Research and Development in
Pulmonary Fibrosis: The Future
is Bright
Glenn D. Rosen, M D
Associate Professor of Medicine
I...
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
re...
IPF Pathogenesis
ATS CONSENSUS STATEMENT FOR
TREATMENT OF IPF
“…lack sufficient clinical evidence that any
treatment improves survival or q...
Potential Treatments for IPF and
other fibrotic lung diseases
Antifibrotic Activity
Anti-inflammatory
Interferon-γ1b
Pirfe...
THE CAPACITY OF
PIRFENIDONE IN IPF
DESIGN OF CAPACITY TRIAL
» Two concurrent, multi-national trials
» Total 779 patients
» CAPACITY 1 (PIPF-006) 344 patient...
PATIENT DISPOSITION
CAPACITY 1 CAPACITY 2
Pirf.
2403mg
Placebo
Pirf.
1197mg
Pirf.
2403mg
Placebo
Randomized 171 173 87 174...
CHANGE IN PERCENT PREDICTED
FVC AT WEEK 72
CAPACITY 1 CAPACITY 2
Week
LS Mean
Change
Relative
reduction
Rank
ANCOVA
P valu...
PROGRESSION-FREE SURVIVAL
(PFS)
*Defined as Time to Death or Disease Progression
(>10% decrease in FVC or >15% decrease in...
CAPACITY TRIAL: Summary
In the CAPACITY 1 study, the group receiving pirfenidone had
a drop in their FVC over 72 weeks of...
Common AEs with Incidence ≥1.5 Times in the
Pirfenidone vs. Placebo Groups
CAPACITY 1 CAPACITY 2
Patients (%)
Pirf.
(N=171...
Phase III trials in IPF
Drug/Trial Name Primary Endpoint N Trial Length (weeks)
STEP (Sildenafil Trial of
Exercise Perform...
BENCH TO BEDSIDE AND BEDSIDE
TO BENCH
In my laboratory at Stanford, we use samples from IPF
lungs to help understand what...
SUMMARY
IPF and other fibrotic lung diseases are processes which
involve lung damage and formation of excessive scar in
r...
THANK YOU FOR LISTENING AND
COMING TODAY!
Stanford Center for Interstitial Lung Disease
300 Pasteur Drive, Rm H3143
Stanfo...
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  • 14.3.1-1
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    1. 1. 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
    2. 2. DISCLOSURES ADVISORY Intermune Celgene Coalition for Pulmonary Fibrosis
    3. 3. WHERE IS THE PROBLEM?
    4. 4. “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
    5. 5. IPF Pathogenesis
    6. 6. 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
    7. 7. Potential Treatments for IPF and other fibrotic lung diseases Antifibrotic Activity Anti-inflammatory Interferon-γ1b Pirfenidone Etanercept ACEIs Statins NAC Immunosuppressants Corticosteroids
    8. 8. THE CAPACITY OF PIRFENIDONE IN IPF
    9. 9. 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
    10. 10. PATIENT DISPOSITION CAPACITY 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 to treatment discontinuation 14% 8% 13% 12% 8% % Patients Completing Study* 92% 95% 94% 93% 95%
    11. 11. 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
    12. 12. 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
    13. 13. 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.
    14. 14. 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
    15. 15. Phase III trials in IPF Drug/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® ) IFIGENIA Change in FVC and DLCO 182 52, completed, positive Pred/Aza/NAC PANTHER Change in FVC 390 52-72 weeks, enrolling Pirfenidone CAPACITY 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
    16. 16. 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
    17. 17. 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!
    18. 18. THANK YOU FOR LISTENING AND COMING TODAY! Stanford Center for Interstitial Lung Disease 300 Pasteur Drive, Rm H3143 Stanford, CA 94305-5236 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) 736-7301 or (650) 725-8082

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