Research and Development in Pulmonary Fibrosis: The

Future is Bright

Glenn D. Rosen, M DAssociate Professor of Medicine

Interim Co-Chief and Program Director Pulmonary and Critical Care Medicine

Director of ILD Program

DISCLOSURESADVISORYIntermuneCelgeneCoalition 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 OFPIRFENIDONE 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 completesWeek 72

PATIENT DISPOSITIONCAPACITY 1 CAPACITY 2

Pirf. 2403mg

Placebo Pirf. 1197mg

Pirf. 2403mg

Placebo

Randomized 171 173 87 174 174

Completed treatment* 82% 90% 85% 83% 90%

Adverse Event leading totreatment discontinuation

14% 8% 13% 12% 8%

% Patients Completing Study* 92% 95% 94% 93% 95%

CHANGE IN PERCENT PREDICTED FVC AT WEEK 72

CAPACITY 1 CAPACITY 2

Week

LS Mean Change

Relative reduction

Rank ANCOVA P value

LS Mean Change

Relative reduction

Rank ANCOVA P valuePirf. Placebo Pirf. Placebo

12 -1.22 -1.32 7% 0.021 -1.10 -2.26 51% 0.061

24 -1.32 -3.82 65% <.001 -1.18 -3.04 61% 0.014

36 -1.91 -3.86 50% 0.011 -2.25 -5.30 58% <.001

48 -3.87 -5.43 29% 0.005 -3.64 -6.70 46% <.001

60 -5.50 -6.23 12% 0.172 -5.23 -7.93 34% <.001

72 -6.49 -7.23 10% 0.501 -6.49 -9.55 32% 0.001

PROGRESSION-FREE SURVIVAL (PFS)

*Defined as Time to Death or Disease Progression (>10% decrease in FVC or >15% decrease in DLCO)

CAPACITY 1 CAPACITY 2

Pirf. (N=171)

Placebo(N=173)

Pirf.(N=174)

Placebo(N=174)

Progression of Disease Events 32% 35% 26% 36%

25th percentile (weeks) 72.3 61.3 77.6 50.3

Hazard Ratio 0.84 0.65

P value (log rank) 0.355 0.023

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 FDA’s response to InterMune’s application for the use of Pirfenidone in patients with IPF.

Common AEs with Incidence ≥1.5 Times in the Pirfenidone vs. Placebo Groups

CAPACITY 1 CAPACITY 2

Patients (%)Pirf.

(N=171)Placebo(N=173)

Pirf.(N=174)

Placebo(N=174)

Nausea 38 16 35 18

Rash 34 13 31 10

Fatigue 33 20 28 21

Diarrhea 33 21 25 17

Dyspepsia 21 6 17 9

Dizziness 18 10 19 10

Gastro-esophageal Reflux 6 7 15 8

Photosensitivity Reaction 10 2 14 1

Vomiting 14 5 14 4

Insomnia 7 6 13 7

Arthralgia 9 6 12 8

Anorexia 11 4 11 4

Urinary Tract Infection 9 12 11 5

Abdominal Distension 11 5 9 7

Common AEs are defined as occurring ≥10% of pirfenidone 2403 mg patients in either study

Phase III trials in IPFDrug/Trial Name Primary Endpoint N Trial Length (weeks)

STEP (Sildenafil Trial of Exercise Performance)

Change in 6-minute walk distance 170 12 weeks, completed,

results pending

ARTEMIS (Ambrisentan) Progression-free survival 600 (2:1) 181 events, enrollment

just starting

N-acetylcysteine (Fluimucil®)

IFIGENIAChange in FVC and DLCO 182 52, completed, positive

Pred/Aza/NACPANTHER

Change in FVC 390 52-72 weeks, enrolling

PirfenidoneCAPACITY 1 & 2

Change in FVC 720 72 weeks, completed, CAPACITY 2 positive

Bosentan (Tracleer®)BUILD 3

Progression-free survival 616 (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

SUMMARYIPF 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 H3143Stanford, CA 94305-5236

Director: Glenn D. Rosen, MDNurse Coordinator: Virginia Adi, RN

Research, Database and Trials: Susan Jacobs, RN, MS and Tessa Hunter, BS

Physician Colleagues: Paul Mohabir, MD and Tushar Desai, MDPhone: (650) 736-7301 or (650) 725-8082