
0.49 (0.06–0.76)
Smoking related ILD
0.51 (0.20–0.73)
For CT diagnosis of pulmonary embolus Kappa =
For CT diagnosis of cystic lung disease Kappa =
Aziz ZA et al, Thorax 2004

17. The Presence of Honeycombing on HRCT
= 0.31 ( )
= 0.21 ( )
Agreement among experts and study site
Agreement among expert readers
Lynch et al, Am J Respir Crit Care Med 2005

18. The Presence of Honeycombing on HRCT
= 0.31 ( )
= 0.21 ( )
Agreement among experts and study site
Agreement among expert readers
Lynch et al, Am J Respir Crit Care Med 2005

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

20. Thomeer M et al, Eur Respir J 2008

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

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

23. The Problem with Pathology

24. The Problem with Pathology
Diagnosis
Lobar diagnosis
(n = 98)
Final diagnosis
(n = 48)
UIP
0.40 Moderate
Moderate
NSIP
0.32 Fair
Fair OP
0.59
0.67 HP
0.39
0.35
Sarcoidosis
0.76
0.82
Normal
0.07
N/A
Overall
0.39 Fair
0.43 Moderate
Kappa coefficients (k) between lobar and final diagnoses in 48 patients
Nicholson AG et al, Thorax. 2004

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

26. NSIP vs. UIP

27. NSIP vs. UIP

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

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

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

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

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

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

34. IPF vs. Fibrotic HP

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

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

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

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

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

40. Olson et al, Chest 2008

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

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

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

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

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

47. Moua T et al, Resp Res 2014

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

49. Connective Tissue Disease-UIP
Idiopathic Pulmonary Fibrosis (IPF)
Strand et al, Chest 2014

50. SSc RA
UCTD
Strand et al, Chest 2014

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

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

53. Park et al, Chest 2007

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

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

56. Summary
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