Transcript Brown - Westie Foundation of America

Management of Lung Fibrosis
in Humans
Kevin K. Brown, MD
Professor and Vice Chair, Department of Medicine
National Jewish Health
Denver, CO USA
Disclosures
Wyeth
Novartis
Actelion
Centocor
Genentech/Roche
Boehringer Ingelheim
Galecto
Veracyte
Fibrogen
Mesoblast
Genzyme
Biogen/Stromedix
Amgen
Gilead
Medimmune
Promedior
Altitude Pharma
Celgene
ImmuneWorks
Pfizer
The problem
Survival in IPF is short
Median survival - 2.8 years
King et al, Am J Respir Crit Care Med 2000
Survival in IPF is short
Median survival - 2.8 years
King et al, Am J Respir Crit Care Med 2000
Quality of life with IPF is poor
Martinez TY et al, Chest 2000
Quality of life with IPF is poor
Martinez TY et al, Chest 2000
Functional Status in IPF is impaired
Functional Status in IPF is impaired
Olson A et al, submitted
The clinical course is
unpredictable
Disease severity
Better
Worse
Time (years)
Recent trial results have
been disappointing
Summary of Selected Multi-centered Trials
Summary of Selected Multi-centered Trials
Trial
N
Primary Endpoint
Result
Summary of Selected Multi-centered Trials
Trial
Interferon-beta (1999)
N
Primary Endpoint
Result
167
Progression free survival time
Negative
Summary of Selected Multi-centered Trials
Trial
N
Primary Endpoint
Result
Imatinib Mesylate
120
Progression free survival
Negative
Bosentan (BUILD-3)
132
Change in 6MW distance
Negative
Etanercept
100
Change in DLCO, FVC
Negative
Interferon-gamma (007)
826
Survival time
Negative
Interferon-beta (1999)
167
Progression free survival time
Negative
Summary of Selected Multi-centered Trials
Trial
N
Primary Endpoint
Result
Pirfenidone (CAPACITY 1)
344
Change in FVC
Negative
Pirfenidone (CAPACITY 2)
435
Change in FVC
Positive
Imatinib Mesylate
120
Progression free survival
Negative
Bosentan (BUILD-3)
132
Change in 6MW distance
Negative
Etanercept
100
Change in DLCO, FVC
Negative
Interferon-gamma (007)
826
Survival time
Negative
Interferon-beta (1999)
167
Progression free survival time
Negative
Summary of Selected Multi-centered Trials
Trial
N
Primary Endpoint
Result
Ambrisentan (ARTEMIS-IPF)
492
Time to disease progression
Potentially Harmful
Pirfenidone (CAPACITY 1)
344
Change in FVC
Negative
Pirfenidone (CAPACITY 2)
435
Change in FVC
Positive
Imatinib Mesylate
120
Progression free survival
Negative
Bosentan (BUILD-3)
132
Change in 6MW distance
Negative
Etanercept
100
Change in DLCO, FVC
Negative
Interferon-gamma (007)
826
Survival time
Negative
Interferon-beta (1999)
167
Progression free survival time
Negative
Summary of Selected Multi-centered Trials
Trial
N
Primary Endpoint
Result
Coumadin (ACE)
145
Time to disease progression
Harmful
Ambrisentan (ARTEMIS-IPF)
492
Time to disease progression
Potentially Harmful
Pirfenidone (CAPACITY 1)
344
Change in FVC
Negative
Pirfenidone (CAPACITY 2)
435
Change in FVC
Positive
Imatinib Mesylate
120
Progression free survival
Negative
Bosentan (BUILD-3)
132
Change in 6MW distance
Negative
Etanercept
100
Change in DLCO, FVC
Negative
Interferon-gamma (007)
826
Survival time
Negative
Interferon-beta (1999)
167
Progression free survival time
Negative
Summary of Selected Multi-centered Trials
Trial
N
Primary Endpoint
Result
Pred/Aza/N-acetylcysteine (PANTHER)
155
Change in FVC
Harmful
Coumadin (ACE)
145
Time to disease progression
Harmful
Ambrisentan (ARTEMIS-IPF)
492
Time to disease progression
Potentially Harmful
Pirfenidone (CAPACITY 1)
344
Change in FVC
Negative
Pirfenidone (CAPACITY 2)
435
Change in FVC
Positive
Imatinib Mesylate
120
Progression free survival
Negative
Bosentan (BUILD-3)
132
Change in 6MW distance
Negative
Etanercept
100
Change in DLCO, FVC
Negative
Interferon-gamma (007)
826
Survival time
Negative
Interferon-beta (1999)
167
Progression free survival time
Negative
What to do?
The future of therapies
Epithelium
Adapted from: Maher, TM, Clin Chest Med 33 (2012) 69–83
Alveolar
Space
Epithelium
Adapted from: Maher, TM, Clin Chest Med 33 (2012) 69–83
Alveolar
Space
Epithelium
Endothelium
▪
▪
▪
▪
▪
▪
▪
Adapted from: Maher, TM, Clin Chest Med 33 (2012) 69–83
Alveolar
Space
Epithelium
Endothelium
▪
▪
▪
▪
▪
▪
▪
Vascular
Space
Adapted from: Maher, TM, Clin Chest Med 33 (2012) 69–83
Alveolar
Space
Epithelium
Mesenchyme
Endothelium
▪
▪
▪
▪
▪
▪
▪
Vascular
Space
Adapted from: Maher, TM, Clin Chest Med 33 (2012) 69–83
Injury
Alveolar
Space
Epithelium
Mesenchyme
Endothelium
▪
▪
▪
▪
▪
▪
▪
Vascular
Space
Adapted from: Maher, TM, Clin Chest Med 33 (2012) 69–83
Injury
Alveolar
Space
Epithelium
Mesenchyme
Endothelium
▪
▪
▪
▪
▪
▪
▪
Vascular
Space
Adapted from: Maher, TM, Clin Chest Med 33 (2012) 69–83
Injury
Alveolar
Space
Epithelium
Mesenchyme
Endothelium
▪
▪
▪
▪
▪
▪
▪
Vascular
Space
Adapted from: Maher, TM, Clin Chest Med 33 (2012) 69–83
Injury
Alveolar
Space
Epithelium
Mesenchyme
Endothelium
▪
▪
▪
▪
▪
▪
▪
Vascular
Space
Adapted from: Maher, TM, Clin Chest Med 33 (2012) 69–83
Injury
Alveolar
Space
Epithelium
Mesenchyme
Endothelium
▪
▪
▪
▪
▪
▪
▪
Vascular
Space
Adapted from: Maher, TM, Clin Chest Med 33 (2012) 69–83
Injury
Alveolar
Space
Epithelium
Mesenchyme
Endothelium
▪
▪
▪
▪
▪
▪
▪
Vascular
Space
Adapted from: Maher, TM, Clin Chest Med 33 (2012) 69–83
•
•
•
•
•
Antioxidants
NOX4 Inhibitors
Anti-reflux therapy
Antimicrobials
Antivirals
Injury
Alveolar
Space
Epithelium
Mesenchyme
Endothelium
▪
▪
▪
▪
▪
▪
▪
Vascular
Space
Adapted from: Maher, TM, Clin Chest Med 33 (2012) 69–83
•
•
•
•
•
Antioxidants
NOX4 Inhibitors
Anti-reflux therapy
Antimicrobials
Antivirals
Injury
Alveolar
Space
Epithelium
Mesenchyme
Endothelium
▪
▪
▪
▪
▪
▪
▪
Vascular
Space
Adapted from: Maher, TM, Clin Chest Med 33 (2012) 69–83
•
•
•
•
•
Antioxidants
NOX4 Inhibitors
Anti-reflux therapy
Antimicrobials
Antivirals
•
•
Injury
Alveolar
Space
Epithelium
Mesenchyme
Endothelium
▪
▪
▪
▪
▪
▪
▪
Vascular
Space
Adapted from: Maher, TM, Clin Chest Med 33 (2012) 69–83
FXa inhibitors
PAR antagonists
•
•
•
•
•
Antioxidants
NOX4 Inhibitors
Anti-reflux therapy
Antimicrobials
Antivirals
•
•
Injury
Alveolar
Space
Epithelium
Mesenchyme
Endothelium
▪
▪
▪
▪
▪
▪
▪
Vascular
Space
Adapted from: Maher, TM, Clin Chest Med 33 (2012) 69–83
FXa inhibitors
PAR antagonists
•
•
•
•
•
Antioxidants
NOX4 Inhibitors
Anti-reflux therapy
Antimicrobials
Antivirals
•
•
Injury
Alveolar
Space
•
•
•
•
Epithelium
Mesenchyme
Endothelium
FXa inhibitors
PAR antagonists
▪
▪
▪
▪
▪
▪
▪
Vascular
Space
Adapted from: Maher, TM, Clin Chest Med 33 (2012) 69–83
EP receptor agonists
HGF
KGF
Anti-IL-13
•
•
•
•
•
Antioxidants
NOX4 Inhibitors
Anti-reflux therapy
Antimicrobials
Antivirals
•
•
Injury
Alveolar
Space
•
•
•
•
Epithelium
inhibition
Mesenchyme
Endothelium
FXa inhibitors
PAR antagonists
▪
▪
▪
▪
▪
▪
▪
Vascular
Space
Adapted from: Maher, TM, Clin Chest Med 33 (2012) 69–83
EP receptor agonists
HGF
KGF
Anti-IL-13
•
•
•
•
•
Antioxidants
NOX4 Inhibitors
Anti-reflux therapy
Antimicrobials
Antivirals
•
•
Injury
Alveolar
Space
FXa inhibitors
PAR antagonists
•
•
•
•
EP receptor agonists
HGF
KGF
Anti-IL-13
Epithelium
inhibition
Mesenchyme
Endothelium
▪
▪
▪
▪
▪
▪
▪
Vascular
Space
Adapted from: Maher, TM, Clin Chest Med 33 (2012) 69–83
•
•
•
•
•
•
•
•
•
•
CTGF inhibition
Kinase inhibitors
Anti-TGFβ
Pirfenidone
Anti-CCL-2
Anti- αVβ6
LPA1antagonists
NOX4 inhibitors
EP receptor agonists
LOXL2 inhibitors
•
•
•
•
•
Antioxidants
NOX4 Inhibitors
Anti-reflux therapy
Antimicrobials
Antivirals
•
•
Injury
Alveolar
Space
FXa inhibitors
PAR antagonists
•
•
•
•
EP receptor agonists
HGF
KGF
Anti-IL-13
Epithelium
inhibition
Mesenchyme
Endothelium
▪
▪
▪
▪
▪
▪
▪
Vascular
Space
Adapted from: Maher, TM, Clin Chest Med 33 (2012) 69–83
•
•
•
•
•
•
•
•
•
•
CTGF inhibition
Kinase inhibitors
Anti-TGFβ
Pirfenidone
Anti-CCL-2
Anti- αVβ6
LPA1antagonists
NOX4 inhibitors
EP receptor agonists
LOXL2 inhibitors
•
•
•
•
•
Antioxidants
NOX4 Inhibitors
Anti-reflux therapy
Antimicrobials
Antivirals
•
•
Injury
Alveolar
Space
FXa inhibitors
PAR antagonists
•
•
•
•
EP receptor agonists
HGF
KGF
Anti-IL-13
Epithelium
inhibition
Mesenchyme
Endothelium
▪
▪
▪
▪
▪
▪
▪
Vascular
Space
•
•
•
•
•
•
•
•
•
•
•
•
•
•
VEGF inhibition
Sildenafil
Anti-CCL-2
CXCR4 antagonists
Adapted from: Maher, TM, Clin Chest Med 33 (2012) 69–83
CTGF inhibition
Kinase inhibitors
Anti-TGFβ
Pirfenidone
Anti-CCL-2
Anti- αVβ6
LPA1antagonists
NOX4 inhibitors
EP receptor agonists
LOXL2 inhibitors