NAVIGATING the NEW ERA in IPF: Idiopathic Pulmonary Fibrosis

NAVIGATING the NEW ERA in IPF: Idiopathic Pulmonary Fibrosis Mark J Rumbak, MD Division Director Pulmonary, Critical Care and Sleep Medicine Morsani College of Medicine University of South Florida, Tampa ILD of Known Cause or Association Medications Radiation Connective Tissue Disease Vasculitis & DAH Hypersensitivity Pneumonitis Pneumoconioses Interstitial Lung Diseases Idiopathic Interstitial Pneumonias Adapted from: ATS/ERS Guidelines for IIP. AJRCCM. 2002;165:277 304. Sarcoidosis & Other Granulomatous Diseases Other LAM Pulmonary LCH Eosinophilic Pneumonias Alveolar Proteinosis Genetic Syndromes Diffuse Parenchymal Lung Disease (DPLD) DPLD of known cause, eg, drugs or association, eg, collagen vascular disease Idiopathic interstitial pneumonias Granulomatous DPLD, eg, sarcoidosis Other forms of DPLD, eg, LAM, HX, etc Idiopathic pulmonary fibrosis IIP other than idiopathic pulmonary fibrosis Desquamative interstitial pneumonia Acute interstitial pneumonia Nonspecific interstitial pneumonia (provisional) Respiratory bronchiolitis interstitial lung disease Cryptogenic organizing pneumonia Lymphocytic interstitial pneumonia Pleuroparenchymal fibroelastosis Travis WD, et al; ATS/ERS Committee on Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med. 2013;188(6):733 748. 1

Cumulative Proportion Surviving Diagnosis Matters! IPF/UIP Confers a Poor Prognosis Time (years) Flaherty KR, et al. Eur Respir J. 2002;19:275 283. Parameter HR (95% CI) IPF Dx 28.46 (5.5, 147) Age 0.99 (0.95, 1.03) Female sex 0.31 (0.13, 0.72) Smoker 0.30 (0.13, 0.72) Physio CRP 1.06 (1.01, 1.11) Onset Sx (yrs) 1.02 (0.93, 1.12) CTfib score 2 0.77 (0.29, 2.04) Correct diagnosis appropriate management 2011 ATS/ERS Diagnostic Criteria for IPF Exclusion of known causes of ILD* AND *also known as diffuse parenchymal lung disease, DPLD Raghu G, et al. Am J Respir Crit Care Med. 2011;183:788 824. UIP pattern on HRCT without surgical biopsy OR Definite/possible UIP pattern on HRCT with a surgical lung biopsy showing definite/probable UIP Pulmonary Function Tests Spirometry Reduced FVC and TLC Normal or increased FEV 1 /FVC ratio Restriction often accompanied by some obstruction Impaired gas exchange Decreased DL CO, PaO 2 Desaturation on exercise oximetry Increased A apo 2 gradient Normal PFTs do not exclude ILD Emphysema + Interstitial Lung Disease Known Causes of ILD: History & Physical Exam Drugs eg, Amiodarone, bleomycin, nitrofurantoin www.pneumotox.com Radiation External beam radiation therapy to thorax Connective Tissue Diseases Rheumatoid arthritis Systemic sclerosis (scleroderma) Idiopathic inflammatory myopathies Vasculitis Occupational/Environmental Inorganic antigens (Pneumoconioses) Asbestosis Coal worker s pneumoconiosis Silicosis Organic antigens (Hypersensitivity Pneumonitis) Birds Mold 2

Advanced Sclerodactyly Gottron's Papules in Dermatomyositis http://images.rheumatology.org. Accessed July 2014. http://images.rheumatology.org. Accessed July 2014. Mechanic's Hands in Anti Synthetase Syndrome Raynaud's Phenomenon http://images.rheumatology.org. Accessed July 2014. http://images.rheumatology.org. Accessed July 2014. 3

Puffy Fingers in Early Scleroderma or Mixed CTD Digital Clubbing http://images.rheumatology.org. Accessed July 2014. Reynen K, et al. N Engl J Med. 2000; 343:1235 NEJM, 2001 Telemere Syndrome Serological Evaluation Minimum: ANA, RF, CCP (ATS/ERS guidelines) Based on history & physical exam, consider: Extractable nuclear antigen (ENA) autoantibody panel Anti centromere antibody ESR & CRP MPO/PR3 (ANCA) antibodies Anti cardiolipin antibodies, lupus anticoagulant Creatine kinase, aldolase Hypersensitivity pneumonitis panel Should be performed before a biopsy 4

UIP Pattern Idiopathic Pulmonary Fibrosis Normal Lung Usual Interstitial Pneumonia Hodnett PA, et al. Am J Respir Crit Care Med. 2013;188:141 149. 5

Higher Mortality Associated With Delays in Accessing Care Survival Years Lamas DJ, et al. Am J Respir Crit Care Med. 2011;184:842 847. 6

HRCT Criteria for UIP Diffusing Capacity Predicts Survival in IPF UIP Pattern Possible UIP Pattern Subpleural, basal predominance + + Reticular abnormality + + Honeycombing (+/ traction bronchiectasis) + Absence of inconsistent features + + Percent Survival DL co 50% DL co 35 49% Dl co < 35% P=0.0001 Months Raghu G, et al. Am J Respir Crit Care Med. 2011;183:788 824. Nathan SD, et al. Chest. 2011;140:221 229. FVC Predicts Survival in IPF Percent Survival Nathan SD, et al. Chest. 2011;140:221 229. Months FVC 70% FVC 55 69% FVC < 55% P=0.0053 Survival Probability 6MWT Parameters Predict Survival in IPF Which 6MWT parameter best predicts survival in IPF? Baseline 6MWT distance Time Weeks du Bois RM, et al. Eur Respir J. 2014;43(5):1421 1429. Swigris JJ, et al. Chest. 2009;136:841 848 P = 0.01 Survival Probability HR 1 minute after 6MWT Days of Follow Up 6MWT distance at 24 weeks Time Weeks P = 0.0007 > 13bpm 13bpm P < 0.001 7

Linking IPF Pathogenesis to Potential Therapies Three Recent IPF Clinical Trials American Thoracic Society 2014 PANTHER ASCEND INPULSIS N acetylcysteine (NAC) pirfenidone nintedanib (BIBF1120) Ahluwalia N, et al. Am J Respir Crit Care Med. 2014 Aug 4. [Epub ahead of print]. RCTs in IPF INPULSIS 2 14 INPULSIS 1 14 ASCEND 14 Pre 2011 Early Evidence for a NAC Cocktail ATS 2011 2011 2013 2014 PANTHER 12 Shulgina 12 Raghu 12 King 11 Noble 11 Richeldi 11 PANTHER 14 Acetylcysteine + azathioprine + + steroids + steroids Placebo + + azathioprine + + steroids Noble 11 Raghu 08 Taniguchi 10 Daniels 10 Kubo 05 Azuma 05 King 08 Demedts 05 Ziesche 99 Douglas 98 Raghu 99 Raghu 04 ACE IPF 12 STEP IPFnet 10 King 09 Slide courtesy of L. Richeldi Demedts M, et al. New Engl J Med. 2005;353:2229 2242. 8

Possible NAC Mechanisms of Action PANTHER 2012 Pre 2011 ATS 2011 2011 2013 2014 Increase glutathione antioxidation Downregulate lysyl oxidase (LOX) activity, (essential for collagen deposition) Li S, et al. Respiration. 2012;84(6):509 517. Rushworth GF, et al. Pharmacol Ther. 2014;141(2):150 159. Raghu G, et al. N Engl J Med. 2012;366:1968 1977. Pre 2011 PANTHER 2012 Interim Results ATS 2011 Primary Triple Therapy Placebo P value FVC (liters) 0.24 0.23 0.85 2011 2013 2014 PANTHER 2014 ATS Pre 2011 2011 2013 2014 2011 Triple therapy has no benefit for FVC Increased risk of death Probability Time to Death Kaplan Meier Analysis Weeks Since Randomization HR 9.26 (95% CI 1.16 74.1) P = 0.01 Raghu G, et al. N Engl J Med. 2012;366:1968 1977. Martinez FJ, et al. N Engl J Med. 2014;370(22):2093 2101. 9

NAC Does Not Reduce FVC Decline Possible Mechanisms of Pirfenidone Action Conclusion: NAC offered no significant benefit with respect to the preservation of FVC in patients with IPF with mild to moderate impairment in lung function Antifibrotic Molecular target unclear Active in several animal models of fibrosis (lung, liver, kidney) TNF α IL 6 TGF β IL 6 Pirfenidone Collagen MMPs Collagenases ROIs Martinez FJ, et al. N Engl J Med. 2014;370(22):2093 2101. Hilberg O, et al. Clin Respir J. 2012;6:131 143. CAPACITY 2011 CAPACITY 2 Pre 2011 ATS 2011 CAPACITY 1 2011 2013 2014 Acute Exacerbations Punctuate Slow Decline (5 10% of patients per year) One pirfenidone trial was positive, one was negative CAPACITY 1 placebo group FVC declined more slowly than expected Noble P, et al. Lancet. 2011;377:1760 1769. King TE Jr, et al. Lancet. 2011;378(9807):1949 1961. 10

ASCEND 2014 ATS Pre 2011 2011 2013 2014 2011 Primary ASCEND Endpoint Achieved Primary Endpoint Patients with 10% FVC Decline or Death (%) 48% Relative Reduction Week King TE, et al. N Engl J Med. 2014;370(22):2083 2092. Pirfenidone Increased Progression Free Survival* Pirfenidone Reduces Loss of FVC Mean Change (ml) Rank ANCOVA P value < 0.00001 at each indicated time point 235 ml 428 ml *Progression is first occurrence of death, 10% FVC, or 50 m 6MWD King TE, et al. N Engl J Med. 2014;370(22):2083 2092. King TE, et al. N Engl J Med. 2014;370(22):2083 2092. Week <0.000001 11

ASCEND Adverse Events Possible Mechanisms of Nintedanib Action Adverse Event Pirfenidone (%) Placebo (%) (N = 278) (N = 277) Δ (%) Nausea 36 13.4 22.6 Rash 28.1 8.7 19.4 Dyspepsia 17.6 6.1 11.5 Anorexia 15.8 6.5 9.3 GERD 11.9 6.5 5.4 Weight Loss 12.6 7.9 4.7 Insomnia 11.2 6.5 4.7 Dizziness 17.6 13 4.6 Vomiting 12.9 8.7 4.2 Dyspnea 14.7 17.7 3 Cough 25.2 29.6 4.4 IPF 9.4 18.1 8.7 King TE, et al. N Engl J Med. 2014;370(22):2083 2092. Triple kinase inhibitor Phosphatase activator Antiangiogenic, antitumor activity VEGF Hilberg F, et al. Cancer Res. 2008;68(12):4774 4782. Tai WT, et al. J Hepatol. 2014;61(1):89 97. Nintedanib PDGF FGF SHP 1 Pleiotropic Effects Nintedanib Showed Promise for FVC Endpoint Pre 2011 ATS 2011 2011 2013 2014 INPULSIS 2014 ATS Pre 2011 2011 2013 2014 2011 Richeldi L, et al. N Engl J Med.2011:365;1079 1089. 12

Primary INPULSIS Endpoint Achieved Annual Rate of Change of FVC INPULSIS 1 52% Relative Reduction INPULSIS 2 45% Relative Reduction Nintedanib Reduces Loss of FVC Mean Observed Change from Baseline in FVC (ml) INPULSIS 1 INPULSIS 2 Richeldi L, et al. N Engl J Med. 2014;370(22):2071 2082. Nintedanib Placebo Richeldi L, et al. N Engl J Med. 2014;370(22):2071 2082. Week Mixed Findings for Time to First Acute Exacerbation Cumulative Incidence of First Acute Exacerbation (%) INPULSIS 1 INPULSIS 2 Common Nintedanib Adverse Events Event Nintedanib (n = 309) INPULSIS 1 Placebo (n = 204) Nintedanib (n = 329) INPULSIS 2 Placebo (n = 219) Any (%) 96 89 94 90 Diarrhea (%) 62 19 63 18 Nausea(%) 23 6 26 7 Richeldi L, et al. N Engl J Med. 2014;370(22):2071 2082. Days Richeldi L, et al. N Engl J Med. 2014;370(22):2071 2082. 13

2015 vs 2011 ATS/ERS Treatment Recommendations: For Use Raghu G, et al; ATS, ERS, JRS, and ALAT. Am J Respir Crit Care Med. 2015;192(2):e3 e19. Raghu G, et al; ATS, ERS, JRS, and ALAT. Am J Respir Crit Care Med. 2015;192(2):e3 e19. Current Phase 2 Trials for IPF Next Generation Therapy? Trial Target N Primary Endpoint Co trimoxazole (Ph 3) Pneumocystis jiroveci 56 Change in FVC or respir. Hospital n FG 3019 Anti CTGF 90 Change in FVC from baseline Rituximab CD 20 58 Titers of anti HEp 2 autoantibodies Simtuzumab Anti LOXL2 500 PFS GC 1008 TGF 25 Safety, tolerability, PK QAX576 Anti IL 13 40 Safety, tolerability, FVC Tralokinumab Anti IL 13 302 Change in FVC from baseline STX 100 αvβ6 32 Adverse events BMS 986020 LPA Receptor 300 Rate of change in FVC Ongoing Phase 2 Drug Trials SAR156597 (N = 300) FG 3019 (N = 136) BMS 986020 (N = 135) BG00011 (N = 40) 2012 2013 2014 2015 2016 2017 2018 Tralokinumab (N = 186) Simtuzumab (N = 500) Lebrikizumab (N = 300) TD139 (N = 60) Slide courtesy of L. Richeldi 14

Lung Transplantation for IPF: 2014 Referral Guidelines Histopathologic or radiographic evidence of usual interstitial pneumonitis (UIP) Abnormal lung function: FVC < 80% predicted or DL CO < 40% predicted Any dyspnea or functional limitation attributable to lung disease Any oxygen requirement, even if only during exertion Delayed Care Associated with Higher Mortality P for trend = 0.04 Weill D, et al. J Heart Lung Transplant.2014 Jun 26. [Epub ahead of print]. Lamas et al. Am J Respir Crit Care Med. 2011;184:842 847. Lung Transplantation is Increasing COPD IPF CF Common Complications and Comorbidities of IPF GERD Pulmonary hypertension Emphysema Acute exacerbation OSA CVD Thromboembolism Depression http://www.ishlt.org/registries/slides.asp?slides=heartlungregistry. Accessed August 2014. 15

IPF and GERD GERD Diagnosis Barium swallow Esophageal manometry 24 hour ph probe Treatment PPI s Nissen fundoplication WRAP IPF trial ClinicalTrials.gov: NCT01982968 Lee JS, et al. Am J Med. 2010;123(4):304 311. Raghu G, et al. Eur Respir J. 2006;27:136 142. GERD Treatment and Survival Distribution of mpaps in IPF Patients 25 20 Survival Not taking GERD medications Taking GERD medications Frequency 15 10 5 Time to Event (days) Lee JS, et al. Am J Respir Crit Care Med. 2011;184(12):1390 1394. 0 10.00 20.00 30.00 40.00 50.00 mpap Lettieri et al. Chest 2006. 129:746 752 PAH: mpap > 25 mm Hg 16

Mean Pulmonary Artery Pressure: Prognostic Value in IPF Cumulative Probability to Survival 1.0 0.8 0.6 0.4 0.2 0.0 P < 0.001 n = 54 n = 25 No (mpap 25 mm Hg) Yes (mpap > 25 mm Hg) 0 1 2 3 4 5 6 Years to Event Lettieri CJ, et al. Chest. 2006;129:746 752. 7 ATS/ERS Recommendation PH should not be treated in the majority of patients with IPF, but treatment may be a reasonable choice in a minority (weak recommendation, very low quality evidence). ( )* In patients with moderate to severe PH (mpap > 35 mm Hg) documented by right heart catheterization, a trial of vasomodulatory therapy may be indicated It is not clear if IPF with PH represents a distinct clinical phenotype (IPF PH) Raghu G, et al. Am J Respir Crit Care Med. 2011;183(6):788 824. * ( ) = GRADE quality of evidence very low Combined Pulmonary Fibrosis and Emphysema Syndrome (CPFE) Management of Patients With Combined Pulmonary Fibrosis and Emphysema (CPFE) No specific treatment for CPFE Absence of specific trials or prospective data IPF trials not adequate Smoking cessation; bronchodilators; supportive care; oxygen supplementation; lung transplant Discuss corticosteroids +/ azathioprine if NSIP considered Adapted from ERS/ESC guidelines, Galiè N et al. Eur Respir J. 2009;34:1219. 17

Management of Patients With Acute Exacerbations Exclude other causes Infection CHF Pulmonary embolism Ischemic heart disease HRCT Bronchoscopy (if permitted by medical status) Patients usually treated with broad spectrum antibiotics and corticosteroids (unproven efficacy) Walter N, et al. Proc Am Thorac Soc. 2006;3:330-338. ATS/ERS Recommendation The majority of patients with acute exacerbation of IPF should be treated with corticosteroids, but corticosteroids may not be reasonable in a minority (weak recommendation, very low quality evidence). Raghu G, et al. Am J Respir Crit Care Med. 2011;183(6):788 824. Sleep Disruption is Common in IPF Impaired physical and social functioning 1 Sleep quality should be a primary therapeutic goal Nocturnal hypoxemia is common Associated with significant sleep disruption, 1 decreased energy levels impaired physical functioning 2 Daytime SpO 2 is a strong predictor of nocturnal SpO 2 3,4 Daytime spirometric measures are poor predictors of nocturnal hypoxia Clinical trial of supplemental oxygen is recruiting (clinicaltrials.gov NCT01961362) 1. Mermigkis C, et al. Med Princ Pract. 2009;18:10 15. 2. Clark M, et al. Thorax. 2001;56:482 486. 3. Douglas NJ, et al. Am Rev Respir Dis. 1990;141:1055 1070. 4. Cormick W, et al. Thorax. 1986;41:846 854. Cardiovascular Disease in IPF Prevalence: 20% of IPF patients have comorbid CVD CVD diagnosed during follow up significantly increased mortality (HR 4.7) Increased incidence of ACS Angina DVT CAD CHF and CAD account for 1/3 deaths in IPF Hyldgaard C, et al. Respir Med. 2014;108(4):647 653. Hubbard RB, et al. Am J Respir Crit Care Med 2008; 178:1257 1261. Izbicki G, et al. Respir Med. 2009; 103(9):1346 1349 18

Odds Ratios for Risk Factors of CVD for Incident Cases of IPF UK database: The Health Improvement Network (THIN) Risk factor Cases (n=3211) (%) Controls (n=12,307) (%) Odds Ratio (95% CI) P value* Hypertension 25.6 21.3 1.31 (1.19 1.44) <0.001 Diabetes 14.0 12.0 1.20 (1.07 1.34) 0.003 Ex smoker 38.7 26.3 2.20 (1.99 2.43) Current smoker 13.54 13.45 1.44 (1.27 1.65) <0.001 Rate Ratios for Ischemic Heart Disease and Stroke IPF vs Control Subjects Outcome # events in cases Crude rate in cases (per 1000 pyrs) # events in controls Crude rate in controls (per 1000 pyrs) Rate Ratio P value* IHD 135 17.6 474 9.9 2.32 < 0.001 Stroke 87 11.3 523 10.3 1.25 0.09 * Likelihood ratio test BMI > 31 15.1 13.3 1.16 (1.02 1.32) <0.001 * Likelihood ratio test http://journal.publications.chestnet.org/. Accessed August 2014. http://journal.publications.chestnet.org/. Accessed August 2014. Cumulative Incidence of IHD is Higher With IPF Percent survival 100 75 50 25 N=21 N=52 P=0.003 Significant CAD Mild or no CAD 0 0 250 500 750 1000 1250 1500 1750 2000 Days http://journal.publications.chestnet.org/. Accessed August 2014. Nathan SN, et al. Respir Med. 2010:104:1035 1041. 19

VTE is Elevated in Patients With IPF National Center for Health Statistics, 1988 2007 46,450,489 total records 218,991 patients with IPF 3815 (1.74%) also diagnosed with VTE Increased risk of IPF VTE decreased life span of patients with IPF Data suggest a link between a pro fibrotic and a procoagulant state Sprunger DB, et al. Eur Respir J. 2012;39(1):125 132. Depression in IPF Observed in ~25% of patients with IPF 9.8% in a general population of elderly subjects 26% in patients with COPD Correlated strongly and independently with dyspnea pain sleep quality FVC Baseline depression score was the strongest predictor of depression score at 6 months (r = 0.59, P < 0.00005) Ryerson CJ, et al. Respirology. 2012 ;17(3):525 32. Conclusions Comorbidities associated with IPF such as GERD, CPFE, CVD, sleep apnea, and depression should be treated Clinical trials testing drugs approved for pulmonary hypertension in patients with IPF and PH have been negative on IPF endpoints Other endpoints have been positive Guidelines recommend against treating IPF patients for PH Acute exacerbation is a serious complication of IPF 20