Idiopathic Pulmonary Fibrosis Standards of Care & Investigational Therapies

1. Idiopathic Pulmonary FibrosisStandards of Care & Investigational Therapies Stephen K. Frankel, MD, FCCP Assistant Professor, Interstitial Lung Disease Program National Jewish Medical & Research Center

2. What are the “Standards of Care” for IPF in 2005? • Non-Pharmacologic Therapy • Disease specific monitoring • Oxygen therapy • Physical & Occupational therapy • Pulmonary rehabilitation • Immunizations • Patient education

3. What are the “Standards of Care” for IPF in 2005? • Non-Pharmacologic Therapy • Disease specific monitoring • Oxygen therapy • Physical & Occupational therapy • Pulmonary rehabilitation • Immunizations • Patient education Do not under-estimate the importance of non-pharmacologic therapy!!!

4. What are the “Standards of Care” for IPF in 2005? • Pharmacologic Therapy • American Thoracic Society 2000 Consensus Statement • Consideration for Lung Transplantation

5. American Thoracic Society Consensus Statement “. . . Conventional Treatment Options Treatment options include corticosteroids, immunosuppressive / cytotoxic agents (e.g., azathioprine, cyclophosphamide), and antifibrotic agents (e.g., colchicine or D-penicillamine) alone or in combination. . .”

6. Conventional Treatment Options • Older studies have suggested a 10-30% response rate for corticosteroids (Rudd et al. Am Rev Respir Dis 124:1, 1981.) • Similarly modest improvements in outcome had been noted with azathioprine (Raghu et al. Am Rev Respir Dis 144:291, 1991.) • Studies suggesting benefit are generally small and often not randomized, placebo-controlled or prospective • Treatment is similar to that used for ILD associated with connective tissue diseases or other IIPs • Significant potential for adverse side effects

7. Survival in Patients Treated with Azathioprine + Corticosteroids vs Corticosteroids Alone Raghu, G. et al. Am Rev Respir Dis 1991; 144: 291-296.

8. Survival in Patients Treated with Cyclophosphamide + Corticosteroids vs “Untreated” Patients Collard, H. R. et al. Chest 2004;125:2169-2174

9. The Quest for Novel Therapeutic Agents: Government-Sponsored • In 2005, the National Institutes of Health established the Idiopathic Pulmonary Fibrosis-Clinical Research Network to identify and test novel therapies for the treatment of IPF. • Familial Pulmonary Fibrosis Study

10. The Quest for Novel Therapeutic Agents: Industry-Sponsored • Gamma Interferon (Actimmune) • Imatinib (Gleevec) • Bosentan (Tracleer) • Etanercept (Enbrel) • N-acetylcysteine • Anti-Transforming Growth Factor-beta • Anti-Connective Tissue Growth Factor • Pirfenidone • Inhaled Iloprost (Ventavis)

11. Is an investigational trial for me? • Participation in research trials is a very personal and individual decision. Patients must be fully informed regarding the risks and benefits, pros and cons of participation. • Satisfied participants are often those who recognize that they are contributing to medical knowledge and potentially to treatment for the disease rather than those who expect a “miracle cure.”

12. Is an Investigational Trial for Me?Benefits • Empowerment • Contributing to developing knowledge and/or therapies for the disease • Access to physicians and centers expert in the disease • Disease and drug-specific monitoring • Latest information • Non-pharmacologic therapies • Physician and health allied professional “comfort” with your disease • Access to the latest medication

13. Is an Investigational Trial for Me? Malefits • Investigational agents may cause unforeseen harms • You may be the placebo control • Demands on time • “Opportunity costs”

14. Investigational Trials:What do you mean I’m not a candidate??! • A clinical diagnosis of IPF does not automatically mean that a person is a candidate for an investigational trial. • Confidence of diagnosis • Severity of disease • Age • Previous and concurrent therapies

15. Gamma-Interferon (IFN -1b)InterMune • 140 amino acid protein • Multiple biologic properties • Anti-fibrotic • Anti-infective • “Immunomodulatory” • Recently completed a phase III randomized, placebo controlled, prospectively trial evaluating the safety and efficacy of gamma-interferon for the treatment of pulmonary fibrosis

16. GIPF 001: ResultsPrimary Endpoint of Progression Free Survival 1.0 IFN -1b 0.8 Placebo P = 0.53 0.6 Probability of Death or Progression 0.4 0.2 0.0 0 100 200 300 400 500 600 Day Raghu G, et al. N Engl J Med. 2004;350:125-133

17. GIPF 001: ResultsITT Analysis-- Survival 1.0 0.8 P = 0.08 Probability ofSurvival 0.6 IFN -1b Placebo 0.4 0 100 200 300 400 500 600 Day 16 IFN -1b and 28 placebo deaths: 41% relative reduction Raghu G, et al. N Engl J Med. 2004;350:125-133.

18. INSPIRE Trial • A randomized, placebo controlled, prospective study of the safety and efficacy of subcutaneous interferon gamma-1b (IFN -1b) in patients with idiopathic pulmonary fibrosis (IPF) • Definitive diagnosis of IPF • Mild-moderate disease severity • Primary endpoint-- survival time • 75+ centers • 600 patient enrollment, 2+ years • Enrollment remains open

19. Imatinib (Gleevec)Novartis • Currently approved for and highly effective for the treatment of chronic myeloid leukemia. • Mechanism of action believed to be the inhibition of fibroblast growth and survival factors PDGF and TGF-b. • Phase II clinical trial with centers in New Orleans (Tulane) and Rochester, Minnesota (Mayo Clinic.)

20. Imatinib (Gleevec) • Definitive diagnosis of IPF • Mild-moderate disease severity • 100 patients, 2+ years • Enrollment status

21. Bosentan (Tracleer): BUILD-1Actelion • Bosentan targets endothelin • Bosentan represents proven effective therapy for primary pulmonary hypertension • BUILD-1 (IPF) and BUILD-2 (Scleroderma) designed to study the safety and efficacy of bosentan for the treatment of fibrotic lung disease. • Phase 2, enrollment complete • Results anticipated in spring 2006.

22. Etanercept TrialWyeth • Blocks tumor necrosis factor signaling • Approved and effective for the treatment of rheumatoid arthritis • Phase II study in 96 patients for the treatment of IPF. Enrollment closed. • Preliminary results expected in winter of 2005-06

23. GC-1008: Anti-Transforming Growth Factor-b (TGF- b) monoclonal Genzyme • Phase I trial • Targets TGF-b, a signaling molecule that promotes fibroproliferation • 5 Centers (NJMRC, Univ of Michigan, Vanderbilt, Univ of Washington, and Mayo Clinic) • Mild-moderate disease severity • Enrollment in the process of opening

24. Anti-Connective Tissue Growth Factor (CTGF) monoclonal antibodyFibrogen • Targets CTGF, a signaling molecule that promotes fibroproliferation • Results of a completed phase I trial are not released but appear to support continuing with the Phase II trial • Phase II trial to begin in late 2005 or early 2006 • Mild-moderate disease severity • Full list of centers not yet available

25. N-acetylcysteine (NAC): IFEGENIAGeneric • Anti-oxidant • Approved for Tylenol overdose, Available OTC as a “health supplement” • A recent European study comparing azathioprine + prednisone versus azathioprine + prednisone + NAC reportedly showed benefit to the NAC arm by physiologic testing • HOWEVER, this trial is not yet published and therefore has not been adequately reviewed • No clinical trials in the United States • No trials of NAC alone

26. PirfenidoneInterMune • Anti-fibrotic, anti-oxidant, anti-inflammatory • Recent study (Am J Respir Crit Care Med 171: 1040, 2005) found benefit to pirfenidone in IPF patients as assessed by lowest SpO2 achieved during a 6MWT in the subset of patients who’s baseline nadir was >80%. • Statistically significant benefit also seen in number of disease exacerbations and vital capacity. • Pirfenidone is NOT yet in clinical trials in the United States.

27. Inhaled Iloprost (Ventavis): ACTIVECoTherix • Vasodilator but also with effects on cell proliferation • Approved for primary pulmonary hypertension with NYHA class III or IV impairment • Phase II trial for pulmonary hypertension associated with mild-moderate pulmonary fibrosis • 50 patients, 15 sites • Will assess functional and hemodynamic endpoints

28. Questions?