IPF Disease Management: Assessing the Options

1
IPF Disease Management Assessing the Options
Learning Objective Identify and apply practical
disease management strategies for patients with
IPF to optimize outcomes
2
Combined Corticosteroid and Cyclophosphamide
Treatment Does Not Improve Survival in IPF
Patients
1.00
Expected
P 0.58
0.75
0.50
Probability of Survival
Untreated (n 82)
Median survival 1431 days
0.25
Treated (n 82)
Median survival 1665 days
0.00
3000
3500
4000
0
500
1000
1500
2000
2500
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. 20041252169-2174. Walt
er N, et al. Proc Am Thorac Soc. 20063330-338.
3
Evolving Model of Pathogenesis Aberrant Response
to Persistent Injury
Cell death impaired reepithelialization
Epithelial cells
Basement Membrane Damage
Oxidative Stress
Growth factors and other products of epithelial
cell injury
Procoagulant Activity
Myofibroblast
TH2-TH1 Balance
Cell survival Resistance to apoptosis, Genetics,
Telomere metabolism
Vascular Remodeling
Collagen matrix remodeling
Adapted from Paul W. Noble, MD, and Victor J.
Thannickal, MD.
4
Potential Strategies for Therapeutic Intervention

• Promote repair/regeneration of the
  alveolar-capillary membrane
• Inhibit fibroblast/myofibroblast activation
• Prevent aberrant vascular and extracellular
  matrix remodeling and basement membrane damage
• Limit oxidative stress responses
• Augment innate immune responses

5
Recent Phase 3 Clinical Trials
http//clinicaltrials.gov/ct/action/GetStudy.
Accessed March 2007. Antoniu SA. Expert Opin
Investig Drugs. 200615823-828. Demedts M, et
al. N Engl J Med. 20053532229-2242. Dempsey OJ.
Respir Med. 20061001871-1885.
6
Interferon g-1bGIPF-001 Trial
Raghu G, et al. N Engl J Med. 2004350125-133.
7
GIPF-001 Study Results
Lung Function (FVC)2
Survival1
1.0
75
70
0.8
65
Probability of Survival
P 0.08
60
0.6
IFN ?-1b
55
Placebo
0.4
50
0
100
200
300
400
500
600
0
12
24
36
48
60
72
Day
Week
N 330
1. Raghu G, et al. N Engl J Med.
2004350125-133. 2. Data on file with InterMune.
8
Interferon g-1b INSPIRE Trial
www.inspiretrial.com. Accessed March 2007.
9
N-acetylcysteine IFIGENIA Trial
UPDATED!
Demedts M, et al. N Engl J Med.
20053532229-2242.
10
IFIGENIA Study Results
DLCO
FVC
2
2
P 0.02
P 0.003
0
0
-2
-2
NAC/Pred/Aza
-4
-4
Vital Capacity ( predicted)
DLco ( predicted)
NAC/Pred/Aza
-6
-6
PBO/Pred/Aza
-8
-8
PBO/Pred/Aza
-10
-10
12 Months
6 Months
Baseline
6 Months
Baseline
12 Months
No. of Patients NAC/Pred/Aza
PBO/Pred/Aza
80 75
63 60
55 51
79 74
58 59
55 51
No mortality difference
Demedts M, et al. N Engl J Med.
20053532229-2242.
11
Prednisone/Azathioprine/NAC PANTHER Trial
Courtesy of Imre Noth, MD.
12
Recent Pirfenidone Results
UPDATED!
Each treatment group different than placebo, P
0.04
Progression-Free Survival
Time, days
Shionogi corporate release available
at http//www.shionogi.co.jp/ir_en/explanatory/pdf
/e_p070322.pdf
13
Pirfenidone CAPACITY 1 2 Trials
www.capacitytrials.com. Accessed March 2007.
14
Bosentan BUILD 3 Trial
http//clinicaltrials.gov/ct/show/NCT00391443.
Accessed March 2007.
15
Anticoagulation Therapy
1
With Anticoagulant Therapy
0.8
n 23
0.6
Probability of Survival
n 33
0.4
Without Anticoagulant Therapy
0.2
P lt 0.05
0
600
800
1000
1200
0
200
400
Time (days)
Kubo H, et al. Chest. 20051281475-1482.
16
Phase 2 Clinical Trials
UPDATED!
http//clinicaltrials.gov/ct/action/GetStudy.
Accessed March 2007. Dempsey OJ. Respir Med.
20061001871-1885. Antoniu SA. Expert Opin
Investig Drugs. 200615823-828.
17
Patient Management Strategies

• Assess for comorbidities
• Pulmonary hypertension
• Obstructive sleep apnea
• Coronary artery disease
• GERD
• Assess whether appropriate for clinical trial
  enrollment
• Discuss experimental therapies
• Nonpharmacological strategies
• Lung transplantation
• Supplemental oxygen
• Pulmonary rehabilitation
• End-of-life and palliative care

ATS/ERS Consensus Statement. Am J Respir Crit
Care Med. 2000161646-664. Khalil N, OConnor
R. CMAJ. 2004171153-160.
18
Causes of Cough
UPDATED!
95
5

• Post nasal drip (PND)
• GERD
• Chronic bronchitis
• Bronchiectasis
• Eosinophilic bronchitis
• ACE inhibitors, other drugs

• Bronchogenic CA
• Metastatic CA
• ILD
• LVF
• TB
• Aspiration

Irwin RS, et al. Chest. 1998114133-181.
19
Treatment of Cough in IPF
UPDATED!
GERD
PND
Obstructive Lung Disease
Nasal steroids Ipratropium Antihistamines
PPI, lifestyle and dietary modifications
If no improvement
Nebulized anesthetics
Opiates
?
Prednisone
Dextro- methorphan Guaifenesin
Benzonatate Baclofen
Slide adapted from Glenn D. Rosen, MD.
20
Management of Patients With Acute Exacerbations
UPDATED!

• Exclude other causes
• Infection
• CHF
• Pulmonary embolism
• Ischemic heart disease
• HRCT
• Bronchoscopy (if permitted by medical status)
• Patients usually treated with broad-spectrum
  antibiotics and corticosteroids (unproven
  efficacy)

Walter N, et al. Proc Am Thorac Soc.
20063330-338.
21
Lung Transplantation

• Only therapy shown to extend life expectancy
• Viable up to age 65, older if patient health is
  exceptional
• Old model was first-come/first-served basis
• New transplant guidelines based on a lung
  allocation score (LAS)
• LAS projected pretransplant 1-year survival vs
  projected posttransplant 1-year survival
• Consider transplant evaluation at time of
  diagnosis
• IPF is the 1 indication of lung transplantation

www.unos.org. Accessed February 2007.
22
ADULT LUNG TRANSPLANTATIONKaplan-Meier Survival
by Procedure Type and Era (Transplants January
1990 June 2005) Diagnosis Idiopathic
Pulmonary Fibrosis, Single Lung
NEW!
ISHLT
Trulock EP, et al. J Heart Lung Transplant.
200726782-795.


23
ADULT LUNG TRANSPLANTATIONKaplan-Meier Survival
by Procedure Type and Era (Transplants January
1990 June 2005) Diagnosis Idiopathic
Pulmonary Fibrosis, Double Lung
NEW!
ISHLT
Trulock EP, et al. J Heart Lung Transplant.
200726782-795.


24
Take Home Messages
UPDATED!

• Little quality evidence supports the efficacy of
  conventional immunosuppressive therapy for IPF
• A multidisciplinary collaboration between
  pulmonologist, radiologist, and pathologist is
  best for accurate diagnosis and management of IPF
• Although there are no FDA-approved drugs for IPF,
  several compounds are in phase 3 clinical trials
• Participation in these trials should be discussed
  as an option for all appropriate patients
• Early referral for lung transplantation is
  recommended