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ATS Highlights 2015
Interstitial Lung Disease
Chicago, USA | July 9th, 2015
The preparation of the slide kit and video recording was sponsored by Boehringer Ingelheim and contains
personal opinions from leading ILD experts. ATS was neither author nor reviewer of the content.
About the ATS 2015
• Held in Denver, Colorado, May 15th
through 20th
• One of the largest gatherings of
pulmonary, critical care and sleep
medicine professionals in the world
• Numerous sessions about idiopathic
pulmonary fibrosis (IPF) and
interstitial lung diseases (ILDs) in
general
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
ATS Highlights Slide Kit
This slide kit aims to provide a balanced summary of new key data and
reoccurring points of discussion in interstitial lung diseases, with a special
focus on IPF*
It has been written in close cooperation with two leading interstitial lung disease
experts
Fernando Martinez (MD)
Imre Noth (MD)
works as an Adjunct Professor at
the University of Michigan and is
the Executive Vice Chair of
Medicine at the Weill Cornell
Medical College and New YorkPresbyterian Hospital/Weill
Cornell Medical Center
is a Professor of Medicine at the
University of Chicago and the
Director of the University’s
Interstitial Lung Disease Program
*Please note that this report is not meant to provide an all-round view of IPF and its
management, but covers only the data presented and discussed at the ATS 2015.
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Declarations of Interest
Fernando Martinez
Personal fees: Ikaria, Genentech, Nycomed/Takeda, Pfizer, Vertex, ATS, Inova Health System,
MedScape, Spectrum Health System, University of Texas Southwestern, Stromedix/Biogen, Axon
Communications, National Association for Continuing Education, Boehringer Ingelheim, Veracyte,
AcademicCME
Grants: NIH
Non-financial support: Bayer, Centocor, Gilead, Promedior
Imre Noth
Board membership/ consultancy: Boehringer Ingelheim, Genentech, Sunovion
Lecture Fees: Boehringer Ingelheim, Genentech, PILOT CME, Rockpointe CME
Clinical Trials: Boehringer Ingelheim, Genentech, Hoffman LaRoche, Promedior, Gilead
This is a private scientific event from Boehringer Ingelheim.
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Overview
Overview
Nintedanib
Pirfenidone
Evaluation of Other
Treatment Options
Diagnosis and
Monitoring
Potential IPF
Biomarkers
Acute
Exacerbations of IPF
IPF
Pathobiology
IPF Future
Challenges
Summary of
ATS 2015
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Overview
State-of-the-art therapy prior to ATS 2015
The preparation of the slide kit and video recording was sponsored by Boehringer Ingelheim and contains
personal opinions from leading ILD experts. ATS was neither author nor reviewer of the content.
2012:
Triple Therapy Harmful for IPF Patients
The PANTHER-IPF trial examined the safety and
efficacy of a triple therapy with prednisone,
azathioprine and N-acetylcysteine.1
Time to Death or Hospitalization
• Randomized, double-blind, placebo-controlled
• Stopped after 50% of the data had been collected
(n=155, 32 weeks) because of increased mortality
and hospitalization in the triple therapy group
At this year’s ATS, repeated appeals were
made to refrain from treating IPF patients with
this therapy.
Adapted from The IPF Clinical Research Network. NEJM 2012;366:1968-77
1.The IPF Clinical Research Network. NEJM 2012;366:1968-77.
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
2014:
NAC Treatment in IPF under Evaluation
The PANTHER-IPF trial was partially continued to
examine the safety and efficacy of N-acetylcysteine
(NAC) treatment versus placebo.1
Change from Baseline in FVC
• Randomized, double-blind, placebo-controlled,
n=264
• Endpoints: FVC, mortality and acute exacerbations
• At the end of the trial (60 weeks), no significant
benefits in favor of N-acetylcysteine treatment
could be shown
New data presented at this year's ATS indicate
that NAC treatment may be effective for
specific genotypes.2
Adapted from The IPF Clinical Research Network. NEJM 2014:370:2093-101
1.The IPF Clinical Research Network. NEJM 2014:370:2093-101.
2.Oldham J. M, et al. AJRCCM 191;2015:A2162.
NAC = N-acetylcysteine; IPF = idiopathic pulmonary fibrosis; FVC = forced vital
capacity
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
2014/2015:
Two Medications Available for the Treatment of IPF
In the past year, the first
medications for the treatment of
IPF have been approved in the
United States
• In October 2014, the US Food and
Drug Administration (FDA) approved
two new drugs, nintedanib and
pirfenidone, for the treatment of
patients with IPF in the United
States1,2
• In January 2015, the European
Commission (EC) approved
nintedanib for the European Union
(pirfenidone has been approved
since 2011)3
1. Boehringer Ingelheim Press Release. 16.10.2014.
2. US Food & Drug Administration. Press Announcement. 15.10.2014.
3. Boehringer Ingelheim Press Release. 19.01.2015.
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Nintedanib
New data presented at ATS 2015
The preparation of the slide kit and video recording was sponsored by Boehringer Ingelheim and contains
personal opinions from leading ILD experts. ATS was neither author nor reviewer of the content.
Pre-clinical Investigations of
Nintedanib in Human Models
Nintedanib has been further investigated in human models
• Nintedanib reduced spontaneous and LPS-induced TNFα and
IL-1β release from primary human lung fibroblasts derived
from patients with IPF or iNSIP, thereby demonstrating antiinflammatory and anti-fibrotic activity1
• Nintedanib, but not pirfenidone, inhibits proliferation of
stimulated human lung fibroblasts at clinically relevant
concentrations2
Inhibition of serum-stimulated proliferation
of primary lung fibroblasts2
Clinically achievable exposure
Clinically achievable exposure
• PDGFR, FGFR and VEGFR were shown to be involved in
fibroblast differentiation. Since nintedanib inhibits those
receptors, the finding suggest that it’s anti-fibrotic effect might
partly be mediated by the inhibition of fibroblast differentiation.3
1. Long X, et al. AJRCCM 191;2015:A4396.
2. Schuett J, et al. AJRCCM 191;2015:A4940.
3. Sato S, et al. AJRCCM 191;2015:A2364.
LPS = lipopolysaccharide; TNF = tumor necrosis factor; IL = interleukin; NSIP= nonspecific interstitial
pneumonia; PDGFR = platelet-derived growth factor receptor; FGFR = fibroblast growth factor
receptor; VEGFR = vascular endothelial growth factor receptor.
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Pre-clinical Investigations of
Nintedanib in Murine Models
Nintedanib showed a pronounced anti-angiogenic effect
in a bleomycin-induced fibrosis model
• The anti-angiogenic activity of nintedanib might
contribute to its clinical efficacy in patients with IPF.2
Vasodilatory activity of nintedanib
in pulmonary arteries
(precision-cut lung slices)1
dilation of arteria [% of precontraction]
Nintedanib has been further investigated in murine
models
Nintedanib exerts vasodilatory activity predominantly in
the pulmonary arteries after endothelin-1 pre-contraction
in precision-cut lung slices as well as isolated perfused
lungs
• Nintedanib might have an impact on treating
pulmonary arterial hypertension, which is a dangerous
comorbidity in patients with IPF.1
160
140
120
100
control
nintedanib
80
control -9
-8
-7
-6
-5
-4
concentration [log M]
1. Rieg A. D, et al. AJRCCM 191;2015:A1956.
2. Ackermann M, et al. AJRCCM 191;2015:A4395.
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Overview Nintedanib
• The randomized, double-blind and placebocontrolled INPULSIS® trials enrolled a broad
range of patient types with 1066 patients in total1
Nintedanib is now included in the 2015 update of
the ATS/ERS/JRS/ALAT evidence based
guidelines for the treatment of IPF, which were
presented by Prof. Dr. Ganesh Raghu at the ATS
2015.2,3
Adjusted annual rate of decline in
FVC (mL/year)
Annual rate of lung function decline
• FDA and EMA approvals were based on the
in FVC1
phase 3 INPULSIS® 1 & 2 trials and data from the
Phase 2 TOMORROW trial
0
-50
-100
-150
-113.6
-200
-250
-300
-223.5
Nintedanib 150 mg bid (n=638)
Placebo (n=423)
109.9 mL/year; (95% CI: 75.9, 144.0); p<0.0001
1. Richeldi L, et al. NEJM 2014;370:2071–2082.
2. Boehringer Ingelheim Press Release. 20.05.2015.
3. ATS 2015, Raghu G. C92. Oral presentation.
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Long-term Efficacy, Safety and Tolerability of
Nintedanib
The efficacy,
safety and
tolerability of
nintedanib beyond
52 weeks was
confirmed in 2
extension trials
TOMORROW phase 2 trial after TOMORROW period 1
(52 weeks), patients could continue with a further blinded
treatment phase (period 2)1
• Slowing of disease progression was maintained up to 76
weeks
• A lower rate of exacerbations in the nintedanib group was
observed throughout periods 1&2
• No new safety concerns were identified after 52 weeks
INPULSIS®-ON interim analysis of the open-label extension
of INPULSIS®2
• Mean (SD) total duration of exposure with nintedanib was
23.8 (4.5) months
• No new safety concerns were identified
1. Richeldi L, et al. AJRCCM 191;2015:A1019.
2. Crestani B, et al. AJRCCM 191;2015:A1020.
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Nintedanib: Safety and Efficacy Beyond Week 52
(TOMORROW trial)
After TOMORROW period 1 (52 weeks),
patients could continue with a further
blinded treatment phase (period 2)
The analysis1 compared
• Patients on placebo (period 1) who switched to
nintedanib 50 mg qd in period 2 (comparator group;
n=44)
• Patients on nintedanib 150 mg bid (period 1)
who continued with nintedanib 150 mg bid in period 2
(nintedanib group; n=36)
•
•
•
Nintedanib 150 mg bid slowed disease progression up to week 76 (-3.1% in the nintedanib vs -6.3% in the comparator group)
Incidence of acute exacerbations across periods 1 and 2 was lower in the nintedanib 150 mg bid group (3.2 versus 13.4 per
100 patient-years)
No relevant changes in the safety and tolerability of nintedanib 150 mg bid were observed
1. Richeldi L, et al. AJRCCM 191;2015:A1019.
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Nintedanib is Safe Beyond Week 52 (INPULSIS®-ON)
After INPULSIS® (52 weeks), patients could
continue with an open label extension trial
(INPULSIS®-ON)1
• 430 patients continued nintedanib and 304 patients initiated on
nintedanib
• Mean (SD) total duration of exposure in patients treated with
nintedanib in INPULSIS® and INPULSIS®-ON was 23.8 (4.5)
months
Most
frequent
Top
3
side
side
effects
effects
Patients (%) who
reported >1 AE
80%
60%
Patients continuing nintedanib (n=430)
Patients initiated on nintedanib (n=304)
• No new safety concerns were identified;
the adverse event profile confirmed the
safety and tolerability profile observed in
the INPULSIS® trials
• Adverse events led to discontinuation of
trial medication in 12.6% of patients
continuing nintedanib and 18.4% of
patients initiated on nintedanib
• The most frequent adverse event was
diarrhea but few patients of either group
had diarrhea adverse events that led to
treatment discontinuation
40%
20%
0%
Diarrhea
Nausea
1. Crestani B, et al. AJRCCM 191;2015:A1020.
Cough
AE = adverse event
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
INPULSIS® Subgroup Analyses
Post hoc subgroup analyses of INPULSIS (n=1061) showed same effect of
nintedanib on annual rate of decline in FVC, time to first
acute exacerbation and change in SGRQ total score over
52 weeks in patients:
• Without honeycombing or biopsy vs. patients with honeycombing and/or biopsy1
• With preserved/marginally impaired lung function (FVC >90% predicted) vs. patients
with more advanced lung function impairment2
1. Kolb M, et al. AJRCCM 191;2015:A1021.
2. Raghu G, et al. AJRCCM 191;2015:A1022.
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Effect of Nintedanib on Patients
with Baseline FVC >90%
INPULSIS® subgroups
Annual rate of decline in FVC by baseline
FVC 90% predicted
• Baseline FVC ≤90% predicted (n=787)
• Similar annual rate of decline in FVC
• Slowed decline in lung function in nintedanib
groups independent of degree of lung function
impairment at baseline
• Time to first acute exacerbation and change in
SGRQ total score consistent in both subgroups
Patients with marginally impaired FVC at baseline
might benefit from treatment with nintedanib.1
1. Kolb M, et al. AJRCCM 191;2015:A1021.
Mean (SE) observed change from
baseline in FVC (mL)
• Baseline FVC >90% predicted (n=274)
50
0
-50
-100
-150
-200
-250
-300
0 2 4 6
12
24
36
Week
FVC ≤90% predicted – nintedanib
FVC >90% predicted – nintedanib
FVC ≤90% predicted – placebo
FVC >90% predicted – placebo
52
FVC = forced vital capacity
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Effect of Nintedanib on Patients
with Different HRCT Diagnostic Criteria
• Decline in FVC in the placebo groups virtually
identical in both subgroups
• Nintedanib reduced the decline in FVC equally in
both subgroups
• The treatment effect of nintedanib for time to first
acute exacerbation and change from baseline in
SGRQ total score was consistent between the
subgroups
These findings have major implications for diagnosis
and clinical trial design
1. Raghu G, et al. AJRCCM 191;2015:A1022.
Annual rate of decline of FVC by HRCT
and biopsy diagnostic criteria
Mean (SE) observed change from
baseline in FVC (mL)
INPULSIS® subgroups (based on HRCT findings)
• Honeycombing and/or confirmation by biopsy
(n=723)
• No honeycombing or biopsy (n=338)
50
0
-50
-100
-150
-200
-250
-300
0 2 4 6
12
24
36
Week
Honeycombing and/or confirmation of UIP by biopsy – nintedanib
Features of possible UIP on HRCT and no biopsy – nintedanib
Honeycombing and/or confirmation of UIP by biopsy – placebo
Features of possible UIP on HRCT and no biopsy – placebo
52
HRCT = high resolution computed tomography; FVC = forced vital capacity
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Pirfenidone
New data presented at ATS 2015
The preparation of the slide kit and video recording was sponsored by Boehringer Ingelheim and contains
personal opinions from leading ILD experts. ATS was neither author nor reviewer of the content.
Pre-clinical Investigations of Pirfenidone
Pirfenidone + anti-oxidants1
Stable lecithinized superoxide dismutase and pirfenidone partly showed a synergistic therapeutic effect against
bleomycin-induced pulmonary fibrosis and lung dysfunction, suggesting a new approach to effective IPF treatments
Pirfenidone + interferon-γ2
The combined administration of both drugs showed the synergistic effects, including inhibition of α-SMA, enhanced
IFN-γ induced apoptosis of human lung fibroblasts, decreased MMP-2 activation and MMP-1 up-regulation in human
lung fibroblasts and A549 cells
Pirfenidone + nintedanib3
The pharmacokinetics were compared for co- and single agent administration in rat, monkey and dog. Coadministration had no significant impact on the PK properties of either compound, suggesting further studies
KL-6 levels as a potential predictor of response to pirfenidone4
KL-6 correlates with change of FVC, DLCO and with survival in IPF. New data from a cohort study present serum
KL-6 as a potential predictor of the response to pirfenidone in patients with IPF independently from FVC.
1.
2.
3.
4.
Kurotsu S, et al, AJRCCM 191;2015:A3471.
Vu T. N, et al, AJRCCM 191;2015:A4918.
Pan L, et al. AJRCCM 191;2015:A4399
Bonella F, et al, AJRCCM 191;2015:A4398
IFN-γ = interferon γ; α-SMA = α smooth muscle actin; MMP= matrix
metalloprotease ; PK = pharmacokinetics; DLCO = diffusing capacity for
CO; FVC = forced vital capacity
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Overview Pirfenidone
• Approved since 2011 by European Commission based
on evidence from the CAPACITY trials (Phase 3; n =
779)1
Proportion of patients with ≥10%
decline in FVC or death (%)2
• FDA approval in 2014 was based on the phase 3
ASCEND trial (highly selected population with 64%
screen failure rate; n = 555)2
Pirfenidone is now included in the 2015 update of
the ATS/ERS/JRS/ALAT evidence based
guidelines for the treatment of IPF, which were
presented by Prof. Dr. Ganesh Raghu at the ATS
2015.3
1. Noble P. W, et al. Lancet 2011;377:1760-1769.
2. King T. E, et al. NEJM 2014;370:2083-2092.
3. ATS 2015, Raghu G. C92. Oral presentation.
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Long-term Safety of Pirfenidone
Analysis of safety data from five clinical trials with
patients who received at least one dose of pirfenidone (n=1299, 75.8% ≥ 1800 mg pirfenidone qd)1
• 3 phase 3 trials (ASCEND/CAPACITY) (n=1247)
• 2 ongoing open-label studies (=integrated population)
(n=1299)
The analysis compared the integrated trial
populations with the pirfenidone and placebo
groups from the pooled ASCEND/CAPACITY trials
• Data cut-off: 15.1.2014
• Median exposure, 1.7 years; range: 1 week–9.9
years
No new treatment-emergent AEs identified
Gastrointestinal and skin-related events were among
the most common AEs (mostly mild to moderate in
severity and rarely leading to treatment discontinuation)
49.2% of patients had at least one treatmentemergent serious AE
Elevations in liver enzymes occurred in 3% of patients,
most of these occurred within the first 6 months
Respiratory AEs more common in integrated
population (consistent with longer period of
observation)
This long-term prospective follow-up data illustrate that pirfenidone is
well-tolerated in patients with IPF.
1. Lancaster L, et al. AJRCCM 191;2015:A1017.
AE = adverse event; IP = integrated population
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Pooled ASCEND/CAPACITY Subgroup Analyses
Pooled
data from the
ASCEND and
CAPACITY
studies (n=1247)
suggest that:
Patients with IPF whose disease has progressed (≥10% decline in FVC %
predicted by month 6) benefit from continued treatment with pirfenidone
(up to month 12)1
Patients with “late/more advanced” IPF had a significantly worse outcome
at month 12 than patients with “early” IPF on 6MWD and dyspnea, but not
on FVC decline, suggesting that patients with IPF whose disease has
progressed still benefit from continued treatment with pirfenidone2
1. Nathan S. D, et al. AJRCCM 191;2015:A1016.
2. Albera C, et al. AJRCCM 191;2015:A1018.
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Effect of Pirfenidone on Patients
with a ≥10% Decline in FVC in the First 6 Months of Treatment
Patients* with a ≥10% decline in FVC %
predicted during the first 6 months of
treatment
Outcomes during the subsequent 6-month
period after an initial ≥10% absolute decline
in %FVC1
• 34 patients (5.5%) in the pirfenidone group
In the following 6 months
• Less patients in the pirfenidone group had
a ≥10% decline in FVC % predicted
• More patients in the pirfenidone group
showed no decline in FVC
• Less patients in the pirfenidone group died
Outcomes (%)
• 68 patients (10.9%) in the placebo group
100%
80%
P=0.059
60%
40%
P=0.009
P=0.018
20%
0%
≥10% decline
in FCV or death
No further
decline in FVC
Pirfenidone (n=34)
Death
Placebo (n=68)
Patients whose disease has progressed might benefit from continued treatment with pirfenidone
1. Nathan S. D, et al. AJRCCM 191;2015:A1016.
FVC = forced vital capacity
* pooled data from ASCEND and CAPACITY
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Efficacy of Pirfenidone on Patients
with Baseline FVC ≥ 80%/GAP1
Pooled data from ASCEND and CAPACITY
was used and IPF progression was
measured by
• Baseline FVC ≥ 80% and GAP1
(mild IPF)
• Baseline FVC < 80% or GAP2-3 (late/more
advanced IPF)
At Month 12
• Patients with “late/more advanced” IPF had a
significantly worse outcome than patients
with “early” IPF on 6MWD and dyspnea
(SOBQ), but not on FVC decline
• No significant difference in the treatment
effect of pirfenidone between the “early” and
“late/more advanced” sub-groups
These findings support the initiation of treatment soon after diagnosis1
1. Albera C, et al. AJRCCM 191;2015:A1018.
FVC = forced vital capacity; GAP = gender, age, physiology
6MWD = 6-min walk distance; SOBQ = shortness of breath questionnaire
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Further Evaluation of Treatment with Pirfenidone
Long-term survival and disease progression of patients treated with pirfenidone has been
evaluated by several groups.
• A partitioned survival model was used to model the effect of pirfenidone on the time to disease
progression, improvement on life expectancy (3.19 years) and prevention of early morbidity and
death in mild to moderate IPF.1
• Bayesian statistical analysis (pooled ASCEND/CAPACITY) showed that the 1-year all-cause
mortality and treatment-emergent IPF-related mortality results were consistent across all 3 studies
with a probability of 98.4% superiority to placebo.2
• A nationwide Danish study (n=113) showed that
– The majority of patients treated experienced side effects but continued treatment (careful follow-up and doseadjustment)
– Median follow-up time was 9.7 months, discontinuation occurred in 23 cases either due to side effects (n=10) or
mortality (n=13). The most frequent side effects included nausea (41.6%), photosensitivity (34.5%), fatigue
(27.4%), weight loss (22.1%) , diarrhea (15.9%) and dyspepsia (14.2%).3
1. Fisher M, et al. AJRCCM. 191;2015:A4413.
2. Berry D, et al. AJRCCM. 191;2015:A4417.
3. Salih G.N, et al, AJRCCM. 191;2015:A4397.
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Evaluation of Other
Treatment Options
The preparation of the slide kit and video recording was sponsored by Boehringer Ingelheim and contains
personal opinions from leading ILD experts. ATS was neither author nor reviewer of the content.
Review:
The Microbiome is Substantially Changed in IPF Lungs
COMET study1
Disease progression and increased mortality is
associated with the presence of specific members of
the Staphylococcus and Streptococcus genera and a
shift in the lung microbiome (preliminary data from
BAL samples)
Molyneaux et al.2
The lung
microbiome is
correlated with
disease progression
and is a biomarker
for disease
severity
Confirmation of COMET: increased bacterial burden in
BAL predicts decline in lung function and death
1. Han M. K, et al. Lancet Respir Med. 2014;2(7):548-56.
2. Molyneaux P. L, et al. AJRCCM. 2014;190(8):906-13.
BAL = bronchoalveolar lavage
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Review: Co-trimoxazole and Improved Survival
Multi-center, randomized, placebocontrolled, double-blind, parallel-group trial
to study the effect of co-trimoxazole over
12 months in 181 patients with fibrotic IIP1
Significant reduction in mortality with
co-trimoxazole treatment vs.
placebo1
• Significant reduction in mortality
compared to placebo
• No effect on disease progression
• The mechanism might be the reduction
of respiratory infection
1. Shulgina L, et al. Thorax 2013; 68:155-162.
IIP = idiopathic interstitial pneumonia
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
EME-TIPAC - New Phase 3 Study with Co-trimoxazole
• Ongoing (initiated in April 2014) study
to evaluate the efficacy and mechanism
of treating IPF with the addition of cotrimoxazole1
• Co-trimoxazole and folic acid are added
to current IPF treatment
• Phase 3, double-blind, parallel-group,
randomized, placebo-controlled multicenter study including 330 patients with
moderate and severe IPF
330 patients with moderate and
severe IPF
Oral co-trimoxazole +
folic acid + current treatment
vs.
placebo + folic acid + current
treatment
Primary Endpoints: Time to death
(all causes) and lung-transplant or
first non-elective hospitalization
1. www.uea.ac.uk/EME-TIPAC
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Pulmonary Rehabilitation and BOC Beneficial for
Patients with ILD
Pulmonary rehabilitation improves exercise capacity
and dyspnea perception1
An individualized PR program for ILD patients including
patient education and exercise training for 12 weeks with 3
sessions per week showed a significantly improved exercise
capacity and dyspnea perception (assessed through 6MWD
and Borg’s scale rating) but not lung function
“Bundle of Care” (BOC) in the initial year of management in IPF may improve survival in patients with IPF2
BOC included: clinic visits with pulmonary function tests at
6-month intervals; 6-minute walk test, screening transthoracic echo, referral to pulmonary rehabilitation and antireflux therapy at initial visit
1. Rastogi S. A, et al. AJRCCM 191;2015:A2020.
2. Kulkarni T, et al. AJRCCM 191;2015:A4401.
PR = pulmonary rehabilitation; ILD = interstitial lung disease;
BOC = bundle of care
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Controversial Results for Oxygen Therapy in
Fibrotic ILDs
Outcomes
from 2
observational
studies
discourage O2
therapy
Patients with IPF who use supplemental oxygen report shortness of breath and dyspnea
more frequently and perceive greater dyspnea with activity as opposed to non-users. The
reasons for this observation remains unclear to date.1,2
Results
encouraging
O2 therapy
Single-blind, randomized, placebo-controlled, cross-over study confirmed beneficial effects
of 80% supplemental oxygen in 6 patients with fibrotic ILD
• Fully reversed arterial O2 desaturation, decreased ventilatory response and neural drive
• Using supplemental oxygen together with pulmonary rehabilitation could enhance
training intensity and lead to greater improvements in exercise tolerance and dyspnea. 3
1. Cao M, et al. AJRCCM 191;2015:A1590.
2. Farnsworth T, et al. AJRCCM 191;2015:A1559.
3. Schaeffer M. R, et al. AJRCCM 191;2015:A4400.
ILD = interstitial lung disease
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Diagnosis and Monitoring
The preparation of the slide kit and video recording was sponsored by Boehringer Ingelheim and contains
personal opinions from leading ILD experts. ATS was neither author nor reviewer of the content.
What is the Prevalence for IPF?
While the ATS/ERS/JRS/ALAT 2011 evidence-based guidelines for IPF estimate that the
incidence for IPF is 10.7/100,000 males and 7.4/100,000 females (0.002% of the general
population)1, results from the Framingham Heart Study suggest that the prevalence might be
as high as 2%.2 New insights on IPF prevalence were presented at this year’s ATS.
• A prospective cohort study of 18 patients with ILD showed that a higher number of elderly
patients (>75 years) were diagnosed with unclassifiable ILD while middle-aged patients (between
40 and 60 years) were more likely to have connective tissue disease-ILD and granulomatous
ILD.3
• A cross-sectional retrospective cohort study, found IPF prevalence rates in the US (ICD-9; 516.3)
in an overall range between 19.8 (2011) and 28.8 (2009)/100,000 persons. The prevalence rate
was highest for patients between 75-84 years old (181.3-245.5/100,00).4
1.Raghu G, et al. AJRCCM 2011;183:788-824.
2. Hunninghake G. M, et al. NEJM 2013;268(23):2192-2200.
3. Patterson K. C, et al. AJRCCM 191;2015:A1570.
4. Raimundo K, et al. AJRCCM 191;2015:A4380.
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
New Methods for IPF Diagnosis
EUROLINE
measurement
An antibody-based commercial detection method which can act
as an additional tool for differentiating NSIP and UIP based on
HRCT pattern (most frequent matching factor: anti-Ro-52).1
Periostin
detection
kit
Serum periostin is elevated in IPF patients and inversely
correlates with lung function. The kit is able to diagnose IPF with
accuracy comparable with the biomarkers KL-6 and SP-D. It can
predict lung function results better than SP-D.2
1. Hayashi R, et al. AJRCCM 191;2015:A1558.
2. Izuhara K, et al. AJRCCM 191;2015:A4381.
UIP = usual interstitial pneumonia; NSIP = nonspecific interstitial
pneumonia; HRCT = high-resolution computed tomography
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Functional Respiratory Imaging (FRI) for IPF Diagnosis
FRI could be used in the future to monitor disease
progression
• Two studies compared the lungs of IPF patients
with healthy lungs1,2
• The IPF lungs showed
– Increased fibrosis parameter1,2
– Increase in specific airway radius (possible
involvement of traction bronchiectasis)1,2
FRI appears
to be a sensitive tool
to describe regional
lung characteristics
and can distinguish
healthy lungs from
lungs affected by
IPF
– Upper lobes appear to be better ventilated2
– More fibrosis and smaller lobe volume in the lower lobes2
1. Vos W, et al. AJRCCM 191;2015:A4377.
2.De Backer J, et al. AJRCCM 191;2015:A1568.
FRI = functional respiratory imaging
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Potential IPF Biomarkers
The preparation of the slide kit and video recording was sponsored by Boehringer Ingelheim and contains
personal opinions from leading ILD experts. ATS was neither author nor reviewer of the content.
New Potential Diagnostic Biomarkers for IPF
• A three-analyte biomarker panel measuring the plasma concentration of
osteopontin, SP-D and MMP-7 could be used to distinguish patients with
IPF from other interstitial lung diseases1
• Mac-2 binding protein glycosylation isomer (M2BPGi) serum levels
might be a potential biomarker for IPF2
– Elevated serum levels found in IPF patients compared to healthy
controls
– These correlated with other IPF markers such as KL-6, neutrophils,
HRCT and biopsy findings and lung function parameters
1. White E. S, et al. AJRCCM 191;2015:A6326.
2. Kono M, et al. AJRCCM 191;2015:A4372.
• Facilitated
differential
diagnosis of
IPF with SP-D,
osteopontin,
and MMP-7
panel
• M2BPGi as
new biomarker
SP-D = surfactant protein D; MMP-7 = matrixmetalloprotease 7;
M2BPGi = Mac-2 binding protein glycolysation isomer
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Biomarkers for IPF Progression in Plasma and BAL
• Elevated levels of soluble Ephrin-B2 were found in plasma and BAL
samples of IPF patients compared to controls. In a murine IPF model,
sEphrin-B2 levels seemed to correlate with lung injury.1
• The diagnostic and prognostic value of BAL differential cell count (DCC)
was evaluated in cases of possible UIP on HRCT without biopsy. It was
found that BAL DCC is of limited clinical value in those patients.2
– There was no significant difference in baseline BAL DCC between
patients with definite and possible UIP.
– The DCC did not differ between progressing and non-progressing
patients.
1. Montesi S, et al. AJRCCM 191;2015:A4374.
2. Nicol L. M, et al. AJRCCM 191;2015:A1560.
• sEphrin-B2
elevated in IPF
patients
• BAL DCC of
limited clinical
use in patients
with possible
UIP on HRCT
BAL = bronchoalveolar lavage; sEphrin-B2 = soluble ephrin-B2; DCC =
differential cell count; ; UIP = usual interstitial pneumonia; HRCT = high
resolution computed tomography
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Biomarkers for IPF Progression in Serum and Urine
• Several serum matrix metalloproteases (MMPs) were evaluated as
potential biomarkers for IPF. MMP-10 significantly correlated with FVC
predicted values and it’s concentration was significantly higher in
progressing patients compared to stable patients, suggesting MMP-10 as
a possible novel biomarker for IPF.1
• Elevated Prostaglandin E- Major Urinary Metabolite (PGE-MUM) levels
were found in the urine of patients with fibrotic lung diseases compared to
other lung diseases examined. PGE-MUM levels correlated with other
measures of fibrosis progression (fibrosing score, DLCO) and it might be a
potential new biomarker for fibrotic lung diseases.2
1. Sokai A, et al. AJRCCM 191;2015:A4375.
2. Hara H, et al. AJRCCM 191;2015:A1572.
• MMP-10
higher in
progressing
IPF patients
• PGE-MUM as
a novel
biomarker for
fibrotic lung
diseases
MMP = matrixmetalloprotease; UIP = usual interstitial pneumonia; HRCT =
high resolution computed tomography; PGE-MUM = prostaglandin E- major
urinary metabolite
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Interleukin Levels are Characteristic of
IPF Disease Progression
IL-4 and IL-13 protein concentrations in lung parenchyma were
analyzed in rapid progressors (characterized by FVC decline
≥10% or DLCO reduction ≥15% one year before transplantation)
and stable IPF patients.1
• Similar baseline characteristics
• Rapid progressors showed significantly elevated IL-4
concentrations
• A higher percentage of rapid progressors had detectable IL-13
concentrations
• Elevated IL-4 and IL-13 concentrations correlate with rapidly
progressive IPF.
• New studies are needed to determine the significance of
these findings for IPF prognosis and pathogenesis.
1. Huynh R. H, et al. AJRCCM 191;2015:A2166.
Do IL-4 and IL13 levels
correlate with
IPF disease
progression?
IL-4; IL-13 ↑
Stable IPF
n=14
Rapid
progression
n=56
IL-4/13 = Interleukin 4/13; FVC = forced vital capacity
DLCO = diffusion capacity for carbon monoxide
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Characteristic Gene Expression in IPF Cohorts
Gene expression
in a Czech cohort of IPF
patients (n=41) revealed
genetic variants (SNPs)
associated with IPF in
the following genes1:
•
MUC5B and MUC2 (mucin production in lungs)
•
OBFC1 (telomerase function)
•
TP53 (regulation of cell cycle)
Limb bud and heart development (LBH) gene expression as a potential
biomarker for IPF was analyzed in the Pittsburgh, LGRC and Comet cohorts.
LBH gene expression was shown to correlate with disease severity,
progression and outcome in IPF patients.2
1. Petrek M, et al. AJRCCM 191;2015:A4382.
2. Herazo-Maya J, et al. AJRCCM 191;2015:A4383.
SNP = single nucleotide polymorphism
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Peripheral Blood Expression Profile in
Patients with Severe IPF
Gene expression profiles were analyzed for IPF patients from the PROFILE study at baseline
(n=60) and over the course of 12 months (n=30)1
• The peripheral blood transcriptome of IPF patients is characteristic
• The study identifies new potential interactions between fibrotic pathways
1358 differentially expressed
transcript clusters in IPF
patients, including:
2 upregulated antimicrobial peptides
Genes known to be associated with IPF, e.g. MMP-9; DEFA-4
Host defense
Immune response
Response to bacteria
Genes correlating with survival, such as LCK, STAT4, TC2N
Genes with varying expression over 12 months and with significant
differences for progressive and stable patients, e.g. MMP9, LCK
1. Molyneaux P. L, et al. AJRCCM 191;2015:A2163.
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Acute Exacerbations of IPF
Markers and treatment evaluation
The preparation of the slide kit and video recording was sponsored by Boehringer Ingelheim and contains
personal opinions from leading ILD experts. ATS was neither author nor reviewer of the content.
Potential Triggers and Predictors of
Acute Exacerbations
• A case of an acute exacerbation as a complication of flexible cryoprobe transbronchial lung biopsy
(FCLB) has been reported. In contrast to transbronchial lung biopsy (TBLB), FCLB has not been
associated with AE-IPF previously and is considered the superior technique for the diagnosis of
ILDs.1
• Lung cancer patients can develop (treatment-induced) interstitial pneumonias and pulmonary
resection in these patients can lead to acute exacerbations (reported in about 10% of patients),
with a high risk of death. A retrospective study was able to confirm these results2:
 Acute exacerbations after surgery occurred in 5 out of 66 patients with lung cancer and interstitial pneumonia
(7.6%)
 3 of the 5 patients with acute exacerbations died
• The initial dose of prednisolone can be predictive of the outcome of acute exacerbations in IIP3
 In a comparison of low (≤0.5mg/kg; n=13) versus high dose (>0.5mg/kg; n=37) in IIP patients with an acute
exacerbation not treated with mechanical ventilation, low-dose prednisolone was
a significant poor prognostic factor of AE-IIP
1. Cortes Puentes G. A, et al. AJRCCM 191;2015:A4393.
2. Ishimoto H, et al. AJRCCM 191;2015:A4391.
3. Arai T, et al. AJRCCM 191;2015:A4385.
FCLB = flexible cryoprobe transbronchial lung biopsy; TBLB =
transbronchial lung biopsy; ILD = interstitial lung disease; IIP = idiopathic
interstitial pneumonia; AE = acute exacerbation
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
The Respiratory Microbiome is Changed in AE-IPF
A study with Korean IPF patients detected substantial
changes in the respiratory microbiome during acute
exacerbations1
• BAL of patients with AE-IPF (n=18) had a 4-times higher
yield of 16S RNA gene/ml compared to stable IPF (n=14)
BAL changes after AE-IPF
60% Proteobacteria
Patient 1
• Microbiome of stable IPF patients consisted mostly of
Firmicutes (34%), Proteobacteria (32%) and Bacteroidetes
(18%); AE-IPF patients had a similar profile, but with 40%
Proteobacteria
Patient 2
•
37% Ralstonia sp
•
6% Neisseria sp
Firmicutes and
Bacteroidetes phyla
•
38% Streptococcus sp
•
18% Prevotella sp
Despite what the current guidelines propose, there are detectable changes in the composition of the
respiratory microbiome during an AE-IPF, such as increased respiratory bacterial burden. It remains
unclear whether the microbial shift triggers the onset of AE or is a result of it.
1. Molyneaux P. L, et al. AJRCCM 191;2015:A2167.
AE = acute exacerbation; BAL = bronchoalveolar lavage
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Biomarkers Characterizing Acute Exacerbations of IPF
In 32 IPF patients after surgical lung biopsy, serum levels of the
glycoproteins angiopoietin-1 and -2 (Ang-1 and -2) correlated with
disease progression and time to acute exacerbation1
• Ang-2/Ang-1 ratio inversely correlated with the change in FVC and
with time to AE-IPF
• Ang-1 level correlated with the time to AE-IPF
Characterization of IPF patients with pneumomediastinum2
• Pneumomediastinum in patients with IPF is rare (5%; 9 out of 182
patients)
• Those patients are more likely to have advanced IPF (characterized
by several parameters) and have a significantly shorter survival rate
(overall survival 30 vs. 100 months)
1. Fujisawa T, et al. AJRCCM 191;2015:A4387.
2. Colombi D, et al. AJRCCM 191;2015:A4389.
• Ang-1 and
Ang-2 correlate
with disease
progression and
time to AE-IPF
• Pneumomediastinum is
a risk factor for
mortality and
disease severity
Ang = angiopoietin; AE = acute exacerbation
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Evaluation of Treatment for Acute Exacerbations of IPF
Positive results for
recombinant
thrombomodulin
(rTM) plus steroid
pulse therapy1
Negative results
for combination
therapy of
ECMO with
mechanical
ventilation2
10 AE-IPF patients were treated with rTM plus steroid pulse therapy. Compared to
conventional therapy, this group showed:
• Significantly improved PaO2/FiO2 ratio
• Significantly longer survival rate (153 days vs. 48 days)
• ECMO + mechanical ventilation (n=5) was compared to mechanical ventilation only
(n=5) in patients with AE-IPF
• This resulted in more severe lung injury with pulmonary hemorrhage and is not
recommended
1. Hayakawa S, et al. AJRCCM 191;2015:A4406.
2. Kolman D, et al. AJRCCM 191;2015:A4392.
AE = acute exacerbation; rTM = recombinant thrombomodulin; PaO2/FiO2
ratio = ratio of arterial oxygen partial pressure to fractional inspired oxygen;
ECMO = extracorporeal membrane oxygenation
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
IPF Pathobiology
Novel findings
The preparation of the slide kit and video recording was sponsored by Boehringer Ingelheim and contains
personal opinions from leading ILD experts. ATS was neither author nor reviewer of the content.
New Findings on IPF Pathobiology
A number of promising results on IPF translational pathogenesis were presented
• MUC5B and MUC5AC expression in IPF lungs was found to be higher than in
other ILDs1
• R-spondin-2 and its receptor LGR6 are upregulated in IPF and might contribute to
excessive fibroblast proliferation and reduced AEC apoptosis2
• Collagen IV secretion in IPF might result in less fibroblast migration
(through the FAK-pathway)3
• TMPRSS4 may be involved in pro-fibrotic processes in IPF and other fibrotic lung
diseases4
1.
2.
3.
4.
Conti C, et al. AJRCCM 191;2015:A2161.
Munguia A, et al. AJRCCM 191;2015:A2164.
Terasaki Y, et al. AJRCCM 191;2015:A2165.
Valero-Jimenez A. M, et al. AJRCCM 191;2015:A2168.
ILD = interstitial lung disease: AEC = alveolar epithelial cell
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Potential Involvement of Mucins in IPF
Characteristic distribution of mucin expression found in IPF lungs (UIP pattern;
n=23) compared to other ILDs (iNSIP; SSc-NSIP; OP; n=46)1
Higher expression of MUC5B in airways of IPF
patients compared to other ILDs
IPF lungs
MUC5B expression higher in airways than in
honeycomb cysts in IPF patients
MUC5B
MUC5AC
Higher expression of MUC5AC in IPF patients
compared to other ILDs
It is likely that mucins are specifically involved in IPF
1. Conti C, et al. AJRCCM 191;2015:A2161.
UIP = usual interstitial pneumonia; ILD = interstitial lung disease; i-NSIP =
idiopathic non-specific interstitial pneumonia; SSc-NSIP = sclerosis/systemic
sclerosis NSIP; OP = organising pneumonia
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Upregulation of R-Spondin2 and its
Receptor LGR6 in IPF
RSPO2 and its receptor LGR6 are upregulated in IPF and are mostly located in fibroblasts
and epithelial cells. Their precise role in IPF pathogenesis needs to be elucidated further.
• Over 100-fold
increased in IPF lungs
• Proteins localized in
fibroblasts and
epithelial cells
Gene expression modified by
RSPO2 in fibroblasts derived from
IPF vs. healthy lungs
Modified
gene expression
RSPO2 and LGR6
expression in IPF vs.
healthy lungs
3116
795
IPF Healthy
1. Munguia A, et al. AJRCCM 191;2015:A2164.
Pathways affected
include apoptosis,
cell cycle and ECM
metabolism
Effect of RSPO2 on
fibroblasts and AECs
• Reduced proliferation
in nomal fibroblasts
• No effect on IPF
fibroblasts
• AECs were protected
from TNFα-/IFNγinduced apoptosis
RSPO = R-spondin protein; ECM = extracellular matrix; AEC = alveolar epithelial cells
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
The Role of Collagen IV α1 and α2 in Fibrotic Processes
Collagen IV in IPF fibroblasts might result in less migration, adding to IPF pathogenesis.
In lung biopsy samples
The role of collagen IV in IPF fibroblasts
Collagen IV
FAK (P)
IPF fibroblasts secrete type IV collagen
UIP
+
-
-
OP
+
Reduced FAK(P)
Less migration
In cultured fibroblasts
+TGF β
+ α1 & α2 siRNA
+α1 & α2 protein
Collagen IV
α1 & α2
expression
FAK (P)
FAK (P)
Migration
Migration
Build-up of ECM in fibrotic lesions
1. Terasaki Y, et al. AJRCCM 191;2015:A2165.
IPF/UIP
UIP = usual interstitial pneumonia; OP = organizing pneumonia; FAK = focal
adhesion kinase; FAK(P) = phosphorylated FAK; ECM = extracellular matrix
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Pro-fibrotic Role of the Cell Surface Protein
TMPRSS4 in IPF
Expression and localization of TMPRSS4 in lungs
IPF
Healthy
qPCR
Antibody stain
+
+ Mast cells
+ Epithelial cells
In vivo effect of TMPRSS4 in mouse
model (bleomycin-induced IPF)
vs.
-
wt
Expression of TMPRSS4 in cultured cells (qPCR)
Fibroblasts
-
Alveolar ECs
+
Bronchial ECs
+
1. Valero-Jimenez A. M, et al. AJRCCM 191;2015:A2168.
TMPRSS4
(+/-)
TMPRSS4(+/-) mice
displayed a lesser
fibrotic response
TMPRSS4
could be
involved in
pro-fibrotic
processes
in IPF and
other
fibrotic lung
diseases
TMPRSS4 = a type II transmembrane serine protease; EMT = epithelial to
mesenchymal transition; EC = epithelial cell
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
IPF Future Challenges
The preparation of the slide kit and video recording was sponsored by Boehringer Ingelheim and contains
personal opinions from leading ILD experts. ATS was neither author nor reviewer of the content.
New Challenges for the IPF Community*
Find new therapeutic targets
Improve clinical trials and clinical care
Analyze genetic pre-disposition
Integrate real-life experiences
*As discussed by several speakers during ATS
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Analyze genetic pre-disposition
Treatment
outcomes
Clinical
trials
The genetic predisposition of IPF patients might be important for
treatment outcomes
Clinical trials should take genetic pre-disposition into account
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Genetic Predisposition of IPF Patients in Clinical Trials1
The genetic profiles of a subgroup of patients enrolled in
the PANTHER-IPF trial were compared to IPF patients
enrolled in a GWAS study
MAF of IPF-associated SNPs (1xMUC5B; 4xTOLLIP) was
compared between a PANTHER subgroup and a GWAS
IPF population and between PANTHER treatment arms
• Significant MAF over-representation of two SNPs
found in PANTHER vs. GWAS population
• MAF imbalance between the PANTHER treatment
and placebo arms detected in 3 SNPs (PAN or NAC
vs. placebo)
• No SNP appeared to be an independent predictor of
composite endpoint risk (death, hospitalization or
10% FVC decline)
• The minor allele of rs3750920 (TOLLIP) changed the
endpoint risk associated with NAC
1. Oldham J. M, et al. AJRCCM 191;2015:A2162.
PAN triple
therapy
PANTHER
subgroup
(n=165)
IPF GWAS
patients
(n=868)
NAC
monotherapy
Placebo
SNP = single nucleotide polymorphism; GWAS = genome-wide association study;
MAF = minor allele frequency; NAC = N-acetylcysteine; PAN = prednisone,
azathioprine, NAC
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Improving Clinical Trials and Clinical Care for IPF*
Improve design and outcomes
Global sharing of clinical data
• Background therapy/standard-of-care instead of
placebo will result in:
• Assign global unique identifiers (GUID) for study
objects and create a common data element set for
ILD
 Slowed disease progression and prolonged time
to events
• Requirements for a shared data platform include1:
 Weaker effect for add-on drugs
 Centralized IPF clinical trials network
 Possible reluctance of patients to enter new trials
 One central repository for academic and
commercial trial data
• New surrogate endpoints (composite endpoints)
should be considered since FVC may not reflect on
survival or other significant primary endpoints
 Data of high standard, independently reviewed,
downloadable, harmonized and global
• Characterize IPF genotypes and their implications on
treatment outcomes
1. Collard H. R, et al. ERJ ERJ-02006-2014 – published ahead of print
*As discussed by several speakers during ATS
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Global ILD Registries
There is a need for multinational collaborations to
address clinically relevant questions1
Why are global ILD registries needed?
• IPF is an uncommon and heterogeneous disease
• Diagnosis is often delayed or inaccurate
• It is difficult to combine data from different IPF cohorts
• Real-life experience has to be monitored
Several national registries exist to date (not overarching or
linked), for example,
• INSIGHTS-IPF-Registry2: 30 European centers,
prospective
• PROOF-Registry3: multinational, observational,
prospective
Registries can provide multiple benefits
Quality control
Disease mechanism studies
Subgroup comparison
Outcome determination
1. Ryerson C, et al. ERJ 2014;44:273–276.
2. Behr J, et al. ERS Express 2015; in press.
3. Wuyts W, et al. AJRCCM 191;2015:A2506.
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Summary of ATS 2015
The preparation of the slide kit and video recording was sponsored by Boehringer Ingelheim and contains
personal opinions from leading ILD experts. ATS was neither author nor reviewer of the content.
Standard of Care for IPF Diagnosis
• Timely diagnosis is important
• IPF diagnosis should strictly follow
the recommendations of international
guidelines1 (currently in revision)
• Patients with suspected IPF should
be transferred to ILD specialists and
multidisciplinary team discussion
since diagnosis can be very difficult
Timely diagnosis
International guidelines
ILD specialists
Multidisciplinary team discussion
1. Raghu G, et al. AJRCCM 2011;183(6):788-824.
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Standard of Care for IPF Management
Treatment
Management
• IPF management should strictly follow the
recommendations of international guidelines1
(currently in revision)
• Symptoms (such as cough) and comorbidities (such
as GERD) should be managed aggressively
 Pirfenidone & nintedanib are now recommended
for treatment of IPF according to the updated
international guidelines2
• Early start of treatment is needed (treatment
response is the same in early and late IPF)
• Lung transplantation should always be considered
• Other measures include smoking cessation,
exercise/pulmonary rehabilitation, supplemental
oxygen, vaccination
• Mechanical ventilation after exacerbations should be
avoided (increased risk of death)
• A good rapport between physician and patient,
communication and patient education are key to
successful therapy (it has to be stressed that there is
no cure for IPF and that approved drugs can only
slow disease progression)
1. Raghu G, et al. AJRCCM 2011;183(6):788-824.
2. ATS 2015, Raghu G. C92. Oral presentation.
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.
Take-Home Messages
New data have been presented for nintedanib and pirfenidone safety and efficacy
A phase 3 trial with co-trimoxazole (EME-TIPAC) for IPF treatment is under way
Numerous new biomarkers have been suggested for IPF diagnosis, evaluation of
progression or disease severity
Advances have been made in understanding IPF pathobiology
New challenges include improved clinical trial design (including standard of care and genetic
predisposition), establishing global IPF registries and sharing IPF patient data
The genetic predisposition of IPF patients needs to be accounted for in clinical trials
ATS Highlights 2015 Slide Kit. Sponsored by Boehringer Ingelheim; not reviewed or approved by ATS.