1. Managing IPF: connecting the dots Pulmonary & Sleep Medicine
Abdullah Alsaeedi
MD, FRCPC, FACP, FCCP
Pulmonary & Sleep Medicine
Aljahra Hospital

2. Managing IPF – Treatment Goals
Preventing disease progression
Preventing / treating acute exacerbations
Improving exercise tolerance and QoL
Improving symptoms: dyspnea, cough
Treating comorbidities: GERD, PH
Improving survival

3. Forced Vital Capacity: Predictive of Clinical Outcome
Managing IPF – Preventing disease Progression
Forced Vital Capacity: Predictive of Clinical Outcome
Correlation between:
%FVC and Mortality† ∆FVC and Mortality 20
*p<0.001 8
*p<0.001 15 6
4.81*
HR, 1-year Mortality
HR, 1-year Mortality 10 4
7.51*
2.11* 5
4.12* 2
1.00
1.97
1.00
<50
51-65
66-79
>80
<5
5-9.9
>10
Baseline %FVC
Decline in %FVC
du Bois R et al, ERS Annual Congress 2010.
†Based on Cox proportional hazards model
du Bois RM, et al. Eur Resp J 2010;36:3632. 3

4. GAP Scoring Gender Age Physiology Multidimensional Index
Ley et al., Ann Intern Med 2012;156:
Multidimensional
Index
Gender
Age
Physiology
[FVC and DLCO])
Stage I
(0-3 pts.)
Stage II
(4-5 pts.)
Stage III
(6-8 pts.)
Preventing disease progression (i.e. decline of lung function)
is an essential treatment goal in IPF patients!

5. Background MUC5B status is linked to disease progression in IPF
14 x overexpression of
MUC5B-Gene in
IPF-lungs due to promotor polymorhism on Chromosom 11:
Major Allel GG vs. Minor Allel TT
Seibold et al., N Engl J Med 2011;364:
MUC5B status is linked to disease progression in IPF

6. Clinical Trials in IPF

7. Pirfenidone Oral bioavailable, small molecule
Shows anti-fibrotic and anti-inflammatory activity in different in vitro- und animal models
Inhibits TGF-b- and TNF-a-effects
CH3 N O
Orally bio-available small molecule
Exhibits antifibrotic and anti-inflammatory properties in vitro and in animal models
Inhibits TGF-beta- and TNF-alpha-effects

8. ASCEND Study: Pirfenidone in IPF King et al. , N Engl J Med, 2014
ASCEND Study: Pirfenidone in IPF King et al., N Engl J Med, (22): p
IPF-Patients 40 – 80 Yrs.
FVC – 90 %
DLco – 90 %
FEV1/FVC ≥ 80 %
6MWD ≥ 150 m
→ 555 of 1562 enrolled
∆FVC 45,1 %
p<0.001
∆6MWD 44,2 %
p=0.036
PFS: HR 0.57

9. ASCEND - Pirfenidon 10% 23% PLacebo Pirfenidon 32% 17%
Pirfenidone, FDA Label;

10. INPULSIS-1 & 2 - Nintedanib
An intracellular inhibitor of tyrosine kinases
Targets VEGF, FGF and PDGF receptors
Phase II TOMORROW study
12 months’ treatment with nintedanib 150 mg bid may reduce lung function decline and acute exacerbations in patients with IPF
INPULSIS trials
Two replicate 52-week, randomized, double-blind, Phase III trials
Compared the efficacy and safety of nintedanib 150 mg bid with placebo in patients with IPF
1. Hilberg F, et al. Cancer Res 2008;68:4774–82; 2.Wollin L, et al. J Pharmacol Exp Ther 2014;349:209–20; 3. Richeldi L, et al. N Engl J Med 2011;365:1079–87; 4. Richeldi L, et al. N Engl J Med 2014; published online May 18, 2014

11. INPULSIS 1& 2 STUDIES: NINTEDANIB IN IPF RICHELDI, ET AL
INPULSIS 1& 2 STUDIES: NINTEDANIB IN IPF RICHELDI, ET AL., N ENGL J MED, (22): P POOLED ANALYSIS
IPF-Patients ≥ 40 Yrs.
FVC ≥ 50 %
DLco – 79 %
Inpulsis-1 → 513 of 718 enrolled
Inpulsis-2 → 548 of 794 enrolled
∆ FVC 49,2 %;
p=0.001
Time to first AE
HR 0,32
(adjud. events!)
SGRQ -1,43 pts.
p=0.09
000

12. INPULSIS - Nintedanib 18% Placebo 30% 43% Nintedanib 29%
Nintedanib, FDA Label;

13. Summary of recent clinical trials in IPF
ASCEND
Pirfenidone
~40 % reduction
44% (26m) reduction
43% rel. risk reduction
not done
-19.3 reduction
In UCSD SOBQ, p=0.16
45% risk reduction
P=0.10
GI-tract and skin
14.4% vs. 10.8%

14. Summary of recent clinical trials in IPF
Conclusions - I
Prifenidone and Nintedanib have shown efficacy in IPF
in reducing annual decline of FVC
Differences in study populations preclude direct comparisons
of effect sizes
Pirfenidone reduces decline in 6MWD, improves PFS and
overall survival, while Nintedanib prolongs time to first AE
Positive trends were seen in different PROs for both drugs
Side effects of both drugs are manageable
There is no robust evidence that NAC is effective in IPF

15. Anti-oxidant therapy in IPF The issue that will not go away
IFIGENIA, the first positive IPF trial, caused major debate due to issues with trial design
PANTHER: Nacetylcysteine monotherapy versus placebo definitively negative?
Even within the IPFnet authorship, major divisions of opinion: efficacy trends differed strikingly with “recruitment climate”
Is there an anti-oxidant efficacy dichotomy?

17. Rationale Lung host defense is influenced by oxidative signaling
Mucin 5B (MUC5B) and toll interactive protein (TOLLIP) polymorphisms influential in host defense. MUC5B status is linked to disease progression in IPF
Are single nucleotide polymorphisms within TOLLIP and muc5B linked to the efficacy of trial interventions in the PANTHER cohort?

18. Methods Post hoc analysis of the PANTHER cohort
Composite end-point of death, FVC 10% decline, transplant (+ hospitalisation in the PANTHER cohort)

19. On multivariate analysis
CC: worse outcome with NAC
HR 3.23 ( ), p=0.10
TT: better outcome with NAC
HR 0.14 ( ), p=0.03

21. Summary of recent clinical trials in IPF
Conclusions II
IPF Patients should be treated with Pirfenidone or
Nintedanib to prevent disease progression
Open Questions:
When should treatment be initiated?
Should definite, probable and possible IPF be treated all the same?
When, if at all, should treatment be stopped?
What about other modalities – PR, LTOT, LTX?

22. Managing IPF – When to initiate therapy?
ASCEND INPULSIS 1 INPULSIS 2
-164ml* vs ml* -115ml vs. -240ml -114ml vs ml
Δ 116ml* (41.5%)* Δ125ml (52%) Δ93ml (45%)
p< *erratum NEJM, Sept p< p<0.001
Baseline Characteristics
ASCEND INPULSIS INPULSIS 2
FVC ± 11 % pred ± 17 % pred ± 18 % pred.
DLco ± 11 % pred ± 12 % pred ± 14 % pred.
∆FVC≤-10% 32 % (placebo) % (placebo, pooled INPULSIS 1+2)
∆FVC≥0% % (placebo) not reported

23. Natural history of IPF – From Placebo Arms of Clinical Trials in IPF
Different types and rates of Progression
∆FVC % of risk of death
(% pred.) population HR
Stable or improved: ≥ – <1.0
Stable, marginal progressive: 0 to
Slowly progressive disease: -5 to – – 3.0
Rapidly progressive disease: > -10 % 20 – – 12.0
Acute exacerbation*: n.a – 8 4,0 – 9,5*
deterioration within 4 weeks
* History of respiratory hospitalisation
IPF: a progressive and fatal lung disease without approved Tx
Median OS 2-5 yrs
Clinical course: increasing dyspnea on exertion, progressive deterioration in lung function
Strong prognostic indicator (predictor of mortality): decrease in FCV (Δ-FVC) over time
Therapeutically meaningful: antifibrotic drugs that slow down the deterioration in FVC
30-40 % of the IPF population will be stable or marginal progressive on
placebo after one year!
60-70 % of the IPF population shows significant progression or acute
exacerbation within one year on placebo
du Bois et al., Am J Respir Crit Care Med 2011; 184:1382–1389; du Bois et al., Am J Respir Crit Care Med 2011; 184: 459–466;
Noble et al, Lancet 2011; 377: ; Demedts et al., NEJM 20015; 353: ; Taniguchi et al., Eur Respir J 2010; 35:821-9;
Richeldi et al., NEJM 2011; 365: ; Richeldi et al., NEJM 2014; 370: ; King et al., NEJM 2014; 370: ;
IPF-net, NEJM 2014; 370: ; 23

24. Managing IPF – When to initiate therapy?
„Let‘s wait and see whether progression occurs -
if the patient progresses let‘s start therapy!“
100 IPF patients on placebo
Decline ≥ 5 % FVC pred. After 3 months
YES 35 %
NO 65 %
Further worsened FVC 12 months later ?
YES 85 %
NO 15 %
YES 50 %
NO 50 %
FVC-stability within 3 months is not a predictor of stability
but is followed by progress in 50 % of the patients!
Taniguchi et al. Respiratory Research 2011, 12:93

25. Severity of IPF and/or rate of progression predicts
response to therapy with pirfenidone?
„This is a mildly affected patient, let‘s wait, he/she will respond
better to active therapy when progress occurs!“
Arai et al., Respir Invest 2014; 52:
Panel A) Severity grade I and II: PaO2 at rest ≥ 70 mmHg and min. SpO2 during 6MWT ≥ 90 %
Panel B) Severity grade III and IV: PaO2 at rest < 70 mmHg or min. SpO2 during 6MWT < 90%
IPF patients with a mild disease, diagnosis by SLB, or both showed indications of a good response to pirfenidone. In addition, acid-secretion inhibitors may reduce the frequency of anorexia, nausea, or both from pirfenidone.
Less severe disease and moderate progression showed
more consistent response to therapy!

26. Managing IPF – When to initiate therapy?
Conclusions III
Limited data available
The overall risk of clinically relevant progression within
one year is at least 50 %
irrespective of diease severity in a wide range
also in patients with previously stable FVC
In actively progressive disease risk of further progression
appears to be even higher (~ 85 %)
Treating later may result in a similar treatment response,
but the patient will start from a lower functional level
There is no evidence that witholding therapy from stable
patients will positively affect overall outcome
IPF patients should be offered active therapy up front!

27. Definite, Probable, Possible IPF – All the Same?
ASCEND
IMPULSIS
Surgical Lung Biopsy not available
Pathology panel: Definite UIP
Pathology panel: Probable UIP
Pathology panel: Possible UIP
Pathology panel: Inconsistent with UIP or Not Classifiable
Radiology Panel: Definite UIP
Radiology Panel: Possible UIP
Radiology Panel: Inconsistent with UIP
Despite including a significant portion of IPF patients with a „possible UIP“
pattern relative treatment effects on FVC observed in the INPUSLIS trials
were comparable to ASCEND, where only „definite & probable UIP“ were
included!

28. Definite, Probable, Possible IPF – All the Same?
Travis et al., AJRRCM 2013; 188:

29. RELIEF-In Lung Fibrosis - Clinical Trial
Titel: Exploring Efficacy and Safety of oral Pirfenidone for progressive,
non-IPF Lung Fibrosis (RELIEF)
Coordinating Investigators: J. Behr, Munich, A. Günther, Giessen
Design: Radomized (1:1) placebo-controlled phase-2 clinical trial
Intervention: Pirfenidon (2403 mg/d) vs. Placebo, 48 wk follow-up
Primary Endpoint: Change in FVC from baseline to week 48
Sec. Endpoints: Time to clincal worsening; progression-free survival; et al.
Sample Size: 500 pts. screened, 348 pts. (174 per arm) enrolled & analysed (ITT)
Trial Duration: 36 months (18 months for recruitment, 48 wk follow-up)
Centers: All 5 DZL-Centers plus at least five non-DZL centers (max. 20 ctrs.)

30. RELIEF-In Lung Fibrosis - Clinical Trial
Key inclusion criteria:
• Confident diagnosis of non-IPF lung fibrosis due to CVD-associated LF, chronic HP, idiopthic fNSIP or
asbestos realted LF
• Progressive disease despite preceding treatment

31. Treatment of IPF – Pulmonary Rehabilitation
PR in ILD
402 ILD-Patients:
60 yrs.
VC 52% pred.
LTOT 80%
acute infect. 13%
RH-strain 28%
pre LTx 74%
>MID
Intervention:
Ø30 days in-patient PR
OVERLALL
***p<0.001
 Clinically relevant improvement of exercis tolerance
Huppmann et al., Eur Respir J Aug;42(2):444-53

32. Treatment of IPF – Pulmonary Rehabilitation
PR in ILD
+11 Pkte***
>MID
+5 Pkte***
Physical score
Psychol. score
Without PH
With PH
***p<0.001
QoL improves
∆ psychological score >> physical Score
patients with right heart strain also benefit
Huppmann et al., Eur Respir J Aug;42(2):444-53

33. Treatment of IPF – Pulmonary Rehabilitation
PR in ILD
Reyerson et al., Res Med 2014; 108:

34. IPF - Comorbidities CVD PH DVT Depression GERD OSAS Lung cancer
Emphysema
Diabetes
Nutrition
Osteoporosis

35. Analyses of the three Placebo-arms of the IPFnet Studies:
STEP – ACE – PANTHER re. Anti-acid therapy (PPI + H2B)
STEP-IPF
N=180
ACE-IPF
N=145
PANTHER-IPF
N=159
PLACEBO
STEP N=91 ACE N=73 PANTHER N=78
IPFnet GERD Substudy
N=242
Taking PPI/H2B
N=124
Not Taking PPI/H2B
N=118
Lee et al., Lancet Respir Med 2013; 1:

36. Analyses of the three Placebo-arms of the IPFnet Studies:
STEP – ACE – PANTHER re. Anti-acid therapy (PPI + H2B)
FVC-dcline in IPF-patients with vs. without anti-acid therapy: WK 30
Anti-acid treatment could be beneficial in patients with IPF, and abnormal acid gastro-oesophageal reflux seems to contribute to disease progression
Lee et al., Lancet Respir Med 2013; 1:

37. Managing IPF – Connecting the Dots
Preventing disease progression
Improving exercise tolerance and QoL
Improving symptoms: dyspnea, cough
Treating comorbidities: GERD, PH
Preventing / treating acute exacerbations
Improving survival
Pirfenidone, Nintedanib,
Clinical Trials
Pirfenidone, Nintedanib,
Pulm Rehab
LTOT, PPI (?), PR,
(Thalidomide?)
GERD: PPI, H2B, (Fundoplication)
PH: PAPm > 35 mmHg? RCT!
Nintedanib (+)
Pirfenidone (+), Nintedanib (?), Ltx (+)

38. Managing IPF – Connecting the Dots
IPF Patient
Mild-Moderate
FVC≥50% DLco≥30% 6MWD≥150m
Severe Disease
FVC<50% DLco<30% 6MWD<150m
Evaluate eligibility for clinical trials and for lung transplantation
Initiate antifibrotic therapy
Symptomatic therapy
Evaluate/treat
GERD
LTOT
Severe PH
et al.
Pulmonary Rehabilitation
Monitoring in 3-monthly intervals: PFT, BGA, 6MWT

39. IPF International Guideline – Update 2015
Negative Recommendation (strong):
a. Anticoagulation (warfarin) (⊕⊕⊝⊝, low confidence in effect estimates).
b. Imatinib (⊕⊕⊕⊝, moderate confidence in effect estimates).
c. Prednisone, azathioprine, and N-acetylcysteine (⊕⊕⊝⊝, low confidence
in effect estimates).
d. Ambrisentan (⊕⊕⊝⊝, low confidence in effect estimates).
Negative Recommendation (conditional):
a. Sildenafil (⊕⊕⊕⊝, moderate confidence in effect estimates.
b. Macitentan, Bosentan (⊕⊕⊝⊝, low confidence in effect estimates.
Positive Recommendation (conditional):
a. Nintedanib (⊕⊕⊕⊝, moderate confidence in effect estimates.
b. Pirfenidone (⊕⊕⊕⊝, moderate confidence in effect estimates.
Updated evidence syntheses related to N-acetylcysteine monotherapy (negative, conditional)
and anti-acid therapy (positive, conditional) were presented to the panel and both
recommendations were left unchanged from the 2011 guidelines.
Raghu et al., ATS,

40. A consensus document for the selection of lung transplant candidates: 2014 Weill et al., J Heart Lung Transplant 2015; 34: 1-15

41. Thank You For Your Attention!