Post on 02-Nov-2014
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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