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Focus on Idiopathic Pulmonary Fibrosis: Advancing Approaches to Diagnosis, Prognosis, and Treatment Discussion Points Diagnosis Prognosis Therapy Imminent future 2

Idiopathic Pulmonary to and - courses.elseviercme.com on Idiopathic Pulmonary... · PBMC Gene Expression Predicts Poor Outcome in IPF 25 Reprinted from The Lancet Respiratory Medicine,

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Focus on Idiopathic Pulmonary Fibrosis: Advancing Approaches toDiagnosis, Prognosis, and Treatment

Discussion Points

Diagnosis 

Prognosis 

Therapy 

Imminent future

2

Discussion Points (con't)

Diagnosis– Overview of current approach to IPF

– Approach to CTD

– Approach to HP

– Evolving imaging criteria

– Role of bronchoscopy

– Role of lung biopsy

– Role of MDT

– Future of biomarker‐driven diagnostics

3

IPF Diagnosis: Current Approach

4

IPF

Suspected ILD

Identifiable cause?

Chest HRCT

NO

YES

UIP

Surgical lung biopsy

Possible UIPInconsistent with UIP

Not UIP

UIPProbable UIPPossible UIP

Not IPFIPF/Not IPF

MDD

IPF

Suspected ILD

Identifiable cause?

Chest HRCT

NO

YES

UIP

Surgical lung biopsy

Inconsistent with UIP

Probable UIP

Reprinted from The Lancet Respiratory Medicine, vol. 5, Martinez FJ, Chisholm A, Collard HR, et al, The diagnosis of idiopathic pulmonary fibrosis: current and future approaches, 61-71, Copyright 2017, with permission from Elsevier.

OR per 5‐year Age 

Increment

Age (Yrs)

Salisbury ML et al. Respir Med. 2016;118:88-95; Reproduced from Thorax, Brownell R, Moua T, Henry TS, et al, 72(5), 424-429, 2017, with permission from BMJ Publishing Group Ltd.

IPF Becomes Increasingly Likely As the Age of the Patient Increases

5

OR per 5‐year Age 

Increment

Age (Yrs)

IPF Becomes Increasingly Likely As the Age of the Patient Increases

6Salisbury ML et al. Respir Med. 2016;118:88-95; Reproduced from Thorax, Brownell R, Moua T, Henry TS, et al, 72(5), 424-429, 2017, with permission from BMJ Publishing Group Ltd.

IPF vs CT ILD Survival in 2 Cohorts

7

Reprinted with permission of the American Thoracic Society. Copyright © 2018 American Thoracic Society. Park JH, Kim DS, Park IN, et al. 2007, Prognosis of fibrotic interstitial pneumonia: idiopathic versus collagen vascular disease-related subtypes. Am J Respir Crit Care Med. 175/7:705-711. The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society; Moua T, Zamora Martinez AC, Baqir M, Vassallo R, Limper AH, Ryu JH. Predictors of diagnosis and survival in idiopathic pulmonary fibrosis and connective tissue disease-related usual interstitial pneumonia. Respiratory Research. 2014;15:154. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4264556/pdf/12931_2014_Article_154.pdf. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) and is available under Public License, https://creativecommons.org/licenses/by/4.0/legalcode.

A Possible Approach to CTD Evaluation

8

History• Joint pain, stiffness, or swelling• Skin thickening or tightening• Rash in sun‐exposed areas• Dryness of the eyes or mouth• Raynaud’s• Heartburn/Regurgitation• Family history of CTD

Physical Examination• Joints• Skin• Hands

Jee AS, Adelstein S, Bleasel J, et al. Role of autoantibodies in the diagnosis of connective-tissue disease ILD (CTD-ILD) and interstitial pneumonia with autoimmune features (IPAF). Journal of Clinical Medicine. 2017;6(5):E51. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5447942/. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) and is available under Public License, https://creativecommons.org/licenses/by/4.0/legalcode.

Taking a Detailed History Can Help Identify Hypersensitivity Pneumonitis

“Dampness” and mold exposure in the home or workplace– Water damage: flooding; leaking pipes– Standing water: hot tubs, humidifiers– Visible mold– Home ventilation systems, particularly with heat or humidification

Animal exposures– Birds– Down/Feather bedding

Ask about a “second/summer home” and hobbies

9

HRCT Criteria for Usual Interstitial Pneumonia (UIP) Pattern

UIP Pattern (All 4 Features)

Possible UIP (All 3 Features)

Inconsistent with UIP (any)

Subpleural, basal predominance

Reticular abnormality Honeycombing 

with/without traction bronchiectasis

Absence of features listed as inconsistent with UIP (column 3)

Subpleural, basal predominance

Reticular abnormality Absence of features listed as 

inconsistent with UIP (column 3)

Upper or mid‐lung predominance Peribronchovascular

predominance Extensive ground glass 

abnormality (extent > reticular abnormality)

Profuse micronodules (bilateral, predominantly upper lobe)

Discrete cysts (multiple, bilateral, away from areas of honeycombing)

Diffuse mosaic attenuation/air‐trapping (bilateral, in 3 or more lobes)

Consolidation in bronchopulmonary segment(s)/lobe(s)

10

Reprinted with permission of the American Thoracic Society. Copyright © 2018 American Thoracic Society. Raghu G, Collard HR, Egan JJ, et al; ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. 2011, An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 183(6):788-824. The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.

Subgroup Analysis by HRCT Diagnostic Subgroups

-108.7 -122.0

-225.7 -221.0

-300

-250

-200

-150

-100

-50

0n=425 n=298 n=213 n=125

Honeycombing on HRCT and/or confirmation of UIP pattern by

surgical lung biopsy

Features of possible UIP pattern* on HRCT and no

surgical lung biopsy

Nintedanib Placebo

Adju

sted

ann

ual r

ate

(SE)

of d

eclin

e in

FV

C (m

L/ye

ar)

Treatment-by-time-by-subgroup interaction

p=0.8139

∆117.0 mL (95% CI: 76.3,

157.8)

∆98.9 mL(95% CI: 36.4,

161.5)

*And traction bronchiectasis.

11Reprinted with permission of the American Thoracic Society. Copyright © 2018 American Thoracic Society. Raghu G, Wells AU, Nicholson AG, et al. 2017, Effect of nintedanib in subgroups of idiopathic pulmonary fibrosis by diagnostic criteria. Am J Respir Crit Care Med. 195(1):78-85.The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.

Fleischner HRCT Criteria for UIP Pattern

Typical UIP  Probable UIP  Indeterminate UIP Non‐IPF pattern

Distribution Basal(occasionally diffuse) Subpleural Often heterogeneous

Subpleural Basal predominance Often heterogeneous

Variable or diffuse

Upper or mid‐lung Peribronchovascular Subpleural sparing

Features Honeycomb Reticular with peripheral traction bronchiectasis or bronchiolectasis Absence of alternate features

Reticular with peripheral traction bronchiectasis or bronchiolectasis No honeycombing Absence of alternate features

Fibrosis with some inconspicuousnon‐UIP features

Any of the following: Predominant consolidation Extensive GGO Extensive mosaicism Diffuse nodules or cysts

12

Reprinted from The Lancet Respiratory Medicine, Lynch DA, Sverzellati N, Travis WD, et al, Diagnostic criteria for idiopathic pulmonary fibrosis: a Fleischner Society White Paper, doi: 10.1016/S2213-2600(17)30433-2 [Epub ahead of print], Copyright 2017, with permission from Elsevier. http://dx.doi.org/10.1016/S2213-2600(17)30433-2. Accessed December 30, 2017.

ILA Associated With  Risk for Mortality

13

Reproduced with permission from JAMA. 2016. Putman RK, Hatabu H, Araki T, et al; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators; COPDGene Investigators. Association between interstitial lung abnormalities and all-cause mortality. 315(7):672-681. Copyright © 2016. American Medical Association. All rights reserved.

Rough Summary of Cryobiopsy

Study Bleeding PTX

Kropski JA et al. 0/25 (0%) 0/25 (0%)

Pajares V et al. 22/39 (56%) 3/39 (8%)

Casoni GL et al. 1/69 (1%) 19/69 (28%)

Griff S et al. None None

Hernández‐González F et al. 10/33 (30%) 4/33 (12%)

Hagmeyer L et al.17/32 (53%) 6/32 (19%)

Tomassetti S et al. NR NR

Poletti V. None 60/297 (20%)

Lentz RJ et al.4/104 (4%) 3/104 (3%)

OVERALL EXPERIENCE 54/709(8%) 95/709(13%)

14

Diagnostic Yield SafetyStudy Yield

Kropski JA et al.PLoS One. 2013;8(11):e78674

20/25 (80%)

Pajares V et al. Respirology. 2014;19(6):900‐906.

20/39 (52%)

Casoni GL et al.PLoS One. 2014;9(2):e86716.

36/69 (52%)

Griff S et al. BMC Pulm Med. 2014;14:171.

41/52 (79%)

Hernández‐González F et al.Arch Bronconeumol. 2015; 51(6):261‐267.

26/33 (79%)

Hagmeyer L et al. Clin Respir J. 2016;10(5):589‐595.

23/32 (72%)

Tomassetti S et al.Am J Resir Crit Care Med. 2016;193(7):745‐752.

40/58 (69%)

Poletti V.Respiration. 2016;91(4):350.

246/297 (83%)

Lentz RJ et al. J BronchologyInterv Pulmonol. 2017 Aug 7. [Epub ahead of print] 

71/104 (68%)

OVERALL EXPERIENCE 523/605 (74%)

Diagnostic Yield in 15 studies of 781 patients 

– 81%[Meta‐analysis]

Safety/Complications in 15 studies of 994 patients –Pneumothorax 10%; 

Moderate bleeding 12%[Meta‐analysis]

MDT Diagnosis Results in Greater Prognostic Accuracy

MDT=multidisciplinary team; MDTM=multidisciplinary team meeting.

15

Reprinted from The Lancet Respiratory Medicine, vol. 4, Walsh SL, Wells AU, Desai SR, et al, Multicentre evaluation of multidisciplinary team meeting agreement on diagnosis in diffuse parenchymal lung disease: a case-cohort study, 557-565, Copyright 2016, with permission from Elsevier.

Unclassifiable ILD Remains Despite All of This Advance

16Reprinted from Chest, 145/4, Ryerson CJ, Vittinghoff E, Ley B, et al, Predicting survival across chronic interstitial lung disease: the ILD-GAP model, 723-728, Copyright 2014, with permission from Elsevier; Hyldgaard C et al. Respirology. 2017;22(3):494-500.

Unclassifiable ILD Remains Despite All of This Advance

17

Unclassifiable ILD in 105/403 (24%)

Unclassifiable ILD in 173/1012 (17%)

Reprinted from Chest, 145/4, Ryerson CJ, Vittinghoff E, Ley B, et al, Predicting survival across chronic interstitial lung disease: the ILD-GAP model, 723-728, Copyright 2014, with permission from Elsevier; Hyldgaard C et al. Respirology. 2017;22(3):494-500.

18Martinez FJ et al. Nat Rev Dis Primers. 2017;3:17074.

Wide Variety of Prognostic Biomarkers Are In Play

With Optimal Results Seen With Five TBBxYielding Excellent Sensitivity/Specificity

Number of random samples to mix

AUC

Mixing 5 is the best

Classification Result

Non-UIP UIP

Central Pathology Label

Non-UIP 22 3

UIP 8 16

Specificity 0.88 (0.68 - 0.97)

Sensitivity 0.67 (0.45-0.84)

Pankratz DG et al. Ann Am Thorac Soc. 2017;14(11):1646-1654.19

Future Diagnostic Approach

20Reprinted from The Lancet Respiratory Medicine, vol. 5, Martinez FJ, Chisholm A, Collard HR, et al, The diagnosis of idiopathic pulmonary fibrosis: current and future approaches, 61-71, Copyright 2017, with permission from Elsevier.

Discussion Points (con't)

Diagnosis

Prognosis

Therapy

21

Traditional Prognostic Factors

Age

FVC

DLCO

Exertional desaturation

Decline in FVC or DLCO

Oxygen requirement

22

HRCT Imaging Features Are Prognostic

23

Reprinted from Respiratory Medicine, vol. 131, Salisbury ML, Tolle LB, Xia M, et al, Possible UIP pattern on high-resolution computed tomography is associated with better survival than definite UIP in IPF patients, 229-235, Copyright 2017, with permission from Elsevier.

24Martinez FJ et al. Nat Rev Dis Primers. 2017;3:17074.

Wide Variety of Prognostic Biomarkers Are In Play

PBMC Gene Expression Predicts Poor Outcome in IPF

25

Reprinted from The Lancet Respiratory Medicine, vol. 5, Herazo-Maya JD, Sun J, Molyneaux PL, et al, Validation of a 52-gene risk profile for outcome prediction in patients with idiopathic pulmonary fibrosis: an international, multicentre, cohort study, 857-868, Copyright 2017, with permission from Elsevier.

26Huang Y et al; COMET-IPF Investigators. Am J Respir Crit Care Med. 2017;196(2):208-219.

Gene Expression Signature Linked to Survival‐associated (TLR) 

Pathways and Inversely Linked to Microbial “Richness”

Discussion Points (con't)

Diagnosis

Prognosis

Therapy

– Which agent?

– Whom to treat?

– How to assess response?

27

TreatmentStrong  For

ConditionalFor

Conditional Against

StrongAgainst

Bosentan/Macitentan X

Ambrisentan X

Imatinib X

NAC/Azathioprine/Prednisone X

NAC X

Anticoagulation X

Pirfenidone X

Nintedanib X

Antacid therapy X

Sildenafil X

Raghu G et al; American Thoracic Society; European Respiratory Society; Japanese Respiratory Society; Latin American Thoracic Association. Am J Respir Crit Care Med. 2015;192(2):e3-e19.):E3-E19.

28

An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatmentof Idiopathic Pulmonary Fibrosis: An Update of the 2011 Clinical Practice Guideline

Discuss the efficacy and safety of FDA‐approved therapies

Listen to patient’s preferences and concerns

Focus on symptom control and management of comorbidities

Set treatment expectations

Look at the option of lung transplantation

Treatment options

Risks and benefits

Personal preferences

Values and concerns

Physician provides Patient provides

Mutually acceptable decision

Engaging in a Shared Decision‐Making Process

29

Network Meta‐analysis Suggests Little Difference Between Pirfenidone and Nintedanib Percent % FVC Decrease 10

0.01 0.1 1 10 100

Pirfenidone vs placebo

Nintedanib vs placebo

Pirfenidone vs nintedanib

0.52 (0.41‐0.67)

0.61 (0.48‐0.78)

0.86 (0.60‐1.20)

Adapted from Canestaro WJ et al. Chest. 2016;149(3):756-766.30

Pirfenidone and Nintedanib Attenuate Loss of FVC Across Multiple Patient Subgroups

Pirfenidone Nintedanib

31

Reproduced with permission of European Respiratory Society. Noble PW et al. Eur Respir J. 2016;47:243-253; Reprinted with permission of the American Thoracic Society. Copyright © 2018 American Thoracic Society. Costabel U, Inoue Y, Richeldi L, et al. 2016, Efficacy of nintedanib in idiopathic pulmonary fibrosis across prespecified subgroups in INPULSIS. Am J Repir Crit Care Med. 193(2):178-185. The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.

Patterns of Pirfenidone Discontinuation in RECAP

32

Reasons for Discontinuation Number of Discontinuations

Reproduced with permission of European Respiratory Society. Costabel U et al. European Respiratory Journal. 2017;50(suppl 61):Abstract OA3399.

Long‐term Safety of Pirfenidone in Real‐World Setting (PASSPORT Registry)

33

European Registry of IPF patients newly prescribed pirfenidone

Followed for 2 years after first prescription

Adapted from Cottin V et al. European Respiratory Journal. 2017;50(suppl 61):Abstract PA2806.

Change in FVC After Initial 10% FVC Decrease in CAPACITY/ASCEND Trials

34

Event Pirfenidone (n=34)

Placebo (n=68)

P value

> 10%  in FVC or death

2 (5.9%) 19 (27.9%) .009

No further in FVC

20 (58.8%) 26 (38.2%) .059

Death 1 (2.9%) 14 (20.6%) .018

Nathan SD, Albera C, Bradford WZ, et al. Effect of continued treatment with pirfenidone following clinically meaningful declines in forced vital capacity: analysis of data from three phase 3 trials in patients with idiopathic pulmonary fibrosis. Thorax. 2016;71(5):429-435. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4862066/pdf/thoraxjnl-2015-207011.pdf. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) and is available under Public License, https://creativecommons.org/licenses/by/4.0/legalcode.

Long‐term Tolerability of Nintedanib(INPULSIS®‐ON)

35Crestani B et al. Presented at: European Respiratory Society (ERS) International Congress; September 9-13, 2017; Milan, Italy. Abstract OA3402.

Long‐term Tolerability of Nintedanib(INPULSIS®‐ON)

36Crestani B et al. Presented at: European Respiratory Society (ERS) International Congress; September 9-13, 2017; Milan, Italy. Abstract OA3402.

Most frequent adverse events leading to treatment discontinuation in INPULSIS® and INPULSIS®‐ON

Progression of IPF

Diarrhoea

Weight decreased

Nausea

Impact of FVC Decline in Nintedanib‐Treated Patients 

FVC Decline in INPULSIS® and INPULSIS®‐ON

37Adapted from Richeldi L et al. European Respiratory Journal. 2017;50(suppl 61):Abstract PA4892.

Recruiting Clinical Trials for IPF

38

Intervention Target Phase StatusGSK3008348 αvβ6 integrin 1 Recruiting

Dasatinib + quercetin BCR‐ABL + COX/LOX 1 Recruiting

KD025 ROCK2 2 Recruiting

Pirfenidone + sildenafil Multiple + PDEs 2 Recruiting

Tipelukast LT + PDE3/4, 5‐LO 2 Recruiting

GBT440 Hemoglobin 2 Recruiting

GLPG1690 Autotaxin 2 Recruiting

Rituximab Autoantibodies 2 Recruiting

Nintedanib + sildenafil TKs + PDEs 3 Recruiting

Nebulized fentanyl Dyspnea 3 Recruiting

Cotrimoxazole or doxycycline

Lung microbiome 3 Recruiting

Palliative care Your patient N/A Recruiting

Home‐basedrehabilitation

Your patient – Recruiting

Azithromycin Cough – Recruiting

www.clinicaltrials.gov. Accessed October 19, 2017.

IPF Studies Closed to Enrollment

39

Intervention Mechanism/Target Phase  Trial Status

Autologous mesenchymal stem cells

Immunomodulation 1

Ongoing

FG‐3019 Anti‐CTGF (FG‐3019) 2

Lebrikizumab Anti‐IL‐13 2

PRM‐151 Pentraxin‐2 2

Sirolimus mTOR inhibition ‐‐

Laparoscopic antireflux surgery Gastroesophageal reflux 2

Tralokinumab Anti‐IL‐13 2

Completed

Pamrevlumab Anti‐CTGF (FG‐3019) 2

Carbon monoxide Injury/inflammation 2

PBI‐4050 Anti‐fibrotic 2

SAR156597  Anti‐IL‐4, Anti‐IL‐13  2

www.clinicaltrials.gov. Accessed October 19, 2017.

IPF Studies Closed to Enrollment

40

Intervention Mechanism/Target Phase  Trial Status

Autologous mesenchymal stem cells

Immunomodulation 1

Ongoing

FG‐3019 Anti‐CTGF (FG‐3019) 2

Lebrikizumab Anti‐IL‐13 2

PRM‐151 Pentraxin‐2 2

Sirolimus mTOR inhibition ‐‐

Laparoscopic antireflux surgery Gastroesophageal reflux 2

Tralokinumab Anti‐IL‐13 2

Completed

Pamrevlumab Anti‐CTGF (FG‐3019) 2

Carbon monoxide Injury/inflammation 2

PBI‐4050 Anti‐fibrotic 2

SAR156597  Anti‐IL‐4, Anti‐IL‐13  2

A Phase II Clinical Trial of Low‐Dose Inhaled Carbon Monoxide in Idiopathic Pulmonary Fibrosis

Rosas IO, Goldberg HJ, Collard HR, El‐Chemaly S, Flaherty K, Hunninghake GM, Lasky JA, Lederer DJ, Machado R, Martinez FJ, Maurer R, Teller D, Noth I, Peters E, Raghu G, Garcia 

JGN, and Choi AMK.

Conclusions: Inhaled CO is well tolerated and can be safely administered to IPF patients in the ambulatory setting; however, 

inhaled CO did not result in significant changes in prespecified study endpoints. The feasibility of administering outpatient inhaled therapies for the treatment of IPF is encouraging and should be 

pursued in future studies.

Chest 2017; Published on‐line as 10.1016/j.chest.2017.09.052

www.clinicaltrials.gov. Accessed October 19, 2017.

IPF Studies Closed to Enrollment

41www.clinicaltrials.gov. Accessed October 19, 2017.

Intervention Mechanism/Target Phase  Trial Status

Autologous mesenchymal stem cells

Immunomodulation 1

Ongoing

FG‐3019 Anti‐CTGF (FG‐3019) 2

Lebrikizumab Anti‐IL‐13 2

PRM‐151 Pentraxin‐2 2

Sirolimus mTOR inhibition ‐‐

Laparoscopic antireflux surgery Gastroesophageal reflux 2

Tralokinumab Anti‐IL‐13 2

Completed

Pamrevlumab Anti‐CTGF (FG‐3019) 2

Carbon monoxide Injury/inflammation 2

PBI‐4050 Anti‐fibrotic 2

SAR156597  Anti‐IL‐4, Anti‐IL‐13  2

FibroGen Presents Latest Data From Phase 2b Study of Pamrevlumab in Idiopathic Pulmonary Fibrosis at European 

Respiratory Society (ERS) International Congress 2017

Pamrevlumab met the primary endpoint of FVC % predicted with statistical significance, as well as absolute FVC volume: in this study, the primary endpoint was met as the average decline in FVC % predicted of 2.85 in the pamrevlumab arm was statistically smaller than 

the average decline of 7.17 in the placebo arm, a difference of 4.33. These results are consistent with the decline in FVC % predicted by 2.29 observed in a subgroup of similar pamrevlumab‐treated patients in an earlier phase 2 open‐label IPF study. 

Is IPF Combination Therapy the Answer?

Combination Therapy and the Start of a New Epoch for Idiopathic Pulmonary Fibrosis?

Maher TM

Maher TM. Am J Respir Crit Care Med. 2018;197(3):283-284.42

NHLBI‐funded “large simple” trial

IPF—“all comers”

Intervention: Cotrimoxazole (or doxycycline)

Control: Standard of care

Primary outcome: Time to respiratory hospitalization or death

Currently open to enrollment

Ongoing Studies With Cotrimoxazole

43ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02759120. Updated November 8, 2017. Accessed December 29, 2017; BioMed Central Ltd. http://www.isrctn.com/ISRCTN17464641. Accessed December 29, 2017.

CleanUP IPF

National Institute for Health Research (UK) trial

IPF

Intervention: Cotrimoxazole

Control: Placebo

Primary outcome: Time to death (all causes), lung transplant, or first nonelective hospital admission

Currently open to enrollment

EME‐TIPAC

INJOURNEY™ Study Results: NintedanibWith Add‐On Pirfenidone

Nintedanib150 mg bidWith Add‐On Pirfenidone(n = 53), n (%)

Nintedanib150 mg bid(n = 51), n (%)

Any AE(s) 47 (88.7) 45 (88.2)

Most frequent AEs

Diarrhea 20 (37.7) 16 (31.4)

Nausea 22 (41.5) 6 (11.8)

Vomiting 15 (28.3) 6 (11.8)

Fatigue 10 (18.9) 6 (11.8)

Upper abdominal pain

7 (13.2) 4 (7.8)

Decrease appetite 6 (11.3) 5 (9.8)

Dyspnea 2 (3.8) 8 (15.7)

Headache 7 (13.2) 1 (2.0)

Any SAE(s) 2 (3.8) 5 (9.8)

Any fatal AE(s) 0 0

44Reprinted with permission of the American Thoracic Society. Copyright © 2018 American Thoracic Society. Vancheri C, Kreuter M, Richeldi L, et al; INJOURNEY Trial Investigators. 2018, Nintedanib with add-on pirfenidone in idiopathic pulmonary fibrosis. Results of the INJOURNEY Trial. Am J RepirCrit Care Med. 197(3):356-363. The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.

Safety of Combined Pirfenidone and Nintedanibin Patients With Idiopathic Pulmonary Fibrosis

45Flaherty KR et al. Presented at: European Respiratory Society (ERS) International Congress; September 9-13, 2017; Milan, Italy. Abstract PA2805.

Weighing Risks and Benefits of Laparoscopic Anti‐Reflux Surgery in Patients With IPF (WRAP‐IPF)

46ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01982968. Updated October 26, 2016. Accessed December 29, 2017.

Phase 2 

Primary outcome: decline in FVC between enrollment and 48 weeks

Enrollment 58

Estimated completion November 2017

Inclusion criteria:– Confirmed diagnosis of idiopathic pulmonary fibrosis

– Abnormal GER on 24‐hour pH monitoring (DeMeester score > 14.7)

– Able to provide informed consent

– Willing to undergo laparoscopic anti‐reflux surgery

Discussion Points (con't)

Diagnosis

Prognosis

Therapy

Imminent future

47

Nintedanib Clinical Trials in ILDs

48ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03062943. Updated February 24, 2017. Accessed December 29, 2017; ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02999178. Updated December 25, 2017. Accessed December 29, 2017; ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02597933. Updated December 4, 2017. Accessed December 29, 2017.

A Study of Nintedanib for LymphAngioleioMyomatosis (LAM)

• Recruiting participants for open‐label, phase 2 trial

Efficacy and Safety of Nintedanib in Patients With Progressive Fibrosing Interstitial Lung Disease (PF‐ILD)

• Recruiting participants for double‐blind, randomized, placebo‐controlled phase 3 trial

SENSCIS (Safety and Efficacy of Nintedanib in Systemic SClerosIS) Study

• Recruiting patients with scleroderma‐related lung fibrosis for double‐blind, randomized, placebo‐controlled phase 3 trial

Pirfenidone Clinical Trials in ILDs

49Khanna D et al. J Rheumatol. 2016;43(9):1672-1679; ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02808871. Updated June 14, 2017. Accessed December 29, 2017; ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02958917. Updated May 3, 2017. Accessed December 29, 2017; ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03099187. Updated December 22, 2107. Accessed December 39, 2017.

Safety and Tolerability of Pirfenidone in Par cipants With Systemic Sclerosis−Related Inters al Lung Disease (SSc‐ILD) (LOTUSS)

• Open‐label, phase 2 trial is completed 

Phase 2 Study of Pirfenidone in Patients With RA‐ILD

• Recruiting participants for randomized, placebo‐controlled phase 2 study

Study of Efficacy and Safety of Pirfenidone in Patients With Fibrotic HP Study

• Recruiting participants for randomized, placebo‐controlled trial

A Study of Pirfenidone in Patients With Unclassifiable Progressive Fibrosing ILD

• Recruiting participants for double‐blind, randomized, placebo‐controlled phase 2 trial

Nintedanib Clinical Trials in ILDs

50ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03062943. Updated February 24, 2017. Accessed December 29, 2017; ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02999178. Updated December 25, 2017. Accessed December 29, 2017; ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02597933. Updated December 4, 2017. Accessed December 29, 2017.

A Study of Nintedanib for LymphAngioleioMyomatosis (LAM)

• Recruiting participants for open‐label, phase 2 trial

Efficacy and Safety of Nintedanib in Patients With Progressive Fibrosing Interstitial Lung Disease (PF‐ILD)

• Recruiting participants for double‐blind, randomized, placebo‐controlled phase 3 trial

SENSCIS (Safety and Efficacy of Nintedanib in Systemic SClerosIS) Study

• Recruiting patients with scleroderma‐related lung fibrosis for double‐blind, randomized, placebo‐controlled phase 3 trial

Discussion Points (con't)

Diagnosis

Prognosis

Therapy

Imminent future

51

52

Conclusions