1. IPF MANAGEMENT: WHAT DO WE DO NOW? Steven A. Sahn, MD Professor of Medicine and Director Division of Pulmonary, Critical Care, Allergy and Sleep Medicine Medical University of South Carolina

2. Combined Corticosteroid and Cyclophosphamide Treatment Does Not Improve Survival in IPF Patients Collard HR, et al. Chest. 2004;125:2169-2174. Walter N, et al. Proc Am Thorac Soc. 2006;3:330-338. Median survival = 1431 days Median survival = 1665 0.00 0.25 0.50 0.75 1.00 0 500 1000 1500 2000 2500 3000 3500 4000 Expected Untreated (n = 82) Treated (n = 82) Days of Follow-up Probability of Survival P = 0.58 No evidence that corticosteroid plus cyclophosphamide treatment improves survival Most patients do not respond to immunosuppressive agents

3. Epithelial cells Collagen – matrix remodeling Myofibroblast Cell death – impaired reepithelialization Growth factors and other products of epithelial cell injury Courtesy of Paul W. Noble, MD, and Victor J. Thannickal, MD. Cell survival – resistance to apoptosis Basement Membrane Damage Oxidative Stress Procoagulant Activity T H 2-T H 1 Balance Vascular Remodeling Evolving Model of Pathogenesis: Aberrant Response to Persistent Injury

4. Therapeutic Targets Alveolar/capillary membrane Fibroblast/myofibroblast Basement membrane The blood vessels The immune response

5. Recent Phase 3 Clinical Trials Drug Trial name Mechanism Primary endpoint (N) Trial length (weeks) IFN  -1b (Actimmune ® ) GIPF-001 Cytokine, Antifibrotic Progression-free survival 330 48, completed IFN  -1b (Actimmune ® ) INSPIRE Cytokine, Antifibrotic Survival time 826 stopped N-acetylcysteine (Fluimucil ® ) IFIGENIA Antioxidant FVC and DL co change 182 52, completed Prednisone/Azathio- prine/NAC PANTHR Anti-inflamm, Immunosuppr, antioxidant Change in FVC 390 52, ongoing Pirfenidone CAPACITY 1 & 2 TGF  inhib, Antifibrotic Change in FVC 720 72, ongoing Bosentan (Tracleer ® ) BUILD 3 ET-1&2R antagonist Safety/efficacy 390 131 events, recruitment pending http://clinicaltrials.gov/ct/action/GetStudy. Dempsey OJ. Respir Med. 2006;100:1871-1885. Antoniu S. Expert Opin Investig Drugs. 2006;15:823-828. Demedts M, et al. N Engl J Med. 2005;353:2229-2242.

6. Probability of Survival 0.4 0.6 0.8 1.0 0100200300400500600 Day IFN  -1b Placebo P = 0.08 1. Raghu G, et al. N Engl J Med. 2004;350:125-133. 2. Data on file with InterMune. 50 55 60 65 70 75 0122436486072 Week Lung Function (FVC) 2 Survival 1 N = 330 GIPF-001 Study Results

7. Interferon  -1b INSPIRE Trial Classification Pleiotropic immunomodulatory cytokine Mechanism Antifibrotic, angiostatic, antiinfective, antiproliferative Trial Design Multinational, randomized, placebo controlled Inclusion Criteria Age 40-79 years, FVC ≥ 55% and DL CO ≥ 35% of predicted Primary Endpoint Survival time Treatment Arms 200 μg TIW vs placebo, 2:1 randomization Number of Patients 826 (enrollment complete) Treatment Duration 2 years from date of 600th patient enrollment www.inspiretrial.com. Accessed February 2007.

8. INSPIRE Trial Discontinued Recommended by DMC Interim analysis on 2/28/07 826 patients randomized 115 deaths No difference in mortality 14.5% (Actimmune) vs 12.7% (placebo)

9. IFIGENIA Study Results Demedts M, et al. N Engl J Med. 2005;353:2229-2242. DL co (% predicted) Vital Capacity (% predicted) 12 Months FVC 6 Months Baseline -10 -8 -6 -4 -2 0 2 NAC Placebo -10 NAC -8 6 Months Baseline 12 Months -6 -4 -2 0 2 Placebo P = 0.02 P = 0.003 DL CO No. of Patients Acetylcysteine Placebo 80 75 63 60 55 51 79 74 58 59 55 51 Mortality, P = NS NAC/Pred/Aza 7/80 (9%) Placebo/Pred/Aza8/75 (11%)

10. Prednisone/Azathioprine/NAC PANTHR Classification Cocktail Mechanisms Anti-inflammatory, immunosuppression, anti-oxidant Trial Design Randomized, double blind, placebo controlled Inclusion Criteria FVC>55% and DL co >35% Primary Endpoint Change in FVC % predicted Treatment Arms Placebo vs Pred/Aza/NAC vs NAC Number of Patients 390 Treatment Duration 52 weeks Result Ongoing Courtesy of Imre Noth, MD.

11. Pirfenidone Classification TGF  inhibitor MechanismAntifibrotic Trial DesignRandomized, double blind, placebo controlled Inclusion Criteria Age 40 – 80 years, confident IPF diagnosis FVC  50% predicted value, DL CO  35% predicted value Efficacy Endpoints Primary: Mean change from baseline in % predicted FVC Secondary: Changes in symptoms, functional capacity, QOL Treatment Arms CAPACITY 1: PFD 2403 mg/d vs placebo CAPACITY 2: PFD 1197 mg/d vs PFD 2403 mg/d vs placebo Number of Patients CAPACITY 1: 320 CAPACITY 2: 400 Treatment Duration60 weeks www.capacitytrials.com. Accessed February 2007. CAPACITY 1 & 2

12. Bosentan BUILD 3 Trial ClassificationEndothelin-1 & 2 receptor antagonist (ERA) MechanismsVasodilator, possible antifibrotic Trial Design Event-driven international, double-blind, randomized (2:1::bosentan:placebo) Inclusion CriteriaProven IPF diagnosis < 3 years, with SLB Primary Endpoint Time to disease worsening (FVC & DL co ), acute exacerbation or death Number of Patients390 Treatment Duration131 events ResultsRecruitment pending http://clinicaltrials.gov/ct/show/NCT00391443?order=1

13. Anticoagulation Therapy Kubo H, et al. Chest. 2005;128:1475-1482. With Anticoagulant Therapy Without Anticoagulant Therapy Time (Days) Probability of Survival 0200400 60080010001200 0 0.2 0.4 0.6 0.8 1 P < 0.05 n = 23 n = 33

14. Patient Management Strategies Assess for comorbidities Assess for clinical trial enrollment Discuss “conventional” immunosuppression versus alternatives (unproven agents) or no therapy Non-pharmacological strategies Pulmonary rehabilitation Supplemental oxygen Lung transplantation End-of-life and palliative care ATS/ERS Consensus Statement. Am J Respir Crit Care Med. 2000;161:646-664. Khalil N, et al. CMAJ. 2004;171:153-160. Pulmonary hypertension Obstructive sleep apnea Coronary artery disease GERD COPD

15. Acute Exacerbation of IPF Worsening dyspnea over 1-4 weeks Increased oxygen requirements New ground glass densities or consolidation on HRCT

16. Management of Acute Exacerbations in IPF Exclude other causes Infection CHF Pulmonary embolism Ischemic heart disease HRCT Bronchoscopy with BAL Careful assessment for a steroid- responsive disease Walter N et al. Proc Am Thorac Soc. 2006;3:330–338.

17. Take Home Points Little quality evidence to support efficacy of “conventional” immunosuppressive therapy No FDA-approved drugs for IPF; several compounds in Phase 3 trials Participation in trials should be discussed as an option for all appropriate patients Early referral and evaluation for lung transplantation are recommended Risk of acute exacerbation Recent allocation guidelines to maximize outcomes