October 30, The Westin Princeton at Forrestal Village 201 Village Boulevard Princeton, NJ Marilyn Glassberg Csete, MD FACP, FCCP

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1 October 3, 215 The Westin Princeton at Forrestal Village 21 Village Boulevard Princeton, NJ 854 Marilyn Glassberg Csete, MD FACP, FCCP Professor of Medicine, Surgery, and Pediatrics at the University of Miami Miller School of Medicine Miami, FL Maria Padilla, MD Professor of Medicine at Ican Mount Sinai School of Medicine Attending Physician/Mount Sinai Hospital New York, NY

2 Session 3: Idiopathic Pulmonary Fibrosis: Raising the Index of Suspicion in Primary Care Learning Objectives 1. Describe the epidemiology and pathophysiology of idiopathic pulmonary fibrosis (IPF) 2. Recognize the signs and symptoms of IPF and identify patients in whom referral and further evaluation for IPF may be warranted 3. Outline current diagnostic criteria and the importance of early identification of IPF 4. Summarize data for recently approved pharmacologic agents for the treatment of IPF Faculty Dr Glassberg Csete, MD, FACP, FCCP Professor of Medicine, Surgery, and Pediatrics at The University of Miami Miller School of Medicine Miami, Florida Marilyn Glassberg Csete, MD, FACP, FCCP is Professor of Medicine, Surgery, and Pediatrics at the University of Miami Miller School of Medicine. She is a leading expert in rare lung diseases. Born at Jackson Memorial Hospital, Dr Glassberg returned to Miami to pursue her medical education after completing her undergraduate studies at Wellesley College and her research training under Drs. Bruce Zetter and Judah Folkman at Harvard Medical School. Dr Glassberg studies and treats interstitial lung disease ailments in which air sacs thicken and limit gas exchange most notably pulmonary fibrosis and lymphangioleiomyomatosis (LAM), a rare disease affecting young women. She was awarded the National Library of Medicine Award in 23 for her achievements. As a result of Dr Glassberg s dedication to patient care and research, in 21, the University of Miami Health System-UHealth was selected to be one of only 15 sites in the country to open a clinic for patients with LAM. Most recently, she was awarded the Dines Named Visiting Professorship at Mayo Clinic Rochester, MN for her seminal studies in cell-based therapies in chronic lung disease. Maria Padilla, MD Professor of Medicine Ican Mount Sinai School of Medicine Attending Physician Mount Sinai Hospital New York, New York After completing her pulmonary fellowship at Mount Sinai School of Medicine and The Mount Sinai Medical Center, Maria Padilla, MD, pursued her studies in lung transplantation by attending the programs at Toronto General Hospital and Stanford University. She was the co-founder of the program at The Mount Sinai Hospital in New York City. During her fellowship training, Dr Padilla conducted research in pathology, developing models of pulmonary diseases under the mentorship of Dr Jerome Kleinerman. She also participated in clinical research in sarcoidosis and interstitial lung diseases. Dr Padilla is board certified in Internal Medicine, Pulmonary Medicine, and Critical Care Medicine. She is the Director of Mount Sinai s Advanced Lung/Interstitial Lung Disease Program and the Medical Director of the Lung Transplantation Program. She is also involved in the Sarcoidosis Service and the adult Cystic Fibrosis program. She is a consultant to other transplant programs at Mount Sinai, and is also the principal investigator of clinical research projects. Dr Padilla specializes in the treatment of diffuse interstitial lung diseases, including idiopathic interstitial pneumonia, acute interstitial pneumonia, lymphocytic interstitial pneumonia, non-specific interstitial pneumonia, organizing pneumonia, bronchiolitis obliterans, and hypersensitivity pneumonia. She also specializes in lung diseases associated with rheumatologic disorders, such as rheumatoid arthritis, dermatomyositis, mixed connective tissue disease, and systemic lupus erythematosus. In addition, she also treats drug-induced lung disease, mycobacterial lung disease, Langerhans cell hystiocytosis, lymphangioleimyomatosis, pulmonary vasculitis, alveolar hemorrhage, and pulmonary alveolar proteinosis. Session 3

3 Faculty Financial Disclosure Statements The presenting faculty reported the following: Marilyn Glassberg Csete, MD, FACP, FCCP: Advisory Board for Boehringer Ingelheim Pharmaceuticals, Inc. and Genentech. Speakers Bureau for Boehringer Ingelheim Pharmaceuticals, Inc. and Genentech. Services Provided for Promotional Purposes for Mesoblast Ltd. Maria L. Padilla, MD: Speakers Bureau for Boehringer Ingelheim Pharmaceuticals, Inc. and Genentech. Education Partner Financial Disclosure Statement The content collaborators at Horizon CME no relationships to disclose. Acronym List Acronym Definition DL CO carbon monoxide FEV 1 forced expiratory volume FVC forced vital capacity TLC total lung capacity IIP idiopathic interstitial pneumonia IPF idiopathic pulmonary fibrosis Suggested Reading List PaO 2 PFT UIP partial pressure of oxygen in arterial blood pulmonary function test usual interstitial pattern Al-Ashkar F, Mehra R, Mazzone PJ. Interpreting pulmonary function tests: Recognize the pattern, and the diagnosis will follow. Cleveland Clinic Journal of Medicine. 23;7(1): Brown AW, Fischer CP, Shlobin OA, et al. Outcomes after hospitalization in idiopathic pulmonary fibrosis: a cohort study. Chest. 215;147(1): Coalition for Pulmonary Fibrosis - Leading the Fight Against PF. Coalition for Pulmonary Fibrosis - Leading the Fight Against PF. May Accessed June 1, 215. Demedts M, Behr J, Buhl R, et al. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med. 25;353(21): Flaherty KR, King TE, Raghu G, et al. Idiopathic interstitial pneumonia: what is the effect of a multidisciplinary approach to diagnosis? Am J Respir Crit Care Med. 24;17(8): Hutchinson JP, McKeever TM, Fogarty AW, et al., Increasing global mortality from idiopathic pulmonary fibrosis in the twenty-first century. Ann Am Thorac Soc. 214;11(8): King TE, Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 214;37(22): Ley B, Ryerson CJ, Vittinghoff E, et al. A multidimensional index and staging system for idiopathic pulmonary fibrosis. Ann Intern Med. 212;156(1): Nathan SD, Shlobin OA, Weir N, et al. Long-term course and prognosis of idiopathic pulmonary fibrosis in the new millennium. Chest. 211;14(1): Noble PW, Albera C, Bradford WZ, et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet. 211;377(9779): Session 3

4 Olson AL, Swigris JJ, Lezotte DC, Norris JM, Wilson CG, Brown KK. Mortality from pulmonary fibrosis increased in the United States from 1992 to 23. Am J Respir Crit Care Med. 27;176(3): Raghu G, Chen S-Y, Yeh W-S, et al. Idiopathic pulmonary fibrosis in US Medicare beneficiaries aged 65 years and older: incidence, prevalence, and survival, Lancet Respir Med. 214;2(7): Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidencebased guidelines for diagnosis and management. Am J Respir Crit Care Med. 211;183(6): Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G. Incidence and Prevalence of Idiopathic Pulmonary Fibrosis. American Journal of Respiratory and Critical Care Medicine. 26;174(7): Richeldi L, du Bois RM, Raghu G, et al. Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis. New England Journal of Medicine. 214;37(22): The Idiopathic Pulmonary Fibrosis Clinical Research Network. Randomized Trial of Acetylcysteine in Idiopathic Pulmonary Fibrosis. New England Journal of Medicine. 214;37(22): The Idiopathic Pulmonary Fibrosis Clinical Research Network, Raghu G, Anstrom KJ, King TE, Lasky JA, Martinez FJ. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med. 212;366(21): Travis WD, Costabel U, Hansell DM, et al. An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 213;188(6): Session 3

5 1:3 11:45 am Idiopathic Pulmonary Fibrosis: Raising the Index of Suspicion in Primary Care SPEAKERS Maria Padilla, MD Marilyn Glassberg Csete, MD Presenter Disclosure Information The following relationships exist related to this presentation: Maria L. Padilla, MD: Speakers Bureau for Boehringer Ingelheim Pharmaceuticals, Inc. and Genentech. Marilyn Glassberg Csete, MD: Speakers Bureau for Boehringer Ingelheim Pharmaceuticals, Inc. and Genentech. Medical Advisory Board for Boehringer Ingelheim Pharmaceuticals, Inc. and Genentech. Consultant for Mesoblast. Off-Label/Investigational Discussion In accordance with pmicme policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. Objectives Maria Padilla, MD Prof. of Medicine, Icahn Mt. Sinai School of Medicine New York, NY Marilyn Glassberg Csete, MD Director, Interstitial Lung Disease Program University of Miami Miller School of Medicine Miami, FL Describe the epidemiology and pathophysiology of idiopathic pulmonary fibrosis (IPF) Recognize the signs and symptoms of IPF and identify patients in whom referral and further evaluation for IPF may be warranted Outline current diagnostic criteria and the importance of early identification of IPF Summarize data for recently approved pharmacologic agents for the treatment of IPF Epidemiology of IPF Approximately 5 million patients worldwide 1 Numbers in the U.S. 2 Epidemiology of Idiopathic Pulmonary Fibrosis (IPF) Incidence: >5, patient/year Prevalence: >13, patients currently More common in men than women 1,2 Mean age at presentation is 66 years 1,2 Two-thirds of all cases diagnosed in patients >6 yrs old Median survival 1,2 2 5 years 1. Meltzer EB, Noble PW. Orphanet J Rare Dis. 28;3:8. 2. Raghu G, et al. Lancet Respir Med. 214;2:

6 Cases per 1, person-years Increasing Prevalence of IPF Raghu G, et al. Lancet Respir Med. 214;2: Medicare Beneficiaries Age 65 Years Cumulative prevalence Annual incidence Factors associated with lower survival Age, index year, male gender Year Median survival = 3.8 years Idiopathic Pulmonary Fibrosis Increasing Global Mortality Age-standardized mortality per 1, Year Age-standardized mortality ~4 and 1 per 1, population Overall 2 3% annual increase in mortality 28, 65, deaths in Europe, and 13, 17, deaths in the U.S. from IPF in 214 Hutchinson JP, et al. Ann Am Thorac Soc. 214;11(8): England and Wales Australia Canada Japan Northern Ireland New Zealand Scotland Spain Sweden United States Deaths 16, 14, 12, 1, 8, 6, 4, 2, Estimated Deaths: IPF 1 vs Common Cancers 2 1. Coalition for Pulmonary Fibrosis. Facts About Idiopathic Pulmonary Fibrosis. Available at: forpf.org/facts-about-idiopathic-pulmonary-fibrosis/. 2. American Cancer Society, Surveillance and Health Services Research, 215. Available at: 5-Year Mortality Rate High in IPF 5-year survival rate (U.S.) is only 2 4% 1 Worse survival rates than many common cancers Prostate Skin Thyroid Breast Uterus Bladder Kidney Colon Lymphoma Leukemia IPF Lung Pancreas year survival rate This material has not been reviewed by European Respiratory Society prior to release; therefore the European Respiratory Society may not be responsible for any errors, omissions, or inaccuracies, or for any consequences arising there from. 1. Reprinted with permission from Vancheri, et al. Eur Respir J. 21; 35(3): What Is IPF? Signs and Symptoms of IPF Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease that belongs to a family of lung disorders known as interstitial lung diseases (ILD), and within this family, IPF is part of a subgroup known as the idiopathic interstitial pneumonias (IIP). IPF is characterized by scar tissue within the lungs of unknown cause and is associated with a pathologic pattern of usual interstitial pneumonia (UIP) Raghu G, et al. Am J Respir Crit Care Med. 211;183(6): Meltzer EB, Noble PW. Orphanet J Rare Dis. 28;3:8.

7 Interstitial Lung Disease (ILD) Diverse group of disorders that involve the pulmonary parenchyma; also known as diffuse parenchymal lung disease (DPLD) Typical presentation Progressive dyspnea and dry cough Abnormal pulmonary physiology Abnormal CXR and/or HRCT Etiology Idiopathic Systemic diseases (connective tissue disorders) Toxic, radiologic, environmental, occupational exposures CXR = chest x-ray; HRCT = high-resolution computed tomography. July 8, 215. Classification of ILD ILD of Known Cause or Association Exposure Occupation Environment Avocation Medication Drug Radiation Smoking Systemic disease Genetic Granulomatous lung disease ILD of Unknown Cause Idiopathic interstitial pneumonia NSIP RB-ILD DIP COP AIP Specific pathology LAM PAP IIP = idiopathic interstitial pneumonia; NSIP = nonspecific IP; RB-ILD = respiratory bronchiolitis ILD; DIP = desquamative IP; COP = cryptogenic organizing pneumonia; AIP = acute IP; LAM = lymphangioleiomyomatosis; PAP = pulmonary alveolar proteinosis. July 8, 215. Travis WD, et al. Am J Respir Crit Care Med. 213;188(6): IPF Pathogenesis of IPF Natural History of IPF Epithelial cell injury and activation Fibroblast migration and proliferation Epithelial apoptosis INJURY Wound clot Basement membrane disruption Myofibroblast accumulation Progressive fibrosis and impaired reepithelialization Angiogenesis Disease progression (some patients) Stable Slow progression (majority of patients) Acute worsening (minority of patients) Rapid progression (some patients) Time Ahluwalia N, et al. Am J Respir Crit Care Med. 214;19(8): Raghu G, et al. Am J Respir Crit Care Med. 211;183(6): Common Risk Factors for IPF Age Male gender Cigarette smoking Gastroesophageal reflux Occupational exposure to metal dust or wood dust?viral infection Genetic predisposition Raghu G, et al. Am J Respir Crit Care Med. 211;183(6): Accessed July 6, 215. How Do IPF Patients Present? Shortness of breath (dyspnea) Dry cough Fatigue Velcro rales at lung bases Clubbing of fingers and/or toes may be present Incidentally ILD on routine CXR or CT chest ILD at bases of abdominal CT Fluoroscopy at time of cardiac catheterization Family history CXR = chest x-ray; CT = computed tomography. Raghu G, et al. Am J Respir Crit Care Med. 211;183(6): Meltzer EB, Noble PW. Orphanet J Rare Dis. 28;3:8. Accessed July 6, 215.

8 When to Suspect IPF? Susceptible individual: Family history of ILD Exposures Symptoms: Shortness of breath Cough usually dry and can be intractable Physical examination: Incidental inspiratory crackles on exam ( Velcro -like) Pulmonary function tests: Restrictive lung disease on PFTs CXR or CT consistent with chronic interstitial changes Exercise desaturation Diagnosis of IPF PFT = pulmonary function test. Raghu G, et al. Am J Respir Crit Care Med. 211;183(6): Meltzer EB, Noble PW. Orphanet J Rare Dis. 28;3:8. Accessed July 6, 215. Upper airways Laryngospasm Vocal cord dysfunction Airway obstruction Tracheomalacia Lower airways/lungs Asthma COPD Pneumonia Pneumothorax Pleural effusion Parenchymal and endobronchial tumors ILD ARDS = The Biggies Dyspnea Differential Cardiovascular system CHF Pulmonary edema Pericardial effusion Arrhythmias Cardiac output Cardiomyopathy Ischemic heart dx Valvular disease Pulmonary embolism Pulmonary hypertension Neuromuscular system Cerebrovascular events Amyotrophic lateral sclerosis Spinal cord injuries above C3 Multiple sclerosis Myasthenia gravis Guillain-Barré syndrome Polymyositis Muscular dystrophy = The Not so biggies, but not to be forgotten Metabolic, renal, and heme Acidosis Renal failure/tubular acidosis Hyperthyroidism Hypothyroidism Cushing s syndrome Obesity Anemia and methemoglobin ARDS Toxins/poisons Botulism Tetanus Organophosphate poisoning CO poisoning Drugs Psychogenic disorders Hyperventilation syndrome Anxiety/panic disorders Depression Somatization disorder IPF 1 Heart failure 2 COPD 3 Distinguishing Dyspnea: IPF Prevalence Disease Prevalence, United States 136, million 15.7 million Million 1. Raghu G, et al. Resp Crit Care Med. 26;174: Go AS, et al. Circulation. 213;127:e6 e Wheaton AG, et al. MMWR Morb Mortal Wkly Rep. 215;64: Workup: Methodical Approach Good history essential Family history of ILD Smoking history Exposure history Organic particles: birds, hot tubs Inorganic particles: occupational (e.g asbestos, silica) CXR is a good screen HRCT is essential Serologic evaluation Surgical lung biopsy if needed Raghu G, et al. Am J Respir Crit Care Med. 211;183(6): Pulmonary Function Tests Spirometry Reduced forced vital capacity (FVC) and total lung capacity (TLC) Normal or increased FEV 1 /FVC ratio Impaired gas exchange Decreased DL CO, PaO 2 Desaturation on exercise oximetry Increased A-aPO 2 gradient Normal PFTs do not exclude ILD May have high baseline lung function Element of emphysema in one-third of IPF patients pseudonormalization of lung function FEV = forced expiratory volume; DL CO = diffusing capacity of the lung for carbon monoxide; PaO 2 = arterial oxygen partial pressure; A-aPO 2 = alveolar arterial oxygen difference. Raghu G, et al. Am J Respir Crit Care Med. 211;183(6):

9 211 ATS/ERS Diagnostic Criteria for IPF Exclusion of known causes of ILD AND UIP pattern on HRCT without surgical biopsy OR Definite/possible UIP pattern on HRCT with a surgical lung biopsy showing definite/probable UIP* Diagnostic Algorithm for IPF Presentation: Dyspnea on exertion History and physical CXR and PFTs Suspected IPF is the pivotal study! Suspected IPF Serologies Rule out identifiable causes of ILD High-resolution CT chest Surgical lung biopsy *Multidisciplinary discussion among ILD experts is recommended because it increases accuracy of IPF diagnosis. UIP = usual interstitial pneumonia; HRCT = high-resolution computed tomography. Raghu G, et al. Am J Respir Crit Care Med. 211;183: Refer to specialist PFT = pulmonary function test. Raghu G, et al. Am J Respir Crit Care Med. 211;183(6): Multidisciplinary discussion HRCT Criteria for UIP Pattern UIP Pattern (all four features) Subpleural, basal predominance Reticular abnormality Honeycombing with or without traction bronchiectasis HRCT Criteria for UIP Pattern Possible UIP Pattern (all three features) Subpleural, basal predominance Reticular abnormality Absence of features listed as inconsistent with UIP pattern Absence of features listed as inconsistent with UIP pattern HRCT = high-resolution computed tomography; UIP = usual interstitial pneumonia. Raghu G, et al. Am J Respir Crit Care Med. 211;183(6): HRCT = high-resolution computed tomography; UIP = usual interstitial pneumonia. Raghu G, et al. Am J Respir Crit Care Med. 211;183(6): HRCT Criteria for UIP Pattern IPF: An Interdisciplinary Diagnosis Inconsistent with UIP Pattern (any of the seven features) Upper or mid-lung predominance Peribronchovascular predominance Extensive ground glass abnormality (extent >reticular abnormality) Profuse micronodules (bilateral, predominantly upper lobes) Discrete cysts (multiple, bilateral, away from areas of honeycombing) Diffuse mosaic attenuation/air-trapping (bilateral, in three or more lobes) Consolidation in bronchopulmonary segment(s)/lobe(s) Radiologist Clinician Pathologist Communication among multidisciplinary team is essential to an accurate diagnosis HRCT = high-resolution computed tomography; UIP = usual interstitial pneumonia. Raghu G, et al. Am J Respir Crit Care Med. 211;183(6): Raghu G, et al. Am J Respir Crit Care Med. 211;183(6):

10 Early Diagnosis Matters in IPF IPF: Survival in the Current Era 2 29 (n = 521) 1 8 Survival (%) 6 4 Median survival: 36 and 42 months IPF no LTx from PFTs 2 IPF no LTx from evaluation Maria Padilla, MD Prof. of Medicine, Icahn Mt. Sinai School of Medicine New York, NY Months Nathan SD, et al. Chest. 211;14(1): Why Refer Early to a Specialist or Specialized Center? Diagnostic expertise Standardized assessment Confirmation of diagnosis Management expertise Choice of an appropriate therapy Oxygen prescription Pulmonary rehabilitation Attention to obesity and sarcopenia/frailty Potential enrollment in a clinical trial Transplant evaluation Flaherty, et al. Am J Respir Crit Care Med. 24;17: Flaherty, et al. Am J Respir Crit Care Med. 27; 175: Lamas, et al. Am J Respir Crit Care Med. 211;184: Higher Mortality Associated With Delays in Accessing Care Survival p for trend =.4 Years Lamas DJ, et al. Am J Respir Crit Care Med. 211;184: <1 Year 1 2 Years 2 4 Years >4 Years Comorbid Conditions Common in IPF Pulmonary hypertension Gastroesophageal reflux disease Coronary artery disease Emphysema Treatment of IPF Obstructive sleep apnea It is unknown if treating these comorbidities improves outcomes Raghu G, et al. Am J Respir Crit Care Med. 211;183(6):

11 Goals of Treatment Stabilize or reduce the rate of disease progression Reduce symptoms Recognize and manage acute exacerbations Prompt referral to lung transplant centers in select patients Manage comorbidities IPF Management Algorithm Risk stratify Symptom management Pulmonary rehabilitation Oxygen Comorbidities / complications Lung transplant evaluation (if appropriate) Pharmacological therapy Enroll in a clinical trial (where available and appropriate) Lung transplant (where available and appropriate) Richeldi L. Eur Respir Rev. 213;22(128): Raghu G, et al. Am J Respir Crit Care Med. 211;183(6): Raghu G, et al. Am J Respir Crit Care Med. 211;183(6): Guidelines Recommendations for Management of IPF Agent 215 Guideline 211 Guideline New and Revised Recommendations Strong recommendation against Conditional recommendation Anticoagulation (warfarin) use* against use Combination prednisone + azathioprine + N-acetylcysteine Selective endothelin receptor antagonist (ambrisentan) Imatinib, a tyrosine kinase inhibitor with one target Nintedanib, a tyrosine kinase inhibitor with multiple targets Pirfenidone Dual endothelin receptor antagonists (macitentan, bosentan) Phosphodiesterase-5 inhibitor (sildenafil) Strong recommendation against use Strong recommendation against use Strong recommendation against use* Conditional recommendation for use* Conditional recommendation for use* Conditional recommendation against use Conditional recommendation against use* Conditional recommendation against use Not addressed Not addressed Not addressed Conditional recommendation against use Strong recommendation against use* Not addressed *Moderate confidence in effect estimates. Low confidence in effect estimates. Very low confidence in effect estimates. Raghu G, et al. Am J Respir Crit Care Med. 215;192(2):e3 e Guidelines Recommendations for Management of IPF Agent 215 Guideline 211 Guideline Unchanged Recommendations Antacid therapy Conditional recommendation for use Conditional recommendation for use N-acetylcysteine monotherapy Antipulmonary hypertension therapy for idiopathic pulmonary fibrosis-associated pulmonary hypertension Lung transplantation: single vs bilateral lung transplantation Conditional recommendation against use Reassessment of the previous Recommendation was deferred Formulation of a recommendation for single vs bilateral lung transplantation was deferred Conditional recommendation against use Conditional recommendation against use Not addressed *Moderate confidence in effect estimates. Low confidence in effect estimates. Very low confidence in effect estimates. Raghu G, et al. Am J Respir Crit Care Med. 215;192(2):e3 e19. Major Phase 3 IPF Trials ASCEND PANTHER Part B Results of Key IPF Trials PANTHER Part A INPULSIS I and II

12 PANTHER Study IPF patients ages years with FVC 5%, DL co 3% were randomized to either N-acetylcysteine (NAC) alone; prednisone, azathioprine, and NAC combination; or placebo. Combination therapy stopped early. IPF patients n = 341 R NAC alone* n = 131 Prednisone, azathioprine, and NAC (n = 77) * n = week follow-up STOP 1 o endpoint: FVC 2 o endpoint: Death; acute exacerbation; disease progression *At time of clinical alert, NAC alone (n = 81) and placebo (n = 78). PANTHER = Prednisone, Azathioprine and N-acetylcysteine: A Study That Evaluates Response in IPF; FVC = forced vital capacity. Raghu G, et al. N Engl J Med. 212;366(21): Martinez FJ, et al. N Engl J Med. 214;37(22): PANTHER Part A: Results Combination therapy of prednisone, azathioprine, and NAC was stopped early for evidence of harm Probability of death or hospitalization Raghu G, et al. N Engl J Med. 212;366(21): Weeks since randomization Combination therapy 6 PANTHER Part B: Results NAC alone showed no difference in FVC decline or any secondary endpoints compared to placebo.5 1. NAC Effectiveness by TOLLIP Genotype Composite endpoint of FVC decline, hospitalization, death or transplant rs37592 CC rs37592 CT rs37592 TT FVC (liters) Baseline Acetylcysteine Week Survival (%) HR 3.23; 95% CI ; p= NAC HR.76; 95% CI ; p= Time (weeks) HR.14; 95% CI.2-.83; p= Martinez FJ, et al. N Engl J Med. 214;37(22): Oldham JM, Ma SF, Martinez FJ, Anstrom KJ, Raghu G, Schwartz DA, Valenzi E, Witt L, Lee C, Vij R, Huang Y, Strek ME, Noth I. Am J Respir Crit Care Med. 215 Sep 2. [Epub ahead of print]. ASCEND Study of Pirfenidone IPF patients ages 4 8 years with FVC between 5% to 9%, DL co between 3% to 9% were randomized to pirfenidone or placebo, 127 sites in 9 countries IPF patients n = 555 R Pirfenidone (243 mg/day) n = 278 n = week follow-up 1 o endpoint: FVC or death 2 o endpoint: 6MWD; PFS; dyspnea; death ASCEND = Assessment of Pirfenidone to Confirm Efficacy and Safety in IPF; PFS = progression free survival; 6MWD = 6-minute walk distance. King TE, et al. N Engl J Med. 214;37: ASCEND Study: Baseline Characteristics Pirfenidone n = 278 n = 277 Age (years) Male sex 8% 77% Former smoker 66% 61% Predicted FVC 68% 69% FEV 1 :FVC Predicted DL co 44% 44% Dyspnea score MW distance (m) FEV 1 = forced expiratory volume in one second; FVC = forced vital capacity. King TE, et al. N Engl J Med. 214;37:

13 Patients (%) ASCEND Study of Pirfenidone: Primary Results Decreased FVC* or Death 35 p = Pirfenidone (n = 278) (n = 277) p=.1 p =.1 Mean change (ml) *Decreased FVC is defined as an absolute decline of 1%. King TE, et al. N Engl J Med. 214;37: Change in FVC Pirfenidone (n = 278) (n = 277) p=.1-4 Relative risk reduction = 45% p < Week Week ASCEND and CAPACITY Trials of Pirfenidone: Pooled Mortality Data* Pirfenidone n = 623 n = 624 Hazard Ratio p Value Deaths no. (%) From any cause 22 (3.5) 42 (6.7).52.1 From respiratory cause 7 (1.1) 22 (3.5).32.6 *Data from the two CAPACITY studies were censored at 1 year to standardize the follow-up for the three studies. King TE, et al. N Engl J Med. 214;37: ASCEND Study: Safety and Tolerability of Pirfenidone INPULSIS 1 and 2 Studies IPF patients ages 4 years with FVC 5%, DL co between 3% to 79% were randomized to nintedanib or placebo, 25 sites in 24 countries Adverse Event King TE, et al. N Engl J Med. 214;37: Pirfenidone n = 623 n = 624 Nausea 36% 13.4% Rash 28.1% 8.7% Dizziness 17.6% 13.% Dyspepsia 17.6% 6.1% Anorexia 15.8% 6.5% Vomiting 12.9% 8.7% Decrease in weight 12.6% 7.9% Gastroesophageal reflux 11.9% 6.5% Insomnia 11.2% 6.5% Discontinuations 14.4% 1.8% ALT and/or AST 3x ULN 2.9%.7% IPF patients n = 166 BID = twice daily; QOL = quality of life. Richeldi L, et al. N Engl J Med. 214;37: R Nintedanib (15 mg/bid) n = 638 n = week follow-up 1 o endpoint: FVC 2 o endpoint: Acute exacerbation; QOL; death INPULSIS 1 and 2 Studies: Baseline Characteristics Nintedanib n = 39 INPULSIS 1 INPULSIS 2 n = 24 Nintedanib n = 329 n = 219 Age (years) Male sex 81% 8% 78% 78% Never smoked 23% 25% 31% 32% Predicted FVC 8% 81% 8% 78% FEV 1 :FVC Predicted DL co 48% 48% 47% 46% Total SGRQ score* *St. George s Respiratory Questionnaire (SGRQ) score ranges from to 1, with higher scores indicating worse quality of life. Richeldi L, et al. N Engl J Med. 214;37: INPULSIS 1 and 2 Studies of Nintedanib: Primary Results Mean observed change from baseline in FVC (ml) Nintedanib, 15 mg twice daily Adjusted mean difference, (95% CI, ) p < Adjusted mean difference, (95% CI, ) p < Richeldi L, et al. N Engl J Med. 214;37: Week INPULSIS 1 INPULSIS 2

14 INPULSIS 1 and 2 Studies of Nintedanib: Pooled Data on Acute Exacerbations INPULSIS 1 and 2 Studies: Safety and Tolerability of Nintedanib Cumulative incidence of first confirmed/suspected acute exacerbation (%) HR.32 (95% CI:.16,.65) p =.1 Nintedanib 15 mg twice daily Time to first confirmed/suspected acute exacerbation (days) Nintedanib n = 39 INPULSIS 1 INPULSIS 2 n = 24 Nintedanib n = 329 n = 219 Diarrhea 62% 19% 63% 18% Nausea 23% 6% 26% 7% Dyspnea 7% 11% 8% 11% Vomiting 13% 2% 1% 3% Weight loss 8% 6% 11% 1% SAE 31% 27% 3% 33% Discontinuations 21% 11% 18% 15% ALT and/or AST 3x ULN 4.9%.5% 5.2%.9% Richeldi L, et al. N Engl J Med. 214;37: SAE = serious adverse event. Richeldi L, et al. N Engl J Med. 214;37: Pirfenidone and Nintedanib FDA approved on October 214 for treatment of IPF No FDA approved therapies until 214 Pirfenidone (267 mg/cap) Liver function monitoring required for both pirfenidone and nintedanib Dosing Days 1 7: 1 cap tid; Days 8 14: 2 caps tid; Day 15 onward: 3 caps tid; Maint/max: 243 mg/day (9 caps/day) Warnings/precautions: Photosensitivity reaction, rash, GI events, increased LFTs; pregnancy category C Nintedanib (1 mg and 15 mg caps) Dosing: 15 mg bid approximately 12 hrs apart; Max: 3 mg/day Warnings/precautions: GI disorders, arterial thromboembolic events, bleeding events, GI perforation, increased LFTs; pregnancy category D IPF Management in Accessed August 3, Accessed August 3, 215. IPF: Implications of Having Approved Drugs The stakes are raised! Need to make an accurate diagnosis Avoid starting patients inappropriately on drug Earlier diagnosis becomes essential Increased awareness Primary care providers: Low threshold for a pulmonary referral Pulmonologists: Low threshold for referral to ILD center Managing Patient Expectations Discussion about what to expect from the drugs Efficacy The drug slows the rate of loss of lung function You won t necessarily feel better! Side effects You won t necessarily have side effects, but here is what they are. Liver function test monitoring Pirfenidone and nintedanib

15 IPF Management Checklist Risk factor reduction Patient education Advocacy group involvement Focus on comorbidities Mental health needs GERD, OSA, CAD, PH, VTE, etc. Supplemental oxygen Age-appropriate vaccinations Discussion about available medical therapies Pulmonary rehabilitation Clinical trials Lung transplant evaluation Address end-of-life issues: palliative and hospice care Pharmacologic therapy IPF Therapies Nintedanib Pirfenidone No head-to-head studies available for these two drugs Oxygen therapy Pulmonary rehabilitation Lung transplantation GERD = gastroesophageal reflux disease; OSA = obstructive sleep apnea; CAD = coronary artery disease; PH = pulmonary hypertension; VTE = venous thromboembolic disease. Monitoring for Disease Progression Every 3 to 6 months by pulmonologist: PFTs 6-minute walk test (distance/nadir saturation) O 2 requirement Comorbidities Consider dyspnea questionnaire (e.g., UCSD SOB questionnaire) HRCT for suspicion of clinical worsening O 2 = oxygen; SOB = shortness of breath; HRCT = high-resolution computed tomography. Take-Home Messages IPF is not uncommon Not all shortness of breath is heart failure, COPD, or asthma. Familiarity with signs and symptoms Recalcitrant dry cough, SOB, coarse inspiratory basilar crackles Awareness and management of associated comorbidities CAD, GERD, OSA, and PH There are now FDA approved novel therapies for IPF Nintedanib and pirfenidone IPF is the most common indication for lung transplantation Small minority of IPF patients are candidates Non-pharmacologic interventions are important Pulmonary rehabilitation and oxygen Support groups End-of-life planning