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

Transcription

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

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 Suspected ILD UIP Identifiable cause? NO Chest HRCT YES YES Possible UIP Inconsistent with UIP Not UIP Surgical lung biopsy UIP Probable UIP Possible UIP MDD IPF IPF/Not IPF Not IPF 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. 4

3 IPF Becomes Increasingly Likely As the Age of the Patient Increases 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), , 2017, with permission from BMJ Publishing Group Ltd. 5 IPF Becomes Increasingly Likely As the Age of the Patient Increases 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), , 2017, with permission from BMJ Publishing Group Ltd. 6

4 IPF vs CT ILD Survival in 2 Cohorts 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: 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: This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) and is available under Public License, 7 A Possible Approach to CTD Evaluation 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. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) and is available under Public License, 8

5 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) Subpleural, basal predominance Reticular abnormality Honeycombing with/without traction bronchiectasis Absence of features listed as inconsistent with UIP (column 3) Possible UIP (All 3 Features) Subpleural, basal predominance Reticular abnormality Absence of features listed as inconsistent with UIP (column 3) Inconsistent with UIP (any) 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/airtrapping (bilateral, in 3 or more lobes) Consolidation in bronchopulmonary segment(s)/lobe(s) 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): The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society. 10

6 Subgroup Analysis by HRCT Diagnostic Subgroups Adjusted annual rate (SE) of decline in FVC (ml/year) 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 n=425 n=298 n=213 n=125 Nintedanib *And traction bronchiectasis ml (95% CI: 76.3, 157.8) Placebo ml (95% CI: 36.4, 161.5) Treatment-by-time-bysubgroup interaction p= Reprinted 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): The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society. 11 Fleischner HRCT Criteria for UIP Pattern Distribution Features Typical UIP Probable UIP Indeterminate UIP Non IPF pattern Basal (occasionally diffuse) Subpleural Often heterogeneous Honeycomb Reticular with peripheral traction bronchiectasis or bronchiolectasis Absence of alternate features Subpleural Basal predominance Often heterogeneous Reticular with peripheral traction bronchiectasis or bronchiolectasis No honeycombing Absence of alternate features Variable or diffuse Fibrosis with some inconspicuous non UIP features Upper or mid lung Peribronchovascular Subpleural sparing Any of the following: Predominant consolidation Extensive GGO Extensive mosaicism Diffuse nodules or cysts 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: /S (17) [Epub ahead of print], Copyright 2017, with permission from Elsevier. Accessed December 30,

7 ILA Associated With Risk for Mortality Reproduced with permission from JAMA 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): Copyright American Medical Association. All rights reserved. 13 Rough Summary of Cryobiopsy Study Diagnostic Yield Yield Kropski JA et al. PLoS One. 2013;8(11):e /25 (80%) Pajares V et al. Respirology. 2014;19(6): /39 (52%) Casoni GL et al. PLoS One. 2014;9(2):e /69 (52%) Griff S et al. BMC Pulm Med. 2014;14:171. Diagnostic Yield in 41/52 (79%) Hernández González 15 studies F of et 781 al. patients Arch Bronconeumol. 2015; 81% 26/33 (79%) 51(6): [Meta analysis] Hagmeyer L et al. Clin Respir J. 2016;10(5): /32 (72%) Tomassetti S et al. Am J Resir Crit Care Med. 40/58 (69%) 2016;193(7): Poletti V. Respiration. 2016;91(4): /297 (83%) Lentz RJ et al. J Bronchology Interv Pulmonol Aug 7. 71/104 (68%) [Epub ahead of print] OVERALL EXPERIENCE 523/605 (74%) Safety Study Bleeding PTX Kropski JA et al. 0/25 (0%) 0/25 (0%) Pajares V et al. 22/39 (56%) 3/39 (8%) Safety/Complications in 15 Casoni GL et al. 1/69 (1%) studies of 994 patients 19/69 (28%) Griff S et al. Pneumothorax 10%; None None Hernández González Moderate F et bleeding 12% al. 10/33 (30%) [Meta analysis] 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

8 MDT Diagnosis Results in Greater Prognostic Accuracy MDT=multidisciplinary team; MDTM=multidisciplinary team meeting. 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, , Copyright 2016, with permission from Elsevier. 15 Unclassifiable ILD Remains Despite All of This Advance Reprinted from Chest, 145/4, Ryerson CJ, Vittinghoff E, Ley B, et al, Predicting survival across chronic interstitial lung disease: the ILD-GAP model, , Copyright 2014, with permission from Elsevier; Hyldgaard C et al. Respirology. 2017;22(3):

9 Unclassifiable ILD Remains Despite All of This Advance Unclassifiable ILD in 173/1012 (17%) Unclassifiable ILD in 105/403 (24%) Reprinted from Chest, 145/4, Ryerson CJ, Vittinghoff E, Ley B, et al, Predicting survival across chronic interstitial lung disease: the ILD-GAP model, , Copyright 2014, with permission from Elsevier; Hyldgaard C et al. Respirology. 2017;22(3): Wide Variety of Prognostic Biomarkers Are In Play Martinez FJ et al. Nat Rev Dis Primers. 2017;3:

10 With Optimal Results Seen With Five TBBx Yielding Excellent Sensitivity/Specificity Mixing 5 is the best Classification Result Non-UIP UIP AUC Central Pathology Label Non-UIP 22 3 UIP 8 16 Specificity 0.88 ( ) Sensitivity 0.67 ( ) Number of random samples to mix Pankratz DG et al. Ann Am Thorac Soc. 2017;14(11): Future Diagnostic Approach 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. 20

11 Discussion Points (con't) Diagnosis Prognosis Therapy 21 Traditional Prognostic Factors Age FVC DLCO Exertional desaturation Decline in FVC or DLCO Oxygen requirement 22

12 HRCT Imaging Features Are Prognostic 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, , Copyright 2017, with permission from Elsevier. 23 Wide Variety of Prognostic Biomarkers Are In Play Martinez FJ et al. Nat Rev Dis Primers. 2017;3:

13 PBMC Gene Expression Predicts Poor Outcome in IPF 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, , Copyright 2017, with permission from Elsevier. 25 Gene Expression Signature Linked to Survival associated (TLR) Pathways and Inversely Linked to Microbial Richness Huang Y et al; COMET-IPF Investigators. Am J Respir Crit Care Med. 2017;196(2):

14 Discussion Points (con't) Diagnosis Prognosis Therapy Which agent? Whom to treat? How to assess response? 27 An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatment of Idiopathic Pulmonary Fibrosis: An Update of the 2011 Clinical Practice Guideline Treatment Strong For Conditional For Conditional Against Strong Against 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

15 Engaging in a Shared Decision Making Process Physician provides Treatment options Risks and benefits Mutually acceptable decision Patient provides Personal preferences Values and concerns 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 29 Network Meta analysis Suggests Little Difference Between Pirfenidone and Nintedanib Percent % FVC Decrease 10 Pirfenidone vs placebo Nintedanib vs placebo Pirfenidone vs nintedanib 0.52 ( ) 0.61 ( ) 0.86 ( ) Adapted from Canestaro WJ et al. Chest. 2016;149(3):

16 Pirfenidone and Nintedanib Attenuate Loss of FVC Across Multiple Patient Subgroups Pirfenidone Nintedanib Reproduced with permission of European Respiratory Society. Noble PW et al. Eur Respir J. 2016;47: ; 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): The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society. 31 Patterns of Pirfenidone Discontinuation in RECAP 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 OA

17 Long term Safety of Pirfenidone in Real World Setting (PASSPORT Registry) 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 PA Change in FVC After Initial 10% FVC Decrease in CAPACITY/ASCEND Trials 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): This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) and is available under Public License, 34

18 Long term Tolerability of Nintedanib (INPULSIS ON) Crestani B et al. Presented at: European Respiratory Society (ERS) International Congress; September 9-13, 2017; Milan, Italy. Abstract OA Long term Tolerability of Nintedanib (INPULSIS ON) Most frequent adverse events leading to treatment discontinuation in INPULSIS and INPULSIS ON Progression of IPF Diarrhoea Weight decreased Nausea Crestani B et al. Presented at: European Respiratory Society (ERS) International Congress; September 9-13, 2017; Milan, Italy. Abstract OA

19 Impact of FVC Decline in Nintedanib Treated Patients FVC Decline in INPULSIS and INPULSIS ON Adapted from Richeldi L et al. European Respiratory Journal. 2017;50(suppl 61):Abstract PA Recruiting Clinical Trials for IPF Intervention Target Phase Status GSK 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 based rehabilitation Your patient Recruiting Azithromycin Cough Recruiting Accessed October 19,

20 IPF Studies Closed to Enrollment Intervention Mechanism/Target Phase Trial Status Autologous mesenchymal stem cells Immunomodulation 1 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 Pamrevlumab Anti CTGF (FG 3019) 2 Carbon monoxide Injury/inflammation 2 PBI 4050 Anti fibrotic 2 SAR Anti IL 4, Anti IL Accessed October 19, Ongoing Completed 39 IPF Studies Closed to Enrollment Intervention Mechanism/Target Phase Trial Status Autologous mesenchymal stem Immunomodulation 1 cells A Phase II Clinical Trial of Low Dose Inhaled Carbon Monoxide in Idiopathic Pulmonary Fibrosis FG 3019 Anti CTGF (FG 3019) 2 Lebrikizumab Rosas IO, Goldberg HJ, Collard HR, Anti IL 13 El Chemaly S, Flaherty K, Hunninghake 2 GM, Lasky JA, PRM 151 Lederer DJ, Machado R, Martinez FJ, Maurer R, Teller D, Noth I, Peters E, Raghu G, Garcia Pentraxin 2 2 Ongoing JGN, and Choi AMK. Sirolimus mtor inhibition Conclusions: Inhaled CO is well tolerated and can be safely Laparoscopic antireflux administered surgery to Gastroesophageal IPF patients in the reflux ambulatory setting; 2 however, Tralokinumab inhaled CO did not result in significant changes in prespecified study Anti IL 13 2 endpoints. The feasibility of administering outpatient inhaled Pamrevlumab therapies for the treatment Anti CTGF (FG 3019) of IPF is encouraging 2and should be Carbon monoxide pursued in future studies. Injury/inflammation 2 Completed PBI 4050 Chest 2017; Published Anti fibrotic on line as /j.chest SAR Anti IL 4, Anti IL Accessed October 19, 2017.

21 IPF Studies Closed to Enrollment Intervention Mechanism/Target Phase Trial Status Autologous mesenchymal stem Immunomodulation 1 FibroGen Presents Latest Data From Phase 2b Study of cells Pamrevlumab in Idiopathic Pulmonary Fibrosis at European FG 3019 Anti CTGF Respiratory (FG 3019) Society (ERS) 2 Lebrikizumab International Anti IL 13 Congress PRM 151 Pentraxin 2 2 Ongoing Pamrevlumab met the primary endpoint of FVC % predicted with statistical significance, as Sirolimus well as absolute FVC volume: in this study, the primary endpoint was met as the average mtor inhibition decline in FVC % predicted of 2.85 in the pamrevlumab arm was statistically smaller than Laparoscopic antireflux surgerythe average Gastroesophageal decline of 7.17 in reflux the placebo arm, 2a difference of These results are consistent with the decline in FVC % predicted by 2.29 observed in a Tralokinumab subgroup of similar pamrevlumab treated Anti IL 13 patients in an earlier phase 2 2 open label IPF study. Pamrevlumab Anti CTGF (FG 3019) 2 Carbon monoxide Injury/inflammation 2 Completed PBI 4050 Anti fibrotic 2 SAR Anti IL 4, Anti IL Accessed October 19, 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):

22 Ongoing Studies With Cotrimoxazole CleanUP IPF 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 EME TIPAC 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 ClinicalTrials.gov. Updated November 8, Accessed December 29, 2017; BioMed Central Ltd. Accessed December 29, INJOURNEY Study Results: Nintedanib With Add On Pirfenidone Nintedanib 150 mg bid With Add On Pirfenidone (n = 53), n (%) Nintedanib 150 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 Reprinted 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 Repir Crit Care Med. 197(3): The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society. 44

23 Safety of Combined Pirfenidone and Nintedanib in Patients With Idiopathic Pulmonary Fibrosis Flaherty KR et al. Presented at: European Respiratory Society (ERS) International Congress; September 9-13, 2017; Milan, Italy. Abstract PA Weighing Risks and Benefits of Laparoscopic Anti Reflux Surgery in Patients With IPF (WRAP IPF) 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 ClinicalTrials.gov. Updated October 26, Accessed December 29,

24 Discussion Points (con't) Diagnosis Prognosis Therapy Imminent future 47 Nintedanib Clinical Trials in ILDs 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 ClinicalTrials.gov. Updated February 24, Accessed December 29, 2017; ClinicalTrials.gov. Updated December 25, Accessed December 29, 2017; ClinicalTrials.gov. Updated December 4, Accessed December 29,

25 Pirfenidone Clinical Trials in ILDs 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 Khanna D et al. J Rheumatol. 2016;43(9): ; ClinicalTrials.gov. Updated June 14, Accessed December 29, 2017; ClinicalTrials.gov. Updated May 3, Accessed December 29, 2017; ClinicalTrials.gov. Updated December 22, Accessed December 39, Nintedanib Clinical Trials in ILDs 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 ClinicalTrials.gov. Updated February 24, Accessed December 29, 2017; ClinicalTrials.gov. Updated December 25, Accessed December 29, 2017; ClinicalTrials.gov. Updated December 4, Accessed December 29,

26 Discussion Points (con't) Diagnosis Prognosis Therapy Imminent future 51 Conclusions 52