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IPF MANAGEMENT: WHAT DO WE DO NOW?

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.

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IPF MANAGEMENT: WHAT DO WE DO NOW?

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

  3. Evolving Model of Pathogenesis: Aberrant Response to Persistent Injury Cell death – impaired reepithelialization Epithelial cells Basement Membrane Damage Oxidative Stress Growth factors and other products of epithelial cell injury Procoagulant Activity Myofibroblast TH2-TH1 Balance Cell survival – resistance to apoptosis Vascular Remodeling Collagen – matrix remodeling Courtesy of Paul W. Noble, MD, and Victor J. Thannickal, MD.

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

  5. Recent Phase 3 Clinical Trials 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. GIPF-001 Study Results Survival1 Lung Function (FVC)2 1.0 75 70 0.8 65 Probability ofSurvival P = 0.08 60 0.6 IFN -1b 55 Placebo 0.4 50 0 100 200 300 400 500 600 0 12 24 36 48 60 72 Day Week N = 330 1. Raghu G, et al. N Engl J Med. 2004;350:125-133. 2. Data on file with InterMune.

  7. Interferon g-1bINSPIRE Trial 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 DLCO FVC 2 2 P = 0.02 P = 0.003 0 0 -2 NAC -2 NAC -4 -4 Vital Capacity (% predicted) DLco (% predicted) -6 -6 Placebo -8 -8 Placebo -10 -10 Baseline 6 Months 12 Months 12 Months 6 Months Baseline No. of Patients Acetylcysteine Placebo 80 75 55 51 79 74 58 59 55 51 63 60 Demedts M, et al. N Engl J Med. 2005;353:2229-2242.

  10. Prednisone/Azathioprine/NAC PANTHR Courtesy of Imre Noth, MD.

  11. Pirfenidone CAPACITY 1 & 2 www.capacitytrials.com. Accessed February 2007.

  12. Bosentan BUILD 3 Trial http://clinicaltrials.gov/ct/show/NCT00391443?order=1

  13. Anticoagulation Therapy 1 With Anticoagulant Therapy 0.8 n = 23 0.6 Probability of Survival n = 33 0.4 Without Anticoagulant Therapy 0.2 P < 0.05 0 600 800 1000 1200 0 200 400 Time (Days) Kubo H, et al. Chest. 2005;128:1475-1482.

  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 • Pulmonary hypertension • Obstructive sleep apnea • Coronary artery disease • GERD • COPD ATS/ERS Consensus Statement. Am J Respir Crit Care Med. 2000;161:646-664. Khalil N, et al. CMAJ. 2004;171:153-160.

  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

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