1. Idiopathic Pulmonary Fibrosis Standards 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: Results Primary Endpoint of Progression Free Survival Probability of Death or Progression IFN  -1b Placebo 0.0 0.2 0.4 0.6 0.8 1.0 0100200300400500600 Day P = 0.53 Raghu G, et al. N Engl J Med. 2004;350:125-133

17. GIPF 001: Results ITT Analysis-- Survival 16 IFN  -1b and 28 placebo deaths: 41% relative reduction Probability ofSurvival Probability of Survival 0.4 0.6 0.8 1.0 0100200300400500600 Day IFN  -1b Placebo P = 0.08 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- . 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-1 Actelion 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 Trial Wyeth 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-  (TGF-  ) monoclonal Genzyme Phase I trial Targets TGF-  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 antibody Fibrogen 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): IFEGENIA Generic 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. Pirfenidone InterMune 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): ACTIVE CoTherix 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?