pulmonary fibrosis when rapidly progressing

1. Progressive Pulmonary Fibrosis
(Previously known as PF-ILDs)
Dr. Subhajit Ghosh
Lead RMA
Cipla Respiratory

2. Chronic fibrosing ILDs
A proportion of patients with distinct clinical diagnoses of chronic fibrosing ILDs develop a progressive
phenotype characterized by:1,2
Worsening
respiratory
symptoms
Progressive
decline in lung
function
Reduced QoL
and functional
status
Early mortality
Progressive
pulmonary
fibrosis
ILD, interstitial lung disease; QoL, quality of life.
1. Flaherty KR et al. BMJ Open Resp Res. 2017;4:e000212.
2. Cottin V et al. Eur Respir Rev. 2018;27:180076.

3. The clinical course of the ‘chronic fibrosing ILDs with a progressive phenotype’
The hypothesis is that the response to
lung injury in chronic fibrosing ILDs
includes the development of fibrosis that
becomes:3
Progressive
Self-sustaining
Independent of original
clinical association or trigger
IPF, idiopathic pulmonary fibrosis.
1. Kolb M, Vasakova M. Respir Res. 2019;20:57.
2. Richeldi L et al. Eur Respir Rev. 2018;27:180074.
3. Flaherty KR et al. BMJ Open Resp Res. 2017;4:e000212.
The natural history of chronic fibrosing
ILDs with a progressive phenotype
follows a clinical course similar to IPF
(referred to as the “prototype” fibrosing
ILD with a progressive phenotype)1,2

4. Classification of ILDs based on disease behavior
Progressive, irreversible disease with potential
for stabilization
Stable with residual disease
Reversible disease with risk of progression
Reversible and self-limited
Progressive, irreversible disease
despite therapy
Progressive but responds to immunomodulation, at least in
short term
Non-progressive
Progressive regardless of treatment considered appropriate
for individual ILDs
ATS/ERS classification for IIPs1 Proposed classification for chronic fibrosing ILDs2
ATS/ERS, American Thoracic Society/European Respiratory Society; IIP, idiopathic interstitial pneumonia.
1. Travis WD et al. Am J Respir Crit Care Med. 2013;188:733-748.
2. Wells AU et al. Eur Respir J. 2018;51 pii: 1800692.

5. • In a patient with ILD of known or unknown etiology other than IPF
who has radiological evidence of pulmonary fibrosis, PPF is defined as
at least two of the following three criteria occurring within the past
year with no alternative explanation:
• 1. worsening respiratory symptoms;
• 2. physiological evidence of disease progression, as defined below;
and
• 3. radiological evidence of disease progression, as defined below.
For Medical Use Only - Do Not Distribute 5
Definition of PPF – ATS/ERS/JRS/ALAT 2022

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Definition of PPF – ATS/ERS/JRS/ALAT 2022

7. For Medical Use Only - Do Not Distribute 7

8. 18
20
21
24
26
29
31
32
100
0 10 20 30 40 50 60 70 80 90 100
Other non-IPF ILDs
Sarcoidosis-ILD
HP
Other AI-ILDs
RA-ILD
Unclassifiable IIP
SSc-ILD
iNSIP
IPF
Estimated proportion of patients with different types of chronic fibrosing ILDs who develop a
progressive phenotypea
aData from online survey of physicians (n=243 pulmonologists, n=203 rheumatologists, n=40 internists).
AI-ILD, autoimmune disease-associated interstitial lung disease; IIP, idiopathic interstitial pneumonia; RA-ILD, rheumatoid arthritis-
associated interstitial lung disease; SSc-ILD, systemic sclerosis-associated interstitial lung disease.
Wijsenbeek M et al. Curr Med Res Opin. 2019;35(11):2015-2024.
Percentage of patients who develop a progressive fibrosing phenotype
18% - 32% non-IPF ILDs may develop a
progressive fibrotic phenotype

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Pirfenidone in PPF
We recommend further research into the efficacy,
effectiveness, and safety of pirfenidone in both
1)non-IPF ILD manifesting PPF in general
and
2) specific types of non-IPF ILD manifesting PPF.

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0
Pirfenidone in PPF - SUMMARY OF EVIDENCE
• The systematic review identified two randomized trials that
enrolled patients with PPF and evaluated the effects of
pirfenidone.
• One trial of uILD randomly assigned 253 patients with fibrotic
uILD to receive pirfenidone or placebo, then followed them for
24 weeks.
• The other trial (RELIEF) randomly assigned 127 patients with
PPF to receive pirfenidone or placebo, then followed them for
48 weeks . The trial included patients with chronic HP, CTD-
related ILD, NSIP, and asbestosis-induced lung fibrosis.

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Pirfenidone in PPF - SUMMARY OF EVIDENCE
Disease progression - When the trials were aggregated by meta-analysis,
pirfenidone reduced the decreases in FVC by 100 ml and in percentage
predicted FVC by 2.3% over 24 weeks.
In the uILD trial, pirfenidone decreased by 1.6 times the likelihood that
percentage predicted FVC would decline >5% and decreased by 1.9 times
the likelihood that percentage predicted FVC would decline >10%
Mortality - The uILD trial did not demonstrate a statistically significant
difference in progression-free survival. Similarly, the RELIEF trial did not
show a statistically significant difference in progression-free survival
ormortality at 48 weeks.

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2
Pirfenidone in PPF - SUMMARY OF EVIDENCE
Lung function - Only the RELIEF trial reported changes in FEV1 and TLC, neither of which
was statistically significant. The RELIEF trial showed that pirfenidone reduced the mean
decrease in DLCO by 0.40 mmol/kPa/min, while the
uILD trial found that patients with fibrotic uILD who received pirfenidone had a 3.7
times reduced risk of a DLCO decline of >15%, although there was no statistically
significant difference in the mean change in percentage predicted DLCO.
When the trials were combined by meta-analysis, pirfenidone attenuated the decline in
6MWD by 25.2m, whereas in the uILD trial the number of patients whose 6MWD
declined by >50 m was unchanged.
Respiratory symptoms - There was no significant difference in mean St. George’s
Respiratory Questionnaire score, Leicester Cough Questionnaire score, UCSD-SOBQ
scores, or visual analog scale score for cough.

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Pirfenidone in patients with unclassifiable progressive fibrosing interstitial lung disease: a
double-blind, randomised, placebo-controlled, phase 2 trial – uILD trial