1. No category

Idiopathic Pulmonary Fibrosis
Ganesh Raghu, MD, FACP, FCCP
Professor of Medicine and Laboratory Medicine
University of Washington Medical Center
Chief, Chest Clinic
Director: Interstitial Lung Disease and Lung Transplant
Program
Classification of Idiopathic Interstitial
Pneumonias
International Consensus Statement (ATS/ ERS 2002)*
*AJRCCM 105: 277-304, 2002
Classification of Idiopathic Interstitial
Pneumonias
International Consensus Statement (ATS/ ERS 2002)*
*AJRCCM 105: 277-304, 2002
Idiopathic Pulmonary Fibrosis
In spite of potent anti-inflammatory therapy:

progressive

irreversible

lethal disease
Idiopathic Pulmonary Fibrosis:
Survival
100
80
60
% survival
Treated (Prednisone
alone)
40
20
Untreate
d
0
0
3
6
M. Turner-Warwick, et al. Thorax. 1980;35:593-599.
9
Time (years)
12
15
18
IPF and corticosteroid therapy
10-30% reported therapeutic response
Problem
 No biopsies
 No strict definition of UIP
 Includes other pathologies
 Few large-scale trials
Stable or improved (%)
Clinical response to therapy in IPF
100
Prednisolone+
cyclophosphamide
Prednisolone
50
0
1
3
12
Months
Johnson MA, et al. Thorax. 1989;44:280-288.
24
36
Effect of therapy of survival in IPF
Survival (%)
100
Prednisolone
Prednisolone + Colchicine
80
Prednisone +D-Penicillamine
60
Prednisone + Colchicine
+ D-Penicillamine
40
20
0
0 10 20 30 40 50 60 70
Months
Selman M, et al. Chest. 1998;114:507-512.
Idiopathic Pulmonary Fibrosis:
Survival
100
80
Prednisone + Imuran*
60
% Survival
Treated (prednisone alone)
40
20
Untreated
0
0
3
6
M Turner-Warwick, et al. Thorax. 1980;35:593-599.
*G. Raghu, et al. ARRD. 1991;144:291-296.
9
Time (years)
12
15
18
Idiopathic Pulmonary Fibrosis:
Overall Survival
100
80
60
% survival
40
20
0
0
3
M Turner-Warwick. Thorax. 1980;35:171.
6
9
Time (years)
12
15
18
Idiopathic Pulmonary Fibrosis (IPF)
Previous and current clinical trends (Yr 2001)
Disease already in mid-to-advanced
stages at diagnosis
Why?
Idiopathic Pulmonary Fibrosis
Previous and current clinical pattern (Yr 2001)
5 - 10 yrs
Genetic predisposition ?
45
50
Injury
55
60
65
70
75
Recurrent
Alveolar wall
1-2 yrs
Middle age
Mild or
no symptoms
Referral to centers
% Survival
40
Years
Primary MD
GP
Internist
(Pulmonary specialist)
Years
80
85
Years
Idiopathic Pulmonary Fibrosis (IPF):
Treatment
Challenges and hurdles – New, multicenter, clinical trials: Yr 2001 
Theoretic goals and clinical realities to improve survival
Specific new Rx
100
•  Quality of life
• Minimal or no
side effects
80
• Identify complications
early and Rx promptly
60
%
survival
40
20
0
Supportive
Rx
Survivorship effect
5 yr
10 yr
Idiopathic Pulmonary Fibrosis (IPF):
Treatment
Challenges and hurdles – New, multicenter, clinical trials: Yr 2001 
Theoretic goals and realities (Yr 2001)
Specific new Rx
•  rate of progression
• Improved function
• Better quality of life
Functional
impairment
Years
Pathogenesis and course of UIP
UIP
Multiple microscopic foci of injury occurring over many years
Focal fibroblast proliferation (fibroblastic foci)
Collagen deposition
Recurrent microscopic injury
Progressive clinical course
Death
Katzenstein AL, et al. Am J Respir Crit Care Med. 1999;157:1301-1315.
Pulmonary Fibrosis of Unknown Etiology
Conceptual pathogenesis of unusual interstitial pneumonia (UIP)
Genetic predisposition factors
Born with “normal” lung
Growing ages
Adult lung exposed to “fibrogenic” stimuli
Environment
Autoimmune
(domestic, occupation)
Infection (viral?)
Drugs
Recurrent, chronic aspiration
Cigarette smoke
Proinflammatory
Others ?
Cell
Modulating
factors
Matrix
Profibrotic cytokines
Cell
Recurrent insult/injury x yrs
Clinical manifestation
Idiopathic Pulmonary Fibrosis
• Fibroblast foci
•  extracellular matrix
(collagens, proteoglycans)
•  gas exchange units
Therapy – antifibrotic
•  fibroblast proliferation
•  extracellular matrix
• Tissue repair
(re-epithelialisation)
•  gas exchange units
Improved outcome
New approach to IPF/UIP therapy
To prevent further fibroproliferation,
aka collagen production, aka scar
formation
Idiopathic Pulmonary Fibrosis:
Antifibrotic Therapy
Interferon-g – A preliminary study
Prospective study (5/96 to 2/99), open label, controlled,
randomized

18 patients, unresponsive to corticosteroids or immunosuppression
during prior 12 months

6 weeks oral prednisone (50 mg/d x 4 wks, 10 mg/d x 2 wks)

Unresponsive patients randomized
- 200 mg g-IFN S/C x 3 week - plus 7.5 mg oral
prednisolone vs 7.5 mg oral prednisolone alone
- 12-month treatment
- Follow up with PFTs
Ziesche, et al. NEJM. 1999; 341:1264-1269.
Idiopathic Pulmonary Fibrosis:
Antifibrotic Therapy
Interferon-g – A preliminary study
Conclusions

Significant improvement in PFTs in all 9
patients receiving 12 months of IFN-g plus
low-dose prednisolone
Ziesche, et al. NEJM. 1999; 341:1264-1269.
Idiopathic Pulmonary Fibrosis
Treatment with Interferon-g 1b
Published Study Revisited*
Too good …to be true?
Ziesche, et al. NEJM. 1999; 341:1264-1269.
* Sponsor Intermune Pharmaceuticals, Brisbane, CA
Idiopathic Pulmonary Fibrosis
Treatment with Interferon-g 1b
Published study revisited*
Methods: Independent review of data of individual study patients

Expert panel:
•
Ganesh Raghu, MD (Seattle, WA)
•
Kevin Brown, MD (Denver, CO)
•
Paul Noble, MD (New Haven, CT)
•
Tom Colby, MD (Scottsdale, AZ)
– With Rolf Ziesche, MD (Vienna, Austria)
– At Mayo Clinic, Scottsdale, AZ (3/2/2000)
Ziesche, et al. NEJM. 1999; 341:1264-1269.
G. Raghu, et al. Independent review. March 2000 (ATS Monograph 2000.)
* Sponsor Intermune Pharmaceuticals, Brisbane, CA
Idiopathic Pulmonary Fibrosis
Treatment with Interferon-g 1b
Published study revisited/re-analyzed*
Control
IFN

Surgical lung bx:15/18 patients
7
8

Transbronchial bx: 3/18 patients
2
1

Definite IPF
5/9
4/9

Probable IPF (UIP±NSIP/chronic HSP/other)
3/9
3/9

Definitely not IPF
1/9(TBB)
2/9
Ziesche, et al. NEJM. 1999; 341:1264-1269.
* G. Raghu, K. Brown, P. Noble, T. Colby: Independent Review with Rolf Ziesche:March 2000, Scottsdale, AZ
Sponsor Intermune Pharmaceuticals, Brisbane, CA (ATS Monograph. 2000.)
Idiopathic Pulmonary Fibrosis
Treatment with Interferon-g 1b
Published study revisited/re-analyzed*
Prednisolone alone
100
80
TLC (% Predicted)
TLC (% Predicted)
100
IFN-g + low-dose prednisolone
60
40
Define IPF
Probable IPF
Not IPF
20
0
80
60
40
20
0
Baseline
12 months
Baseline
12 months
Ziesche, et al. NEJM. 1999; 341:1264-1269.
G. Raghu, et al. Independent review. (ATS Monograph 2000.) * Sponsor Intermune Pharmaceuticals, Brisbane, CA
Idiopathic Pulmonary Fibrosis
Treatment with Interferon-g 1b
Published study revisited/re-analyzed*
IFN-g + low-dose prednisolone
100
100
80
80
VC (%Predicted)
VC (%Predicted)
Prednisolone alone
60
40
Define IPF
Probable IPF
Not IPF
20
0
60
40
20
0
Baseline
12 months
Baseline
12 months
Ziesche, et al. NEJM. 1999; 341:1264-1269.
G. Raghu, et al. Independent review. (ATS Monograph 2000.) * Sponsor Intermune Pharmaceuticals, Brisbane, CA
Idiopathic Pulmonary Fibrosis
Treatment with Interferon-g 1b
Published study revisited/re-analyzed*
IFN-g + low-dose prednisolone
80
80
60
60
A-a gradient
A-a gradient
Prednisolone alone
40
Define IPF
Probable IPF
Not IPF
20
0
40
20
0
Baseline
12 months
Baseline
12 months
Ziesche, et al. NEJM. 1999; 341:1264-1269.
G. Raghu, et al. Independent review. (ATS Monograph 2000.) * Sponsor Intermune Pharmaceuticals, Brisbane, CA
Idiopathic Pulmonary Fibrosis
Treatment with Interferon-g 1b
Published study revisited*
Conclusions

Patients with IPF + steroid resistant unclassifiable IIP
(Not BOOP) improved with IFN-g

Some variability between Bx+HRCT findings
(timing ± Bx)(sample)

Side effects: In most patients;first 3 months, intensity
decreased thereafter
Ziesche, et al. NEJM. 1999; 341:1264-1269.
* G. Raghu, K. Brown, P. Noble, T. Colby: Independent Review with Rolf Ziesche:March 2000, Scottsdale, AZ
Sponsor Intermune Pharmaceuticals, Brisbane, CA (ATS Monograph. 2000.)
Idiopathic Pulmonary Fibrosis
Treatment with Interferon-g 1b
Published study revisited*
Implications

Definitive phase III clinical trial with large
number of well defined study patients needed
to confirm the potential benefits of IFN-g in
patients with IPF and IIP resistant to steroids
Ziesche, et al. NEJM. 1999; 341:1264-1269.
* G. Raghu, K. Brown, P. Noble, T. Colby: Independent Review with Rolf Ziesche:March 2000, Scottsdale, AZ
Sponsor Intermune Pharmaceuticals, Brisbane, CA
Interferons and
Idiopathic Pulmonary Fibrosis
Summary

Type I (IFN-, , , ) and Type II (IFN-g)
• Distinct differences (molecular, receptor level, and inducibility)

Type I
• IFN- : no role ( Bleomycin induced pulmonary fibrosis)
• IFN-: Phase II, multicenter clinical trial in well defined IPF*
– Not efficacious* (subgroup analyses)

Type II (IFN-g)
• Preliminary observation (Phase II clinical trial) promising†
• Efficacy: to be determined (ongoing Phase III multicenter, clinical trial**)
• Until study completed: IFN-g experimental
*
G. Raghu et al. AJRCCM. 2001;163(5, Part 2):A707. Sponsor: Biogen Inc, Cambridge, MA
Ziesche, et al. NEJM. 1999;341:1264-1269
** Sponsor: Intermune Pharmaceuticals, Brisbane, CA
†
Idiopathic Pulmonary Fibrosis (IPF):
Treatment with IFN-g
Current status (April 2002)

Multicenter, phase III, clinical trial* (9/00
)

Double-blind, placebo-controlled, prospective, randomized

Target N=306 (enrollment completed in US/Canada 9/01)

Current sites: US/Canada (51 sites), Europe (4), South Africa (1)

Primary endpoint
– Decrease rate of progression
– Minimum duration of study = 12 months (306th patient)

Randomized N=330 patients

European sites: Ireland (1), Netherlands (1), Spain (2), UK (2)

Study ongoing

Anticipated analysis: September 2002 — December 2002
* Sponsor: Intermune, Inc, Brisbane, Calif.
Idiopathic Pulmonary
Fibrosis
Other Potential
Therapies for the
Future
Other potential antifibrotic
therapies for IPF
IFN-g
Subcutaneous vs inhaled
Other potential antifibrotic
therapies for IPF

N-Acetylcysteine (NAC)

Pirfenidone

Anti TGF-B therapies

Lovastatin

Relaxin

ACE Inhibitors

PGE2

Leukotriene receptor antagonist

Endothelin receptor antagonist

Anti TNF-alpha Therapies

Others
Other potential antifibrotic
therapies for IPF
N-Acetylcysteine (NAC) Trial (Europe)

Glutathione deficiency in IPF (ARDS, HP)

Powerful antioxidant protecting lung epithelial cells (H2O2)

N-acetylcysteine is a GSH agonist

Extracellular glutathione suppresses human lung fibroblast
proliferation

Attenuation of bleomycin model (inhaled)

Oral NAC augments lung glutathione and improves pulmonary
functions in some patients with IPF

Prospective clinical trial
• Prednisone + Azathioprine + NAC
vs
Prednisone + Azathioprine
Other potential antifibrotic
therapies for IPF
Pirfenidone

Decreases fibroblast proliferation

Decreases ECM production

Inhibits TGF- collagen synthesis

Inhibits mitogenic effects of PDGF
Ameliorated fibrosis in a hamster model of
bleomycin lung
Other potential antifibrotic
therapies for IPF
Pirfenidone

Inhibits TGF- and PDGF affect on ECM production

Raghu et al. 1999

• 54 patients, open label
(4.6 years mean duration)
• 78% 1-year, 63% 2-year survival
• Stabilization
Prospective clinical trial (Phase II, Japan)
• Prednisone + Pirfenidone
vs
Prednisone
Raghu, et al. Am J Respir Crit Care Med. 1999;159:(4):1061-1069.
Other potential antifibrotic
therapies for IPF
Potential anti-TGF- therapies

Antibodies

Soluble receptor

Decorin

Smad 7
Idiopathic Pulmonary Fibrosis (IPF):
Yr 2002

Well designed prospective, multicenter
clinical trials

Concerted effort with dedication and
commitment
– Patients, physicians, investigators,
health care agencies and providers,
funding agencies, foundations,
associations, donors, pharmaceutical
companies
Idiopathic Pulmonary Fibrosis (IPF): Yr 2002
Determinants of an efficacious regimen in new clinical trials

Ideal primary end point: survival

Secondary end points: change in PFTs, oxygenation
(resting, exertion), imaging studies, quality of life,
biological/molecular markers

Tolerance: side effects, route of administration,
complications

Safety

Cost effectiveness
* Personal opinion
Idiopathic Pulmonary Fibrosis (IPF): Yr 2002
New, multicenter, clinical trials
Environment for new directions just right !

Emerging consensus among experts from
multidisciplinary services encouraging

Several potential specific agents targeted to
decrease fibrosis available

Commitment from all concerned to work in a
concerted and cooperative manner

Eager physicians, investigators, patients,
pharmaceutical companies

Resources becoming apparent
Idiopathic Pulmonary Fibrosis (IPF): Yr 2002
New, multicenter, clinical trials
Challenges and Hurdles*
IPF: “Death sentence” (progressive dyspnea  death within a
few years of diagnosis)

Clinical/scientific factors

Behavioral patterns: physicians, patients

Health care systems

Other confounding factors
* Personal observation and opinion
Idiopathic Pulmonary Fibrosis (IPF):
Yr 2002

Realistic hope for better and successful
management
–  Awareness: distinct entity, lone
corticosteroid Rx useless and harmful
– Early diagnosis: better defined criteria
– Referral to regional experts and centers
– Initiation early Rx intervention
– Careful monitoring for complications and
appropriate Rx
Idiopathic Pulmonary Fibrosis (IPF):
Yr 2002

Better defined and characterized: consensus among experts

Increased awareness and cooperation: affected
person/families/public; physician

Increased and earlier detection

Pathogenesis: newer concepts  development of
newer/better agents to abort fibrosis and enhance tissue
repair

New strategies and better clinical management

Feasibility of large, multicenter, clinical trials demonstrated
(-IFN trial)

Several multicenter, clinical trials ongoing worldwide:
g-IFN, Perfenidone, N-acetyl-cysteine, others

Hope: realistic
Idiopathic Pulmonary Fibrosis (IPF): Yr 2002
New, multicenter, clinical trials
A realistic hope amidst true hurdles

An evolutionary path to lessen/ease
human suffering with a successful
outcome is just around the corner!
ADULT LUNG TRANSPLANTATION
INDICATIONS (1983-2000)
A1A
11%
ReTX
3%
CF
3%
A1A
ReTX 9.8%
CF
33.3%
COPD 2.2%
47%
PPH
9.0%
PPH
4%
Misc.
11%
IPF
21%
Single Lung
Misc.
17.7%
IPF
7.8%
COPD
20.1%
Bilateral/Double
Lung
Survival Benefit of Lung Transplantation
for End-Stage Lung Disease

All patients listed for transplant with
UNOS Jan 1, 1992 - Dec 31, 1994.

Included: CF (1234), IPF (919),
Emphysema (2425)

Excluded: Patients supported by
ventilators, children with emphysema
or IPF, all patients with CF > age 50.
Hosenpud, et al. Lancet 1998; 351: 24-27.
Survival while on waiting list
100
Survival
in percent
90
80
CF
IPF
Emphysema
70
60
50
0
6
12
18
24
Time (months)
30
36
Hosenpud, et al. Lancet 1998; 351: 24-27.
Survival After Transplantation
100
Survival
in percent
90
80
CF
IPF
Emphysema
70
60
50
0
6
12
18
24
Time (months)
30
36
Hosenpud, et al. Lancet 1998; 351: 24-27.
General Medical Conditions that Impact
on Eligibility for Lung Transplantation
Symptomatic Osteoporosis
Relative Contraindication
Severe musculoskeletal
disease affecting the thorax
Progressive neuromuscular
disease is an absolute
contraindication
Chronic Corticosteroids
Relative Contraindication.
Ideally discontinued,
< 20mg a day acceptable.
Nutritional Status
Mortality increases with
IBW < 70% or > 130%
ATS Statement AJRCCM 158: 335-339, 1998.
General Medical Conditions that
Impact on Eligibility for Lung
Transplantation
Substance Addictions
Free of use for 6
months. Testing
appropriate in at risk
individuals
Psychosocial Issues
Those which are unable
to be resolved and have
a high likelihood of
impacting negatively on
the patient’s outcome.
Invasive Ventilation
Relative
contraindication by ATS
ATS Statement AJRCCM 158: 335-339, 1998.
General Medical Conditions that Impact
on Eligibility for Lung Transplantation
Colonization with Fungi or
atypical mycobacterium
NOT an absolute
contraindication
History of M. TB that has
been adequately treated
NOT an absolute
contraindication
Chronic Bacterial
Colonization/Infection
(Pseudomonas and
Burkholderia Cepacia)
ATS Statement AJRCCM 158: 335-339, 1998.
Absolute Contraindications to
Lung Transplant

Single > 65 years Double > 60 years

Creatinine Clearance < 50 mg/ml/min

Significant untreatable CAD or LV dysfunction
(consider heart/lung transplantation)
ATS Statement AJRCCM 158: 335-339, 1998.
Absolute Contraindications to
Lung Transplant

HIV infection

Hepatitis B antigen positivity

Hepatits C with biopsy-proven histologic
evidence of liver disease

Active malignancy within 2 years
ATS Statement AJRCCM 158: 335-339, 1998.
Guidelines for Referral: Idiopathic
Pulmonary Fibrosis

Symptomatic, progressive disease with
failure to improve or maintain lung
function while being treated with steroids
or other immunosuppressive drug therapy.

If pulmonary function is abnormal.

Vital capacity < 60-70% predicted and/or
diffusing capacity (corrected for alveolar
volume) below 50-60% predicted.
ATS Statement AJRCCM 158: 335-339, 1998.
Acknowledgements

Patients, families, community and academic physicians,
scientists, and nurses

Colleagues, IPF/ILD experts

IPF advisory committee (-IFN Phase II trial):
S. Aguayo, K. Brown, D. Center, T. King, D. Lynch, D.
Schwartz

IPF steering-advisory committee (INF-g Phase III trial):
K. Brown, T. King, P. Noble, D. Schwartz

Biogen Inc, Cambridge, MA

Intermune Pharmaceuticals, Brisbane, CA

Critics and skeptics

Shanthi (“Peace”) and Preethi (“Love”)

…and everyone else who puts up with me
Thank You