Research and Development in Pulmonary Fibrosis: The Future is Bright Glenn D. Rosen, M D Associate Professor of Medicine Interim Co-Chief and Program Director Pulmonary and Critical Care Medicine Director of ILD Program

DISCLOSURES ADVISORY Intermune Celgene Coalition for Pulmonary Fibrosis

WHERE IS THE PROBLEM?

The test of a first-rate intelligence is the ability to hold two opposed ideas in the mind at the same time, and still retain the ability to function. F. Scott Fitzgerald, the Crack-Up 1936

IPF Pathogenesis

ATS CONSENSUS STATEMENT FOR TREATMENT OF IPF …lack sufficient clinical evidence that any treatment improves survival or quality of life for patients with IPF Therapy is not indicated in all patients For appropriate patients, start therapy at first clinical or physiological evidence of impairment or documentation of decline in lung function

Potential Treatments for IPF and other fibrotic lung diseases Antifibrotic Activity Anti-inflammatory Interferon- 1b Pirfenidone Etanercept ACEIs Statins NAC Immunosuppressants Corticosteroids

THE CAPACITY OF PIRFENIDONE IN IPF

DESIGN OF CAPACITY TRIAL »Two concurrent, multi-national trials »Total 779 patients »CAPACITY 1 (PIPF-006) 344 patients –PFD 2403mg: Placebo (1:1) »CAPACITY 2 (PIPF-004) 435 patients –PFD 2403mg: Placebo: PFD 1197mg (2:2:1) »Primary endpoint: Change in percent predicted Forced Vital Capacity (FVC) at 72 weeks (Rank ANCOVA) »Secondary endpoints –Measures of lung function, exercise tolerance, patient-reported outcomes, etc. –Primary analysis of secondary endpoints to be pooled (2403mg vs. placebo) if primary endpoint in both studies is met »Patients continue on study until last enrolled patient completes Week 72

PATIENT DISPOSITION CAPACITY 1CAPACITY 2 Pirf mg Placebo Pirf mg Pirf mg Placebo Randomized Completed treatment* 82%90%85%83%90% Adverse Event leading to treatment discontinuation 14%8%13%12%8% % Patients Completing Study* 92%95%94%93%95%

CHANGE IN PERCENT PREDICTED FVC AT WEEK 72 CAPACITY 1CAPACITY 2 Week LS Mean Change Relative reduction Rank ANCOVA P value LS Mean Change Relative reduction Rank ANCOV A P value Pirf.PlaceboPirf.Placebo % % %< % % %< % %< % %< % %0.001

PROGRESSION-FREE SURVIVAL (PFS) * Defined as Time to Death or Disease Progression (>10% decrease in FVC or >15% decrease in DL CO ) CAPACITY 1CAPACITY 2 Pirf. (N=171) Placebo (N=173) Pirf. (N=174) Placebo (N=174) Progression of Disease Events 32%35%26%36% 25 th percentile (weeks) Hazard Ratio P value (log rank)

CAPACITY TRIAL: Summary In the CAPACITY 1 study, the group receiving pirfenidone had a drop in their FVC over 72 weeks of 6.49% and the placebo group had a drop of 7.23%. There was no significant difference in the change in FVC between these 2 groups. In the CAPACITY 2 study, the group receiving regular dose pirfenidone had a drop in FVC over 72 weeks of 6.49% whereas the placebo group had a drop of 9.55% which was significantly different (pirfenidone group deteriorated less). In the CAPACITY 2 study, the pirfenidone group had significantly fewer events of disease progression (death or worsening breathing tests) than the placebo group. Next step: Await the FDAs response to InterMunes application for the use of Pirfenidone in patients with IPF.

Common AEs with Incidence 1.5 Times in the Pirfenidone vs. Placebo Groups CAPACITY 1CAPACITY 2 Patients (%) Pirf. (N=171) Placebo (N=173) Pirf. (N=174) Placebo (N=174) Nausea Rash Fatigue Diarrhea Dyspepsia Dizziness Gastro-esophageal Reflux67158 Photosensitivity Reaction Vomiting145 4 Insomnia76137 Arthralgia96128 Anorexia114 4 Urinary Tract Infection Abdominal Distension11597 Common AEs are defined as occurring 10% of pirfenidone 2403 mg patients in either study

Phase III trials in IPF Drug/Trial NamePrimary EndpointNTrial Length (weeks) STEP (Sildenafil Trial of Exercise Performance) Change in 6-minute walk distance weeks, completed, results pending ARTEMIS (Ambrisentan) Progression-free survival600 (2:1) 181 events, enrollment just starting N-acetylcysteine (Fluimucil ® ) IFIGENIA Change in FVC and DL CO 18252, completed, positive Pred/Aza/NAC PANTHER Change in FVC weeks, enrolling Pirfenidone CAPACITY 1 & 2 Change in FVC weeks, completed, CAPACITY 2 positive Bosentan (Tracleer ® ) BUILD 3 Progression-free survival616 (2:1) Approximately 200 events (150 to date), in progress

BENCH TO BEDSIDE AND BEDSIDE TO BENCH In my laboratory at Stanford, we use samples from IPF lungs to help understand what causes IPF and to identify better treatments Fibroblasts are isolated from lungs of patients undergoing a biopsy for diagnosis of IPF or lung transplantation and analyzed in our laboratory We and others have discovered genes and pathways active in IPF which may help us understand why the lungs scar. Blocking these genes or pathways may lead to new treatments for IPF

SUMMARY IPF and other fibrotic lung diseases are processes which involve lung damage and formation of excessive scar in response to this damage Cause is unknown but likely represents a combination of genetic, environmental, aging, and unknown factors Many clinical trials of new therapies for IPF are ongoing and planned Pirfenidone in a Japanese and an American trial slowed disease progression, using decline in FVC as a surrogate Keep asking questions, remain hopeful, and let Congress know that more funding is needed!

THANK YOU FOR LISTENING AND COMING TODAY! Stanford Center for Interstitial Lung Disease 300 Pasteur Drive, Rm H3143 Stanford, CA Director: Glenn D. Rosen, MD Nurse Coordinator: Virginia Adi, RN Research, Database and Trials: Susan Jacobs, RN, MS and Tessa Hunter, BS Physician Colleagues: Paul Mohabir, MD and Tushar Desai, MD Phone: (650) or (650)