1. IPF Disease Management Strategies With an Update on Clinical Trials
and Ongoing Research
SECTION 3
IPF Disease Management Strategies With an Update on Clinical Trials and Ongoing Research

2. Objectives
Explain the rationale for investigating targeted therapeutic approaches to the management of IPF
Discuss the latest clinical trial information and research in the area of IPF
Review future treatment options for IPF
Objectives
The objectives of this section are to explain the rationale for research into targeted therapeutic approaches to the treatment of IPF, to discuss the latest clinical trial information and research in the area of IPF, and to review future treatment options for IPF.

3. Current Therapies for IPF
Treatment remains controversial
Little good-quality evidence to support safety and efficacy of traditional agents (eg, immunosuppressive/ cytotoxic agents, corticosteroids)
Limited efficacy
Significant side effects
Limitations of older studies (eg, small sample size, variable study design, inconsistent diagnostic criteria)
Current Therapies for IPF
The treatment of IPF remains controversial. Traditional agents have shown limited efficacy and are associated with significant side effects.
Corticosteroid use is associated with endocrine and metabolic alterations, musculoskeletal complications, and psychological changes. Cytotoxic therapy with cyclophosphamide or azathioprine can lead to hemorrhagic cystitis, cardiotoxicity, and gastrointestinal irritation.
Past clinical trials have been limited by variable study design (heterogeneous patient populations, variable duration), differences in medication formulations, dosages, and routes of administration, lack of placebo controls, and variable assessment criteria.
Collard HR, Ryu JH, Douglas WW, et al. Combined corticosteroid and cyclophosphamide therapy does not alter survival in idiopathic pulmonary fibrosis. Chest. 2004;125:
Richeldi L, Davies HR, Ferrara G, Franco F. Corticosteroids in idiopathic pulmonary fibrosis. Cochrane Database Syst Rev. 2003;(3):CD
Davies HR, Richeldi L, Walters EH. Immunomodulatory agents for idiopathic pulmonary fibrosis. Cochrane Database Syst Rev. 2003;(3):CD
Collard HR, et al. Chest. 2004;125:
ATS/ERS Consensus Statement. Am J Respir Crit Care Med. 2000;161:
Richeldi L, et al. Cochrane Database Syst Rev. 2003(3):CD002880;
Davies HR, et al. Cochrane Database Syst Rev. 2003;(3):CD

4. Effects of Conventional Treatment on Survival in IPF Patients
1.00
0.75
Probability of Survival
0.50
Untreated (n = 82)
Median survival = 1431 days
0.25
Treated (n = 82)
Median survival = 1665 days
Effects of Conventional Treatment on Survival in IPF Patients
This graph shows Kaplan-Meier survival curves for a retrospective study that compared survival in patients treated with corticosteroid and cyclophosphamide therapy (orange line; n = 82) with untreated patients (blue line; n = 82). The expected survival of 68-year-olds in the general US population is also shown (yellow line). Circles and squares represent censored observations.
There was no significant difference in survival time between treated and untreated patients.
These results suggest that inflammation may play only a minimal role in IPF progression, and underscore the importance of weighing the risk and benefits of conventional treatment approaches.
Collard HR, Ryu JH, Douglas WW, et al. Combined corticosteroid and cyclophosphamide therapy does not alter survival in idiopathic pulmonary fibrosis. Chest. 2004;125:
0.00
500
1000
1500
2000
2500
3000
3500
4000
Days of Follow-up
Collard HR, et al. Chest. 2004;125:

5. Rationale for New Therapeutic Approaches to IPF
Increased
understanding of
disease pathogenesis
points to targeted
therapies
Limitations of older
studies highlight
need for prospective,
randomized,
controlled studies
Rationale for
New
Therapeutic
Approaches
Evidence for survival
benefit of IFN-g
suggests
new targets
Shift in focus from
inflammation
to epithelial cells
and myofibroblasts
Rationale for New Therapeutic Approaches to IPF
The limitations of older IPF clinical studies highlight the need for larger, prospective, randomized, controlled studies of new agents.
Evolving concepts regarding the pathogenesis of IPF point to therapies that target specific aberrant pathways. With a shift in the prevailing focus of disease pathogenesis from inflammation to the role of epithelial cells and myofibroblasts, potential new therapeutic approaches are emerging. Additionally, evidence of a potential survival benefit of interferon gamma underscores the need to investigate new targets in large, well-designed, randomized trials.
Brown KK, Raghu G. Medical treatment for pulmonary fibrosis: current trends, concepts, and prospects. Clin Chest Med. 2004;25:
Brown KK, Raghu G. Clin Chest Med. 2004;25:

6. IPF Clinical Research Network: NHLBI Commitment
Objective:
Establish a clinical research network of 6–7 clinical centers to design and conduct multiple therapeutic trials in newly diagnosed IPF patients
Evaluate potential therapeutic interventions
Establish a data coordinating center for the network
IPF Clinical Research Network: NHLBI Commitment
The IPF Clinical Research Network (CRN) is an initiative of the National Heart, Lung, and Blood Institute. Its purpose is to establish a CRN of 6 to 7 clinical centers to design and perform randomized, controlled, multi-therapeutic trials for the treatment of patients with newly diagnosed IPF. Additionally, the initiative will establish a data coordinating center for the network.
Each research center will enroll about 40 to 50 patients per year during the 5-year project period. Multiple trials using common protocols evaluate patients during treatment and follow-up periods. Approaches involving multi-drug treatment, including combination therapy, will be evaluated. Each trial will need to be completed in a reasonably short period of time, and will require that each center has access to a large number of research subjects, experienced personnel, and appropriate laboratory facilities.
Available at: Accessed December 2004.
Accessed December 2004.

7. Recent and Ongoing Clinical Trials for IPF
Target N
Primary Endpoints
Phase 3
Interferon-gamma GIPF-001
Multiple
330
Progression-free survival time
Interferon-gamma INSPIRE trial (ongoing)
600
Survival time
N-acetylcysteine (NAC) IFIGENIA trial
Oxygen radicals
184
Change in FVC, DLco
Phase 2/3
Bosentan BUILD trial (ongoing)
Endothelin
132
Change in 6MWT
Phase 2
Etanercept
TNF-
100
DLCO, FVC
Imatinib mesylate (ongoing)
PDGF, TGF-
Disease progression
Pirfenidone (ongoing)
450
Time to disease progression
Phase 1
FG-3019
CTGF 21
Safety, tolerability, PK
Recent and Ongoing Clinical Trials for IPF
This table summarizes recent and ongoing IPF clinical trials in various phases of development. It specifies the biological target, number of patients enrolled, and primary endpoints of each study. This summary highlights the fact that multiple targets for therapeutic intervention are being pursued, and an unprecedented number of clinical trial opportunities are now available for patients with IPF.
Available at: Accessed December 2004.
Available at: Accessed December 2004.
National Heart, Lung, and Blood Institute Strategic Plan. FY
Accessed December 2004.
Accessed December 2004.
National Heart, Lung, and Blood Institute Strategic Plan. FY

8. Biological Effects of Interferon Gamma
Interferon gamma (IFN-g) has pleiotropic effects:
– Activates cell-mediated immunity
– Inhibits fibroblast proliferation
– Reduces collagen synthesis
– Attenuates fibrosis in animal models
– Reduces tissue myofibroblast numbers
Biological Effects of Interferon Gamma
The most widely studied therapy in IPF to date is IFN -1b, a pleiotropic cytokine that effects multiple biologic pathways believed to be involved in the pathogenesis of IPF. Among these are direct inhibition of fibroblast proliferation and collagen synthesis, attenuation of collagen deposition in the mouse bleomycin-induced fibrosis model, and reduction in myofibroblast numbers.
In addition to its antifibrotic and antiproliferative properties, IFN- also has anti-infective properties that include enhancing activation of macrophages and up-regulating expression of antimicrobial peptides.
Raghu G, Chang J. Idiopathic pulmonary fibrosis: current trends in management. Clin Chest Med. 2004;25:
Selman M, Thannickal VJ, Pardo A, Zisman DA, Martinez FJ, Lynch JP 3rd. Idiopathic pulmonary fibrosis: pathogenesis and therapeutic approaches. Drugs. 2004;64:
Raghu G, Brown KK, Bradford WZ, et al. A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis: New Engl J Med. 2004;350:
Raghu G, Chang J. Clin Chest Med. 2004;25:
Selman M, et al. Drugs. 2004;64:
Raghu G, et al. New Engl J Med. 2004;350:

9. Clinical Trials of Interferon Gamma-1b
GIPF-001 Trial
Trial Design
Multicentered, double-blind, placebo-controlled, phase 3
Inclusion Criteria
Age 20 to 79, with symptoms of IPF for ≥ 3 months
Primary Endpoint
Progression-free survival time, FVC, A-a gradient
Treatment Arms
200 g, three times per week, SC or placebo
Number of Patients
330
Number of Sites 58
Minimum Duration
48 weeks
Clinical Trials of Interferon Gamma-1b
This slide summarizes the design of the GIPF-001 study, a phase 3 trial conducted to investigate the effect of IFN- on the course of IPF through its antifibrotic, anti-inflammatory, or anti-infective properties.
The trial enrolled 330 patients from 58 centers in the United States, Europe, Canada and South Africa. Eligible patients were between 20 and 79 years of age with clinical symptoms of IPF for at least 3 months and forced vital capacity (FVC) that was 50% to 90% of the predicted value. Patients were randomly assigned to receive IFN- or placebo subcutaneously 3 times weekly. The primary endpoint was progression-free survival, measured from randomization to either disease progression [defined as a decrease from baseline of at least 10% in FVC or an increase of at least 5 mm Hg in P(A-a)O2 at rest].
Raghu G, Brown KK, Bradford WZ, et al. A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2004;350:
Available at: Accessed December 2004.
Raghu G, et al. N Engl J Med. 2004;350:
Accessed December 2004.

10. Lung Function and Survival Outcomes in GIPF-001
Lung Function (FVC)
Survival*
Intention-to-treat (N = 330) 75
1.0
IFN -1b 70
P = NS
0.8
P = 0.08 65
IFN -1b
Probability of Survival
Mean % Predicted FVC
Placebo 60
IFN -1b
Placebo
0.6
IFN -1b 55
Placebo
Placebo
Lung Function and Survival Outcomes in GIPF-001
There was no statistically significant difference between treatment groups in the primary endpoint of progression free survival. However, a subsequent analysis of the individual components of the endpoint revealed that, while there was no statistically significant effect on physiologic parameters, a trend toward enhanced survival was observed in patients treated with IFN-. These results suggest that a continued decline in lung function does not necessarily mean that the therapy is not working.
Slide courtesy of Steven D. Nathan, MD
Raghu G, Brown KK, Bradford WZ, et al. A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2004;350: 50
0.4 12 24 36 48 60 72
100
200
300
400
500
600
Week
Day
Slide courtesy of Steven D. Nathan, MD.
*Raghu G, et al. N Engl J Med. 2004;350:

11. GIPF-001 Study: Mortality
Placebo
(N = 168)
IFN g-1b
(N = 162)
Number reaching primary endpoint
87 (51.8%)
75 (46.3%)
Disease progression
75 (44.6%)
68 (42.0%)
> 5 mm Hg increase in A-a gradient
46 (27.4%)
43 (26.5%)
> 10% decrease in FVC
12 (7.1%)
8 (4.9%)
Both A-a gradient and FVC
17 (10.1%)
17 (10.5%)
Death prior to disease progression
7 (4.3%)
GIPF-001 Study: Mortality
These data come from the recent study by King and colleagues that retrospectively analyzed the components of the primary endpoint used in the GIPF-001 trial. The table summarizes the number of patients who met the primary endpoint by cause. A primary endpoint event (disease progression according to change in P(A-a)O2, or percentage of FVC criteria, or death) occurred in 87 (51.8%) placebo patients and 75 (46.3%) IFN--treated patients. The majority of patients who met the the primary endpoint did so on the basis of disease progression (75/87 [86.2%] placebo, 68/75 [90.7%] IFN--treated) rather than death. The majority of disease progression events were due to a protocol-specified increase in P(A-a)O2 (46/87 events placebo, 43/75 IFN--treated). The frequency with which the FVC-dependent endpoints were met was considerably lower than predicted for both treatment groups (12/87 placebo, 8/75 IFN--treated). Concurrent changes in both P(A-a)O2 and percentage of predicted FVC occurred in 34 subjects (17 placebo, 17 IFN--treated). A total of 44 (28 placebo, 16 IFN--treated) deaths occurred; of these, 43% (12 placebo, 7 IFN--treated) occurred prior to disease progression. This final observation lends support to the suggestion that acute events may account for a significant percentage of deaths among patients with IPF.
King TE Jr, Safrin S, Starko KM, et al. Analyses of efficacy end points in a controlled trial of interferon gamma-1b for idiopathic pulmonary fibrosis. Chest. 2005;127: 28 16
King TE Jr, et al. Chest. 2005;127:

12. Likelihood of Mortality Multivariate Analysis Baseline Risk Factors
Hazard Ratio** (95% CI)
P-value*
HRCT Overall Disease Extent Score
2.71 (1.61 – 4.55)
<
100% - % predicted DLCO
1.06 (1.02 – 1.11)
0.0042
Randomization assignment to IFN- 1b
0.53 (.28 – .99)
0.0417
Likelihood of Mortality: Multivariate Analysis Baseline Risk Factors
In a study that evaluated the risk of mortality associated with baseline HRCT findings, Lynch and colleagues found that baseline HRCT overall disease extent score correlated with a significantly increased hazard ratio (2.71, P < ). Baseline % predicted DLCO also significantly affected the likelihood of mortality (hazard ratio 1.06, P = ), while randomization to treatment with IFN-1b reduced the risk of death (hazard ratio 0.53, P = ).
Lynch D, et al. Paper presented at: 2004 American Thoracic Society; 2004; Orlando, Florida. Abstract A706.
Lynch D, et al. Paper presented at: 2004 American Thoracic Society; 2004; Orlando, Florida. Abstract A706.

13. Mortality by Baseline FVC
Total* %
Baseline % Predicted FVC (Categorized)
 80%
3/19
16%
70 – 79%
6/33
18%
60 – 69%
5/44
11%
50 – 59%
12/65
19%
40 – 49%
2/7
29%
Baseline % Predicted FVC (Dichotomized)
 70%
9/52
17%
 60%
14/96
15%
 50%
26/161
 40%
28/168
Mortality by Baseline FVC
In an analysis of the clinical trial of IFN-1b, King and colleagues assessed the impact of baseline physiologic characteristics on mortality. Mortality associated with baseline percentage of predicted FVC values for the placebo group is summarized in this table according to category as well as dichotomized subgroup. Of interest was the unexpected observation that baseline FVC did not appear to correlate with mortality, suggesting that even patients with relatively mild disease may be at risk of death within 1 year.
King TE Jr, Safrin S, Starko KM, et al. Analyses of efficacy end points in a controlled trial of interferon gamma-1b for idiopathic pulmonary fibrosis. Chest. 2005;127:
King TE, et al. Chest. 2005;127:

14. Martinez FJ, et al. Ann Intern Med. In review.
Predictors of Near-Term Mortality Multivariate Analysis Using Dynamic Variables
Characteristic
Odds Ratio
95% CI
P-value
Respiratory Hospitalization
6.0
2.0 – 18.2
0.001
Decrease in FVC > 10% Pred
5.9
2.1 – 17.1
< 0.001
Increase in UCSD SOBQ > 10%
3.3
1.4 – 7.8
0.008
Increase in A-a > 15 mm Hg
2.0
0.4 – 9.2
0.376
Age > 65
1.3
0.5 – 3.1
0.586
Predictors of Near-Term Mortality: Multivariate Analysis Using Dynamic Variables
In a recent multivariate analysis of predictors of near-term mortality, Martinez and colleagues found that respiratory hospitalization, decrease in percentage of predicted FVC  10%, and increase in UCSD SOBQ  10% were associated with significant increases in the risk of mortality in the subsequent 3-month period. Neither increase in A-a  15 mm HG nor age  65 correlated with a significant increase in the risk of mortality.
UCSD SOBQ = University of San Diego Shortness of Breath Questionnaire
Martinez FJ, et al. Predictors of near-term mortality. Ann Intern Med. In review.
Martinez FJ, et al. Ann Intern Med. In review.

15. Key Implications of GIPF-001 Trial
Potentially significant survival benefit in mild-to-moderate patients could not be ruled out
Preliminary evidence of improved survival in the absence of any effect on lung function
Survival as a key endpoint for future clinical trials
Risk of death is similar across various degrees of disease severity
Stability of lung function does not necessarily mean stability of disease
Key Implications of GIPF-001 Trial
The results of the GIPF-001 Trial suggest a possible survival benefit associated with IFN- in patients with mild-to-moderate IPF. Furthermore, the results show that the risk of death is similar across various degrees of disease severity and improved survival can occur in the absence of any effect on lung function. Stability of lung function does not necessarily mean stability of disease. These findings suggest that survival may be a key endpoint for future clinical trials. This study was limited, however, in its retrospective design and analysis of a highly selective subgroup of patients (mild-to-moderate IPF, FVC of 50% to 90% of predicted, and DLCO  25% of predicted).
Raghu G, et al. A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2004;350:
King TE Jr, Safrin S, Starko KM, et al. Analyses of efficacy end points in a controlled trial of interferon gamma-1b for idiopathic pulmonary fibrosis. Chest. 2005;127:
Raghu G, et al. N Engl J Med. 2004;350:
King TE, et al. Chest. 2005;127:

16. Clinical Trials of Interferon
GIPF-002 (complete)
Trial Design
Multinational, randomized, double-blind, placebo-controlled
Inclusion Criteria
Male or female, 20 to 79 years old, failed corticosteroid treatment
Primary Endpoint
Change in mRNA for TGF-b and CTGF
Treatment Arms
200 mg IFN g-1b (subcutaneous) or placebo 3 times per week for 26 weeks
Number of Patients 32
Number of Sites 15
Clinical Trials of Interferon: GIPF-002 (complete)
This slide summarizes the design of the GIPF-002 study completed and published in The trial was a phase II randomized, double-blind, placebo controlled trial of IFN g-1b in patients with IPF. The objectives of the study were to characterize the biological and clinical effects of IFN g-1b administered to patients with IPF. All patients included failed previous treatment with corticosteroids and subsequently received 200 mg IFN g-1b, three times per week or placebo for 26 weeks. The primary endpoints included change in mRNA for TGF-b and CTGF in TBB tissue at 6 months. An open-label extension was included in this trial.
Strieter RM, Starko KM, Enelow RI, Noth I, Valentine VG; Idiopathic Pulmonary Fibrosis Biomarkers Study Group. Effects of interferon-gamma 1b on biomarker expression in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2004;170:
Strieter RM, et al. Am J Respir Crit Care Med. 2004;170:

17. Key Implications of GIPF-002 Trial
IFN g-1b appears to favorably affect multiple biologic pathways in IPF patients, including:
Inhibition of fibrosis molecules, growth factors, inflammatory/ angiogenic ENA-78/CXCL5
Enhanced expression of immunomodulatory, antiangiogenic, and antimicrobial molecules ITAC/CXCL11
These activities may translate into beneficial clinical effects on fibrosis and/or antimicrobial defense in IPF patients
Key Implications of GIPF-002 Trial
As discussed on the previous slide, IFN g-1b appears to favorably affect multiple biologic pathways in IPF patients, including inhibition of ENA-78/CXCL5 and upregulation of ITAC/CXCL11. These activities may translate into beneficial clinical effects on fibrosis and/or antimicrobial defense in IPF patients.
Strieter RM, Starko KM, Enelow RI, Noth I, Valentine VG; Idiopathic Pulmonary Fibrosis Biomarkers Study Group. Effects of interferon-gamma 1b on biomarker expression in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2004;170:
Strieter RM, et al. Am J Respir Crit Care Med. 2004;170:

18. Hellenic IPF Study: Interim Analysis of Survival
1.0
0.8
0.6
Survival Distribution
0.4
P = 0.01
Log-rank test
IFN -1b (n = 27)
0.2
Colchicine (n = 15)
Hellenic IPF Study: Interim Analysis of Survival
Interim analysis of survival in the Hellenic study shows 2 of 27 (7.4%) patients in the IFN γ-1b–treated group and 6 of 15 (40%) in the colchicine-treated group died, which represented an 81% relative reduction in risk of death in favor of the IFNγ-1b group (P = 0.01).
Antoniou KM, et al. Abstract Presented at ATS International Conference May 2003, Seattle, WA.
Antoniou KM, Polychronopoulos V, Dimadi M, et al. Comparison of interferon gamma-1b (IFN-γ) and colchicines in the treatment of idiopathic pulmonary fibrosis: results of a prospective, multicenter randomized study. Abstract presented at: The American Thoracic Society International Conference; May 2003; Seattle, Wasington.
Time (days)
Slide courtesy of V. Polychronopoulos and D. Bouros on behalf of the Hellenic Interstitial Lung Disease Group; Antoniou KM, et al. Abstract presented at ATS International Conference May 2003, Seattle, WA.

19. Clinical Trials of Interferon
The INSPIRE Trial (ongoing)
Trial Design
Multinational, randomized, placebo-controlled, phase 3
Inclusion Criteria
Age 40 to 79 years, diagnosed within past 36 months, with evidence of disease progression within past year
Primary Endpoint
Survival time
Treatment Arms
IFN g-1b (200 μg, three times per week, SC) or placebo, randomized at a ratio of 2:1
Number of Patients
600
Number of Sites 75
Minimum Duration
2 years
Clinical Trials of Interferon: The INSPIRE Trial (ongoing)
This slide summarizes the design of the INSPIRE Trial, an ongoing, phase 3 trial designed to further evaluate the possible survival effect of IFN g-1b in IPF patients. The trial will include 600 patients with an FVC ≥ 55% predicted and DLCO ≥ 35% predicted. Patients enrolled in the trial should be 40 to 79 years old, and have evidence of disease progression within the last year.
Available at: Accessed December 2004.
Accessed December 2004.

20. The Role of N-acetylcysteine (NAC) in IPF
Increased levels of reactive oxygen species in IPF lung
NAC acts as anti-oxidant to scavenge hydrogen peroxide
NAC is a precursor to glutathione (an anti-oxidant), which is deficient in IPF
Preliminary evidence from a small (n = 18) proof-of-concept study suggests NAC in addition to immunosuppressive therapy increases levels of reduced glutathione and improves pulmonary function in IPF patients
The Role of N-acetylcysteine (NAC) in IPF
Reduced glutathione (GSH) is part of a major anti-oxidant system in the lungs and is significantly reduced in the lungs of IPF patients. N-acetylcysteine (NAC) is a precursor of GSH synthesis. When given intravenously or orally, NAC results in a significant increase in GSH. NAC has antioxidant properties and can directly inhibit growth-factor induced fibroblast proliferation in vitro. Evidence from a small pilot study suggests that NAC used as an adjunct to immunosuppressive therapy increases levels of GSH and stabilizes pulmonary function in IPF patients after 12 weeks of therapy.
Behr J, Maier K, Degenkolb B, Krombach F, Vogelmeier C. Antioxidative and clinical effects of high-dose N-acetylcysteine in fibrosing alveolitis. Adjunctive therapy to maintenance immunosuppression. Am J Respir Crit Care Med. 1997;156:
Available at: Accessed November 2004.
National Heart, Lung, and Blood Institute Strategic Plan. FY
Behr J, et al. Am J Respir Crit Care Med. 1997;156:
Accessed November 2004.
National Heart, Lung, and Blood Institute Strategic Plan. FY

21. Phase 3 Clinical Trial of NAC for IPF
The IFIGENIA Trial
Trial Design
Multinational, double-blind, randomized, placebo-controlled
Primary Endpoint
Change in FVC and DLco at 6 and 12 months
Secondary Endpoint
Survival
Treatment Arms
NAC 1800 mg/daily or placebo plus prednisone
(0.5 mg/kg/day) and azathioprine (2 mg/kg/day)
Number of Patients
184
Treatment Duration
1 year
Phase 3 Clinical Trial of NAC for IPF: The IFIGENIA Trial
The IFIGENIA (Idiopathic Pulmonary Fibrosis International Group Exploring NAC I Annual) trial was designed to compare the clinical efficacy of NAC in combination with prednisone and azathioprine to prednisone and azathioprine alone. The primary endpoints were change in FVC and DLco at 6 and 12 months. Secondary endpoints included HRCT, quality of life, and survival.
Behr J. Paper presented at: 2004 American Thoracic Society; 2004; Orlando, Florida. Abstract B73.
Behr J. Paper presented at: 2004 American Thoracic Society; 2004; Orlando, Florida. Abstract B73.

22. Preliminary Results of IFIGENIA Trial
Patient disposition: of 184 randomized, 57 (71%) NAC-treated patients, and 51 (68%) placebo-treated patients completed the trial
Preliminary results:
NAC-treated patients showed less decline in FVC and DLco than placebo-treated patients
Generally no effect on secondary efficacy endpoints
Preliminary Results of IFIGENIA Trial
The IFIGENIA trial results showed a significant difference in favor of NAC/prednisone/azathioprine for both primary endpoints (FVC and DLco) after 12 months of therapy. Meaningful interpretation of the results, however, is confounded by the lack of a true control arm.
Demedts M, et al. Poster presented at: 14th ERS Congress; 2004; Glasgow, Scotland. Poster 4077, Poster 4078.
Behr J, et al. Poster presented at: 14th ERS Congress; 2004; Glasgow, Scotland. Poster 4079.
National Heart, Lung, and Blood Institute Strategic Plan. FY
Demedts M, et al. Poster presented at: 14th ERS Congress; 2004; Glasgow, Scotland. Poster 4077, Poster 4078.
Behr J, et al. Poster presented at: 14th ERS Congress; 2004; Glasgow, Scotland. Poster 4079.
National Heart, Lung, and Blood Institute Strategic Plan. FY

23. IFIGENIA Study: Results
N = 184 pts enrolled from March 2000–June 2002
N = 155 suitable for final analysis
Demographics
Age = 63 (mean age)
47% surgical lung biopsy
52% diagnosed within 6 months of enrollment
Male = 71%
FVC = 65%
TLC = 62%
DLCO = 44%
PaO2 maximal exercise = 53 mm Hg
IFIGENIA Study: Results
This slide summarizes the demographic analysis of the IFIGENIA trial subjects.
Behr J. Paper presented at: 2004 American Thoracic Society: 2004; Orlando, Florida. Abstract B73.
Behr J. Paper presented at: 2004 American Thoracic Society; 2004; Orlando, Florida. Abstract B73.
Slide courtesy of Steven D. Nathan, MD

24. IFIGENIA Study: Results
FVC
DLCO 8%
24%
Pred/Aza/NAC
Pred/Aza
P < 0.05
P < 0.005 6 12 6 12
IFIGENIA Study: Results
This slide shows that, after 12 months of treatment, there was a significant difference in the rate of decline of both FVC (P < 0.05) and DLCO (P < 0.005) in favor of the NAC treatment group. It remains unclear whether this difference is attributable to a direct effect on disease progression or an attenuation of a possible prednisone/azathioprine-induced decline in lung function. There was no significant difference in mortality between the 2 groups.
Behr J. Paper presented at: 2004 American Thoracic Society; 2004; Orlando, Florida. Abstract B73.
Slide courtesy of Steven D. Nathan, MD.
Month
Month
Mortality (%)
Pred/Aza/NAC
7/80 (8.8%)
Pred/Aza
8/75 (10.7%)
Behr J. Paper presented at: 2004 American Thoracic Society; 2004; Orlando, Florida. Abstract B73.
Slide courtesy of Steven D. Nathan, MD.

25. The Role of Endothelins in IPF
Endothelin-1 (ET-1) is a potent vasoactive and mitogenic peptide produced by the endothelium. It stimulates fibroblast proliferation, migration, and conversion to myofibroblasts, increases collagen synthesis, and decreases collagen breakdown. Endothelin causes vasoconstriction, fibrosis, remodeling, and hypertrophy of blood vessels, predisposing them to inflammation.
In IPF patients, ET-1 plasma levels are increased and lung biopsies show an increase in ET-1 that correlates with disease activity.
The expression of ET-1 increases in the bleomycin-induced lung fibrosis model and can be partially blocked by bosentan, a nonselective ET(A) and ET(B) receptor antagonist.
Based on these findings, a multicentered, double-blind, placebo-controlled study of bosentan in IPF patients has been initiated.
Available at: Accessed January 2005.
Selman M, Thannickal VJ, Pardo A, Zisman DA, Martinez FJ, Lynch JP 3rd. Idiopathic pulmonary fibrosis: pathogenesis and therapeutic approaches. Drugs. 2004;64:
Accessed January 2005.
Selman M, et al. Drugs. 2004;64:

26. Phase 2/3 IPF Clinical Trials
The BUILD Trial (completed)
Trial Design
Double-blind, placebo-controlled, multicentered
Primary Endpoint
Change from baseline in 6MWT distance
Number of Patients
132 (1:1 randomization)
Number of Sites 31
Treatment Duration
2 years
Phase 2/3 IPF Clinical Trials: The BUILD Trial (ongoing)
The efficacy of bosentan in IPF patients is currently being evaluated in the BUILD (Bosentan Use in Interstitial Lung Disease) trial. This study will include 132 patients at 31 clinical sites. The primary endpoint is change from baseline in 6-minute walk test (6MWT) distance.
Available at: Accessed December 2004.
Accessed December 2004.

27. Pirfenidone in IPF 5-methyl-1-phenyl-2-(1H)-pyridone
Has antifibrotic activity in vivo and in vitro
Inhibits TGF-β-induced collagen synthesis in IPF-derived lung fibroblasts
Inhibits mitogenic effects of profibrotic cytokines on lung fibroblasts
CH3
Pirfenidone in IPF
Pirfenidone is an investigational pyridone molecule that has antifibrotic activity in vitro and in vivo. While its exact mechanism of action is unclear, it inhibits TGF-β-stimulated collagen synthesis, decreases extracellular matrix, and blocks the mitogenic effect of profibrotic cytokines in adult human lung fibroblasts derived from IPF patients. In the bleomycin-induced fibrosis animal model, pirfenidone ameliorates fibrosis.
Available at: jcem.endojournals.org/cgi/content/full/83/1/219/F1. Accessed January 2005.
Raghu G, Johnson WC, Lockhart D, Mageto Y. Treatment of idiopathic pulmonary fibrosis with a new antifibrotic agent, pirfenidone: results of a prospective, open-label, phase II study. Am J Respir Crit Care Med. 1999;159: N O
jcem.endojournals.org/cgi/content/full/83/1/219/F1. Accessed January 2005.
Raghu G, et al. Am J Respir Crit Care Med. 1999;159:

28. Phase 2/3 Trials of Pirfenidone
Design
Endpoints
Preliminary Results
Raghu
(N = 54)
Open-label
Pulmonary function
Stability/improvement after 6 months
Shionogi
(N = 107)
Randomized, double-blind, placebo-controlled
FVC, SpO2
Significant improvement in FVC at 9 months
PIPF-001
(N = 53)
Randomized, double-blind, vs prednisone
6MWT, lung function
Evidence of treatment effect
Phase 2/3 Trials of Pirfenidone
The efficacy of pirfenidone in IPF patients has been investigated in several phase 2 clinical trials.
Raghu and colleauges conducted a phase 2 open-label trial to evaluate the efficacy and tolerability of pirfenidone in 54 terminally ill patients with advanced IPF who had failed or did not tolerate conventional therapy. After 6 months of pirfenidone therapy, pulmonary function tests showed stabilization or improvement in some patients. Adverse effects were relatively minor.
A phase 2, randomized, double-blind, placebo-controlled trial sponsored by Shionogi & Co, Ltd, was designed to evaluate the efficacy of pirfenidone in 107 IPF patients treated for 1 year. Primary efficacy endpoints included arterial oxygen saturation during a 6 MWT and measures of lung function and dyspnea. Patients completed 9 months of blinded treatment. The study was terminated early due to an increased incidence of acute exacerbations in the placebo group. At study termination, there was a significant difference in the minimal exercise saturation between the groups at 6 months and 9 months, and a smaller decrease in FVC at 9 months in favor of the pirfenidone group.
The PIPF-001 trial is a randomized, double-blind, multinational trial of pirfenidone (40 mg/kg/d) vs prednisone in 53 patients with a treatment duration of 3 years. Primary efficacy endpoints were the 6MWT and lung function. Analysis at 12 months showed evidence of a beneficial treatment effect for pirfenidone.
Raghu G, Johnson WC, Lockhart D, Mageto Y. Treatment of idiopathic pulmonary fibrosis with a new antifibrotic agent, pirfenidone: results of a prospective, open-label, phase II study. Am J Respir Crit Care Med. 1999;159:
Azuma A, Nukiwa T, Tsuboi E, et al. Double blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2005;doi: /rccm C.
Available at:
National Heart, Lung, and Blood Institute Strategic Plan. FY
Raghu G, et al. Am J Respir Crit Care Med. 1999;159:
Azuma A, et al. Am J Respir Crit Care Med. 2005;doi:

29. Pirfenidone Phase 3 Trial
Proposed Trial Design
Primary Endpoint
Time to disease progression or death
Treatment Arms
Pirfenidone or placebo (2:1 randomization)
Number of Patients
Approximately 450
Number of Sites
Approximately 80
Treatment Duration
60 weeks
Pirfenidone Phase 3 Trial: Proposed Trial Design
This slide summarizes the proposed study design of a planned phase 3 trial of pirfenidone. The study will enroll approximately 450 patients at 80 sites. Patients will be randomized (2:1) to receive pirfenidone or placebo for 60 weeks.
Data on file with InterMune.
Data on file with InterMune.

30. The Role of Tumor Necrosis Factor-alpha in IPF
TNF-a:
Pleiotropic cytokine
May stimulate fibroblast proliferation and collagen gene expression through TGF-b and/or PDGF
Enhanced expression in patients with IPF
In an open-label, pilot study in 9 IPF patients, etanercept (TNF-a antagonist) appeared to be well tolerated
Suggestion of improvement in FVC, DLCO, P(A-a)O2 in some patients
The Role of Tumor Necrosis Factor-alpha in IPF
The cytokine TNF- has pleiotropic effects on inflammatory and fibrotic processes. TNF- stimulates fibroblast proliferation and collagen gene expression through a TGF- or PDGF pathway. Alveolar macrophages from lungs of IPF patients produce increased amounts of TNF- . These properties provide the basis for a recent open-label pilot study of the TNF- receptor antagonist etanercept in 9 IPF patients.
ATS Abstract Niden A, Koss M, Boylen CT, Azizi N, Chan K. A open label pilot study to determine the potential efficacy of TNFR: FC in the treatment of usual interstitial pneumonitis (UIP).
ATS Abstract Niden A, Koss M, Boylen CT, Wilcox A. A open label pilot study to determine the potential efficacy of TNFR: FC in the treatment of usual interstitial pneumonitis (UIP).
Brown KK, Raghu G. Medical treatment for pulmonary fibrosis: current trends, concepts, and prospects. Clin Chest Med. 2004;25:
ATS Abstract Niden A. et al.
ATS Abstract Niden A. et al
Brown KK. Clin Chest Med. 2004;25:

31. Phase 2/3 IPF Clinical Trials
Etanercept
Trial Design
Prospective, multicentered, double-blind, placebo-controlled, phase 2
Primary Endpoint
FVC, DLCO
Secondary Endpoints
Quality of life, pharmacokinetics
Number of Patients
100
Treatment Duration
80 Weeks
Phase 2/3 IPF Clinical Trials: Etanercept
The safety and efficacy of etanercept in IPF is currently being evaluated in a double-blind, placebo-controlled, randomized study. This study has completed enrollment. Approximately 100 patients at 25 sites will be treated for 80 weeks with twice-weekly subcutaneous etanercept. The primary endpoints are change in FVC and DLCO. Secondary endpoints will evaluate quality of life and pharmacokinetics.
Available at: Accessed December 2004.
Available at: Accessed December 2004.
Accessed December 2004.
Accessed December 2004.

32. Role of Imatinib Mesylate in IPF
Antineoplastic agent
Targets the c-Abl gene, which initiates the destructive, abnormal growth of lung tissue
Inhibits profibrotic growth factors TGF-b and PDGF
Significantly inhibits lung fibrosis in bleomycin-induced pulmonary fibrosis in mice
Role of Imatinib Mesylate in IPF
It is postulated that the profibrotic cytokines (transforming growth factor-beta) TGF- and platelet-derived growth factor (PDGF) activate common downstream targets including the c-Abl proto-oncogene. The c-Abl has a potential role in regulating cytokine-mediated fibrosis, since it functions in cell cycle regulation and cytoskeletal remodeling. Since imatinib mesylate inhibits Abl kinases and was originally developed as a PDGF receptor inhibitor, it is hypothesized that it may inhibit both PDGF- and TGF--stimulated fibrosis.
A recent study by Daniels and colleagues, which examined the role of imatinib mesylate in a mouse bleomycin-induced pulmonary fibrosis model, found a significant inhibition of lung fibrosis by imatinib. In addition, inhibition of c-Abl by imatinib prevented TGF--induced ECM gene expression, morphologic transformation, and cell proliferation.
Daniels CE, Wilkes MC, Edens M, et al. Imatinib mesylate inhibits the profibrogenic activity of TGF-beta and prevents bleomycin-mediated lung fibrosis. J Clin Invest. 2004;114:
Daniels CE, et al. J Clin Invest. 2004;114:

33. Phase 2 IPF Clinical Trials
Imatinib Mesylate Trial (ongoing)
Trial Design
Randomized, double-blind, placebo-controlled
Treatment Arms
Imatinib mesylate 600 mg orally daily vs placebo
Primary Endpoint
Progression of IPF (> 10% decline in FVC) or death
Number of Patients
100
Treatment Duration
2 years
Phase 2 IPF Clinical Trials: Imatinib Mesylate Trial (ongoing)
A phase 2 clinical trial of imatinib mesylate is currently underway. Approximately 100 subjects at 20 to 25 sites will participate in this randomized, double-blind, placebo-controlled trial. Study subjects will receive imatinib mesylate 600 mg daily (PO) or placebo for up to 2 years. The primary endpoint is progression of IPF defined as a greater than 10% decline in the FVC or death.
Available at: Accessed December 2004.
Accessed December 2004.

34. FG-3019: Phase 1 Trial for IPF
Human monoclonal antibody against connective tissue growth factor (CTGF), a growth factor that plays a key role in fibrosis
Reduces scarring and excess deposition of ECM in preclinical models
Phase 1 trial of FG-3019
Evaluated safety, pharmacokinetics, immunogenicity in patients with IPF
Patients treated with FG-3019 at 1, 3, or 10 mg/kg by IV infusion for 2 hours
FG-3019 was safe and well tolerated
Phase 2 trial planned for 2005
FG-3019: Phase 1 Trial for IPF
FG-3019 is a human monoclonal antibody directed against connective tissue growth factor (CTGF), a protein that plays a key role in the excessive and persistent formation of scar tissue that occurs in fibrosis and is considered the final common pathway of various profibrotic processes. Preclinical models of fibrosis show that FG-3019 reduces scarring associated with CTGF and excess deposition of ECM components.
An open-label, single-dose, dose-escalation, phase 1 study evaluated the safety, tolerability, and pharmacokinetics of FG-3019 in 21 IPF patients.
FG-3019 (1 mg/kg [6 patients], 3 mg/kg [9 patients], or 10 mg/kg [6 patients]) was administered by intravenous infusion over 2 hours. No dose-limiting toxicities were reported. The mean plasma levels of FG-3019 varied from patient to patient but were above the predicted minimum effective concentration based on animal models of fibrosis. The data suggested that FG-3019 was safe and well tolerated. A phase 2 trial of FG-3019 is expected to begin in 2005.
Coalition for Pulmonary Fibrosis. ACT. October-December 2004.
Mageto Y, et al. CHEST. October 26, 2004; Seattle, WA.
Coalition for Pulmonary Fibrosis. ACT. October-December 2004.
Mageto Y, et al. CHEST. October 26, 2004; Seattle, WA.

35. Therapeutic Approaches to IPF: Where We’ve Been, Where We’re Going…
Anti-inflammatory
Anti-fibrotic
Immunomodulation
Future
Immunosuppression
Anti-oxidant
Antiproliferative
Colchicine
D-penicillamine
IFN-g 1b
Etanercept
Pirfenidone
Imatinib
Bosentan
FG-3109?
Statins?
LO Inhibitors?
Combo Tx?
Corticosteroids
azathioprine
cyclophosphamide
NAC
glutathione
Therapeutic Approaches to IPF: Where We’ve Been, Where We’re Going…
This slide summarizes the evolution of treatments for IPF over the past 5 decades. Traditional approaches such as corticosteroids and immunosuppressants that were introduced in the 1950s targeted the inflammatory process in IPF. We now know that these agents have no proven benefit and significant side effects. With an increased understanding of the pathogenesis of IPF, new therapeutic approaches have been introduced. These interventions comprise anti-fibrotic, anti-oxidant and immunomodulatory targets. More recent recognition of the role of profibrotic growth factors in IPF pathogenesis has lead to the investigation of growth factor modulators as therapeutic agents. Future potential targets for investigation include statins, which have been shown to induce fibroblast apoptosis in an animal model, inhibitors of angiotensin converting enzyme, which appear effective against fibrosis in animal models, and lipoxygenase inhibition, which may inhibit the production of pro-inflammatory leukotrienes.
1950s
1990s
2005

36. Guidelines for Transplant Referral for IPF
Symptomatic, progressive disease persists despite steroids or other immunosuppressive drug therapy
Withdraw steroids or other cytotoxic agents if no meaningful benefit has been achieved
Vital capacity < 60%–70% predicted and/or the diffusing capacity (corrected for alveolar volume) < 50%–60% predicted
Consider referral to transplant center, although patient may be minimally symptomatic
New guidelines pending publication
Guidelines for Transplant Referral for IPF
This slide summarizes the guidelines for IPF patient transplant referral developed by an international group of lung transplant physicians and surgeons in Patients who meet these criteria are considered to be within the transplant window. New guidelines are pending publication.
Maurer JR. International guidelines for the selection of lung transplant candidates. Am J Respir Crit Care Med. 1998;158:
Maurer JR. Am J Respir Crit Care Med. 1998;158:

37. Adult Lung Transplantation Kaplan-Meier Survival by Diagnosis (Transplants: January 1990 – June 2002)
100
COPD (N= 4,955)
IPF (N= 2,119)
PPH (N= 737)
Sarcoidosis (N = 317) 75
Survival (%) 50 25
Adult Lung Transplantation: Kaplan-Meier Survival by Diagnosis
This slide shows survival over a two-and-a-half year period for adult lung transplant recipients suffering from various lung diseases. Survival was calculated using the Kaplan-Meier method, which incorporates information from all transplant patients for whom any follow-up has been provided. Since many patients are still alive and some patients have been lost to follow-up, the survival rates are estimates because the time of death is not known for all patients. The half-life is the estimated time point at which 50% of all of the recipients have died.
Survival rates were compared using the log-rank test statistic.
Trulock EP, Edmonds LB, Taylor DO, Boucek MM, Keck BM, Hertz MI. The Registry of the International Society for Heart and Lung Transplantation: 21st official adult heart transplant report J Heart Lung Transplant. 2004;23:
Adapted from website: Accessed January 2005.
HALF-LIFE COPD: 4.6 Years; IPF: 3.4 Years; PPH: 4.0 Years; Sarcoidosis: 3.8 Years 1 2 3 4 5 6 7 8 9 10
Years
International Society for Heart and Lung Transplantation
Trulock EP, et al. J Heart Lung Transplant. 2004;23:
Adapted from website: Accessed January 2005.

38. Adult Lung Transplantation Kaplan-Meier Survival by Procedure Type (Transplants: January 1990 – June 2002)
Diagnosis: IPF
100 75
Survival (%) 50
N = 18
N=18 25
Adult Lung Transplantation: Kaplan-Meier Survival by Procedure Type
This slide shows survival specific to IPF patients who received a single or double lung transplant during the same period of time. Survival was calculated using the Kaplan-Meier method, which incorporates information from all transplants for whom any follow-up has been provided. Since many patients are still alive and some patients have been lost to follow-up, the survival rates are estimates because the time of death is not known for all patients. Survival rates were compared using the log-rank test statistic.
Trulock EP, Edmonds LB, Taylor DO, Boucek MM, Keck BM, Hertz MI. The Registry of the International Society for Heart and Lung Transplantation: 21st official adult heart transplant report J Heart Lung Transplant. 2004;23:
Adapted from website: Accessed January 2005.
Single Lung (N = 1,645)
N = 22
Double Lung (N = 474)
P = 0.5 1 2 3 4 5 6 7 8 9 10
Years
International Society for Heart and Lung Transplantation
Trulock EP, et al. J Heart Lung Transplant. 2004;23:
Adapted from website: Accessed January 2005.

39. Lung Allocation System
Major changes planned for 2005
Allocation will be based on scores for:
Estimated transplant benefit (survival after 1 year)
Estimated mortality (at 1 year) without transplant
Lung Allocation System
Major changes in the lung allocation system are planned for The new allocation system is based on the severity of patients’ medical conditions before transplant and their likelihood of success after a transplant. The current practice gives priority to patients based on the amount of time spent on the waiting list.
According to the new system, every lung transplant candidate will receive an individual lung allocation score. These scores will be based on estimated transplant benefit (survival after 1 year) and estimated mortality (at 1 year) without transplant.
Available at: Accessed December 2004.
Thabut G, Mal H, Castier Y, Groussard O, et al. Survival benefit of lung transplantation for patients with idiopathic pulmonary fibrosis. J Thorac Cardiovasc Surg. 2003;126:
Available at: Accessed December 2004.
Accessed December 2004.
Thabut G, et al. J Thorac Cardiovasc Surg. 2003;126:
Accessed December 2004.

40. Factors Used to Predict Death
On the Waitlist
FVC
PA systolic
O2 required at rest
Age
BMI
IDDM
NYHA class
6MWT distance
Ventilator use
Diagnosis
After Lung Transplant
FVC
PCW pressure > 20
Ventilator use
Age
Creatinine
NYHA class
Diagnosis
Factors Used to Predict Death
This slide summarizes some of the factors used to predict death in IPF patients before and after lung transplant.

41. Survival Benefit of Lung Transplantation in IPF Patients
Most common indication for adult lung transplantation (17%) after COPD/emphysema (39%)
50% survival at year 3
46 IPF patients accepted for lung transplantation during a 12 year period showed:
Survival of 79% at year 1, 63% at year 2 and 39% at year 5
Mean waiting time for organ: 51 days
Risk of death reduced by 75%
(95% CI = 8%–86%; P = 0.03)
Survival Benefit of Lung Transplantation in IPF Patients
IPF is the most common indication for lung transplantation after COPD. Lung transplant recipients have an overall 50% survival rate at year 3 following transplantation. A study that followed 46 IPF patients over a 12-year period found that survival at 1 year was nearly 80%, with 63% survival at year 2, and 39% survival at year 5. These transplant recipients waited an average of 51 days for a lung, and transplantation reduced their risk of death by 75%.
Available at: Accessed December 2004.
Thabut G, Mal H, Castier Y, Groussard O, et al. Survival benefit of lung transplantation for patients with idiopathic pulmonary fibrosis. J Thorac Cardiovasc Surg. 2003;126: .
Accessed December 2004.
Thabut G, et al. J Thorac Cardiovasc Surg. 2003;126:

42. Nonpharmacological and Additional Management Strategies of IPF
Supplemental oxygen
Pulmonary rehabilitation
Improvement in general and disease-specific health status
Increase exercise tolerance
End-of-life care and use of palliative care
Screen for pulmonary hypertension, obstructive sleep apnea, cough, gastroesophageal reflux disease, and coronary artery disease
Nonpharmacological and Additional Management Strategies of IPF
This slide summarizes several nonpharmacological measures that can be employed to manage IPF patients. Along with supplemental oxygen and pulmonary rehabilitation to improve health status and increase exercise tolerance, IPF patients should be provided with end-of-life and palliative care. IPF patients should be screened for pulmonary hypertension, obstructive sleep apnea, cough, GERD, and CAD.
In addition to these strategies, lifestyle modifications that includes smoking cessation, eating and sleeping well, and maintaining a positive attitude and support system can provide important benefits to the IPF patient.
Adapted from Accessed December 2004.
Adapted from Accessed December 2004.

43. Take Home Messages
Little good-quality evidence supports the safety and efficacy of traditional therapies for IPF
Survival and  10% improvement in FVC may be key endpoints for future clinical trials
Evolving concepts regarding disease pathogenesis point to new therapeutic targets
Ongoing clinical trials may lead to therapies targeting multiple pathogenic mechanisms  many of these trials are still accepting new patients
Lung transplantation can significantly reduce the risk of death for IPF patients
Nonpharmacological treatments are important adjuncts to pharmacotherapy for IPF
Take Home Messages
The key take home messages of the slide set are succinctly listed here.