Recently Completed Trials in IPF: What have we learned? Where do we go from here?

1. Recently Completed Trials in IPF:What have we learned?Where do we go from here? Charlene D Fell University of Calgary

2. Disclosures Scientific Advisory Board Actelion InterMune Speaker’s Fees GSK, AstraZeneca, Boehringer Ingelheim

3. Objectives List recent clinical trials in IPF and their outcomes Discuss the challenges in selecting clinically meaningful endpoints for clinical trials in IPF Discuss how the natural history of IPF and IPF phenotypes contribute to challenges faced in designing clinical trials for this disease

4. Recent Phase 3 Trials in IPF

5. Recent Phase 3 Trials in IPF

6. Challenges in selecting endpoints for IPF trials • Optimal endpoint characteristics • Clinically meaningful • Reproducible • Responsive • Safe • Simple • Cheap

7. CAPACITY Trials Phase III, RDBPC trial PIPF-004: pirfenidone 1197mg/day vs. 2403mg/day vs. placebo PIPF-006: pirfenidone 2403mg/day vs. placebo “Early IPF” 1º Endpoint: % change in FVC at w 72

8. PIPF-004 CE-14 0 -5 Mean change from baseline in %FVC -10 Pirfenidone 2403 mg/d Pirfenidone 1197 mg/d Placebo -15 0 12 24 36 48 60 72 Weeks Slide courtesy of InterMune

9. PIPF-006 CE-23 Pirfenidone 2403 mg/d Placebo Slide courtesy of InterMune

10. PIPF-004 and PIPF-006  In PIPF-006, patients in the placebo arm had more stable disease Data courtesy of InterMune

11. CAPACITY: Analysis Did we choose the right endpoint? FVC of 10% an accepted surrogate marker for mortality in IPF Was the trial long enough? − 72 weeks Was n large enough? − > 750 patients

12. BUILD-3 Phase III RDBPC trial Bosentan 125 mg BID vs. placebo (2:1) “Early IPF” Biopsy proven UIP <5% honeycombing on HRCT Composite 1º endpoint: Time to death, disease progression, or hospitalization King, TE. AJRCCM. 181:A6838. 2010

13. BUILD-3 Primary Outcome HR 0.85 (0.66 - 1.1), p=0.21 King, TE. AJRCCM. 181:A6838. 2010

14. BUILD-3 Analysis Did we choose the right outcome? − Time to death, disease progression, or hospitalization Was the trial long enough? − 4 week intervention − 1 year follow up Was n large enough? − Needed 202 events to detect a 35% RRR in 1º endpoint

15. STEP-IPF Phase III, RDBPC trial Sildenafil 20 mg TID vs. placebo (1:1) “Late IPF” DLCO <35% predicted 1º outcome: proportion of patients with an increase in 6MWD of 20% or more Zisman, D et al. NEJM. 363:620. 2010

16. STEP-IPF 1º Outcome Improvement of 20% or more in 6MWD Sildenafil: 9 of 89 Placebo: 6 of 91 p=0.39 Zisman, D et al. NEJM. 363:620. 2010

17. STEP-IPF: Analysis Did we choose the right outcome? 20% increase in 6MWD at 12 w Baseline 6MWD = 265m; 20% = 51m After 12 w pulmonary rehab: 53m MCID in 6MWD is estimated to be 24-40m Was the trial long enough? 12 weeks of blinded therapy Was n large enough? 180 patients Zisman, D et al. NEJM. 363:620. 2010 Salhi B. et al. CHEST. 137:273-9. 2010

18. ARTEMIS ARTEMIS-IPF Phase III, RDBPC trial Ambrisentan 10 mg OD vs. placebo IPF 1 Outcome: Time to death or disease progression ARTEMIS-PH Early termination: failed to meet endpoints at interim analysis • Phase III, RDBPC trial • Ambrisentan 10 mg OD vs. placebo • IPF + PAH • 1 Outcome: change in 6MWD www.ClinicalTrials.gov

19. Selecting trial outcomes for IPF:

20. 3 Important Lessons from Recent Clinical Trials Most patients have stable disease Stable disease is punctuated by periods of acute deterioration There are probably multiple phenotypes of IPF

21. Survival in IPF may be better than we think it is… 1.0 0.8 IFN (INSPIRE) 0.6 Survival 0.4 0.2 0.0 0 2 4 6 8 Years Flaherty et al. AJRCCM. 2003 King et al. Lancet. 2004

22. Change in FVC and dyspnea in 36 patients in the placebo arm of GIPF-001 who died during follow up. Change in physiologic and dyspnea indices In patients in the placebo arm of GIPF-001 Who survived during follow up. FVC Dyspnea Martinez, FJ et al. Ann Int Med. 2005

23. GIPF-001 Trial: IFN-gamma in IPF The majority of patients with IPF have a stable course. Patients with mild/moderate disease can have acute exacerbations of IPF. More frequent evaluation of patients Early referral for lung transplantation Martinez, FJ et al. Ann Int Med. 2005

24. Raghu, G. et al. AJRCCM 183.788-824. 2011

25. Pulmonary hypertension and IPF Lettieri C J et al. Chest 2006;129:746-752

26. Gender differences in PH in IPF patientsSubanalysis of the STEP-IPF Trial Han, MK et al. AJRCCM. 181:A1112. 2010

27. Emphysema and IPF Mejía M et al. Chest 2009;136:10-15

28. Challenges in selecting endpoints for IPF trials  Applicable across all phenotypes • Optimal endpoint characteristics • Clinically meaningful • Reproducible • Responsive • Safe • Simple • Cheap

29. Some challenges in clinical research in IPF Patients with IPF are more stable than once thought There are likely multiple phenotypes of IPF Males vs. Females IPF and PAH IPF and emphysema ….others? Acute exacerbations must be accounted for in trial outcomes

30. Summary Pirfenidone is promising but lacks regulatory approval in Canada The role of ET antagonists in IPF is unclear Clinical trials have been negative Most patients have stable disease Stable disease is punctuated by acute exacerbations There are probably multiple IPF phenotypes

31. What can we learn from these trials? www.ClinicalTrials.gov

32. Thank You

34. What is Idiopathic Pulmonary Fibrosis? Chronic, progressive fibrotic pulmonary disease No known cause No effective therapies currently available outside Japan Mean survival after diagnosis is 3 years May 2005 Nov 2005 Apr 2006

35. Slides courtesy of Dr. M Kelly

36. Thannickal VJ et al. Annu Rev Med. 2004.

37. Management of IPF Refer for lung transplantation Enroll in a clinical trial Weak evidence against the use of: Combined NAC/AZA/prednisone NAC monotherapy Anticoagulation Pirfenidone Pulmonary rehabilitation Supportive care/palliation Raghu, G. et al. AJRCCM 183.788-824. 2011

38. Retrospective analysis of patients in the placebo arm of GIPF-001 • 36 patients in the placebo arm died • 31 had deaths related to IPF Martinez, FJ et al. Ann Int Med. 2005

39. INSPIRE Trial: IFN-gamma in IPF Du Bois et al. AJRCCM. 2010:A1103

40.  A classification of IPF based on simple lung function criteria Egan JJ et al. Thorax 60:270-273. 2005

41. “I like to say that we can describe the conduct of a trial three ways: it can be trustworthy, fast, or cheap. Generally speaking, a trial can have only two of these characteristics. If a trial is fast and cheap, it is unlikely to be trustworthy.” Zivin, JA. Scientific American 282(4):69-75. 2000

42. Some challenges in clinical research in IPF Heterogeneity in outcomes Uncertain surrogate markers of mortality FVC 10% or 5%? The problem of missing data (LOCF not appropriate in this disease) Inadequate # of expert clinical sites Agents are expected to stabilize disease, not reverse it. Treatment effects will be small. Therefore need longer/larger trials to see an effect. Patients are referred late in their course - ineligible for “early IPF” trials

43. FVC Time