Transcript Slide 1

IPF MANAGEMENT:
WHAT DO WE DO NOW?
Steven A. Sahn, MD
Professor of Medicine and Director
Division of Pulmonary, Critical Care,
Allergy and Sleep Medicine
Medical University of South Carolina
Combined Corticosteroid and Cyclophosphamide
Treatment Does Not Improve Survival in IPF Patients
1.00
Expected
P = 0.58
0.75
0.50
Untreated (n = 82)
Median survival = 1431 days
0.25
Treated (n = 82)
Median survival = 1665
0.00
0
500 1000 1500 2000 2500 3000 3500 4000
Days of Follow-up
• No evidence that corticosteroid plus cyclophosphamide
treatment improves survival
• Most patients do not respond to immunosuppressive agents
Collard HR, et al. Chest. 2004;125:2169-2174.
Walter N, et al. Proc Am Thorac Soc. 2006;3:330-338.
Evolving Model of Pathogenesis:
Aberrant Response to Persistent Injury
Epithelial cells
Cell death – impaired reepithelialization
Basement
Membrane
Damage
Growth factors and other
products of epithelial
cell injury
Oxidative
Stress
Procoagulant
Activity
Myofibroblast
TH2-TH1
Balance
Cell survival –
resistance to apoptosis
Collagen – matrix remodeling
Courtesy of Paul W. Noble, MD, and Victor J. Thannickal, MD.
Vascular
Remodeling
Therapeutic Targets
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Alveolar/capillary membrane
Fibroblast/myofibroblast
Basement membrane
The blood vessels
The immune response
Recent Phase 3 Clinical Trials
Drug
Trial name
IFNg-1b (Actimmune®)
GIPF-001
IFNg-1b (Actimmune®)
INSPIRE
N-acetylcysteine
(Fluimucil®)
Mechanism
Cytokine,
Antifibrotic
Progression-free survival
Cytokine,
Antifibrotic
Survival time
Antioxidant
IFIGENIA
Prednisone/Azathioprine/NAC PANTHR
Pirfenidone
CAPACITY 1 & 2
Bosentan (Tracleer®)
BUILD 3
Primary endpoint
(N)
330
826
FVC and DLco change
182
Trial length
(weeks)
48, completed
stopped
52, completed
Anti-inflamm, Change in FVC
Immunosuppr,
390
antioxidant
52, ongoing
TGFb inhib,
Antifibrotic
Change in FVC
720
72, ongoing
ET-1&2R
antagonist
Safety/efficacy
http://clinicaltrials.gov/ct/action/GetStudy.
Dempsey OJ. Respir Med. 2006;100:1871-1885.
Antoniu S. Expert Opin Investig Drugs. 2006;15:823-828.
Demedts M, et al. N Engl J Med. 2005;353:2229-2242.
390
131 events,
recruitment pending
GIPF-001 Study Results
Survival1
Lung Function (FVC)2
1.0
Probability of Survival
75
70
0.8
65
P = 0.08
60
0.6
IFN g-1b
55
Placebo
0.4
50
0
100
200
300
400
500
600
Day
0
12
24
36
Week
N = 330
1. Raghu G, et al. N Engl J Med. 2004;350:125-133.
2. Data on file with InterMune.
48
60
72
Interferon g-1b
INSPIRE Trial
Classification
Pleiotropic immunomodulatory cytokine
Mechanism
Antifibrotic, angiostatic, antiinfective, antiproliferative
Trial Design
Multinational, randomized, placebo controlled
Inclusion Criteria
Age 40-79 years, FVC ≥ 55% and DLCO ≥ 35% of predicted
Primary Endpoint
Survival time
Treatment Arms
200 μg TIW vs placebo, 2:1 randomization
Number of Patients
826 (enrollment complete)
Treatment Duration
2 years from date of 600th patient enrollment
www.inspiretrial.com. Accessed February 2007.
INSPIRE Trial Discontinued
• Recommended by DMC
• Interim analysis on 2/28/07
• 826 patients randomized
• 115 deaths
• No difference in mortality
• 14.5% (Actimmune) vs 12.7% (placebo)
FVC
2
DLCO
2
P = 0.02
0
NAC
-2
-4
-6
Placebo
-8
DLco (% predicted)
Vital Capacity (% predicted)
IFIGENIA Study Results
P = 0.003
0
-2
NAC
-4
-6
-8
Placebo
-10
-10
Baseline
6 Months
12 Months
Baseline
6 Months
12 Months
No. of Patients
Acetylcysteine 80
63
55
79
58
55
Placebo
60
51
74
59
51
75
Mortality, P = NS
NAC/Pred/Aza
7/80 (9%)
Placebo/Pred/Aza
8/75 (11%)
Demedts M, et al. N Engl J Med. 2005;353:2229-2242.
Prednisone/Azathioprine/NAC
PANTHR
Classification
Cocktail
Mechanisms
Anti-inflammatory, immunosuppression, anti-oxidant
Trial Design
Randomized, double blind, placebo controlled
Inclusion Criteria
FVC>55% and DLco>35%
Primary Endpoint
Change in FVC % predicted
Treatment Arms
Placebo vs Pred/Aza/NAC vs NAC
Number of Patients
390
Treatment Duration
52 weeks
Result
Ongoing
Courtesy of Imre Noth, MD.
Pirfenidone
CAPACITY 1 & 2
Classification
TGFb inhibitor
Mechanism
Antifibrotic
Trial Design
Randomized, double blind, placebo controlled
Inclusion Criteria
Age 40 – 80 years, confident IPF diagnosis
FVC  50% predicted value, DLCO  35% predicted value
Efficacy Endpoints
Primary: Mean change from baseline in % predicted FVC
Secondary: Changes in symptoms, functional capacity, QOL
Treatment Arms
CAPACITY 1: PFD 2403 mg/d vs placebo
CAPACITY 2: PFD 1197 mg/d vs PFD 2403 mg/d vs placebo
Number of Patients
CAPACITY 1: 320
CAPACITY 2: 400
Treatment Duration
60 weeks
www.capacitytrials.com. Accessed February 2007.
Bosentan
BUILD 3 Trial
Classification
Endothelin-1 & 2 receptor antagonist (ERA)
Mechanisms
Vasodilator, possible antifibrotic
Trial Design
Event-driven international, double-blind, randomized
(2:1::bosentan:placebo)
Inclusion Criteria
Proven IPF diagnosis < 3 years, with SLB
Primary Endpoint
Time to disease worsening (FVC & DLco), acute
exacerbation or death
Number of Patients
390
Treatment Duration
131 events
Results
Recruitment pending
http://clinicaltrials.gov/ct/show/NCT00391443?order=1
Anticoagulation Therapy
Probability of Survival
1
With Anticoagulant Therapy
0.8
n = 23
0.6
n = 33
0.4
Without Anticoagulant Therapy
0.2
P < 0.05
0
0
200
400
600
Time (Days)
Kubo H, et al. Chest. 2005;128:1475-1482.
800
1000
1200
Patient Management Strategies
• Assess for comorbidities
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Pulmonary hypertension
Obstructive sleep apnea
Coronary artery disease
GERD
COPD
• Assess for clinical trial enrollment
• Discuss “conventional” immunosuppression versus
alternatives (unproven agents) or no therapy
• Non-pharmacological strategies
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Pulmonary rehabilitation
Supplemental oxygen
Lung transplantation
End-of-life and palliative care
ATS/ERS Consensus Statement. Am J Respir Crit Care Med.
2000;161:646-664.
Khalil N, et al. CMAJ. 2004;171:153-160.
Acute Exacerbation of IPF
• Worsening dyspnea over 1-4 weeks
• Increased oxygen requirements
• New ground glass densities or
consolidation on HRCT
Management of Acute Exacerbations in IPF
• Exclude other causes
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Infection
CHF
Pulmonary embolism
Ischemic heart disease
• HRCT
• Bronchoscopy with BAL
• Careful assessment for a steroidresponsive disease
Walter N et al. Proc Am Thorac Soc. 2006;3:330–338.
Take Home Points
• Little quality evidence to support efficacy of
“conventional” immunosuppressive therapy
• No FDA-approved drugs for IPF; several
compounds in Phase 3 trials
• Participation in trials should be discussed as an
option for all appropriate patients
• Early referral and evaluation for lung
transplantation are recommended
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Risk of acute exacerbation
Recent allocation guidelines to maximize outcomes