Strategies for Updated Treatment Options for IPF

Strategies for Updated Treatment Options for IPF Paul W. Noble, MD Vera and Paul Guerin Family Distinguished Chair in Pulmonary Medicine Professor and Chair Department of Medicine Director, Women's Guild Lung Institute Cedars-Sinai Medical Center Los Angeles, California Paul W. Noble, MD, has a financial interest/relationship or affiliation in the form of: Consultant for: Boehringer Ingelheim Pharmaceuticals, Inc.; Celgene Corporation; Genentech, Inc./F. Hoffmann-La Roche Ltd.; GlaxoSmithKline; and InterMune. Clinical Insights for Improving IPF Recognition and Diagnosis 1

Rachel: 61 Year Old With Persistent Cough and Dyspnea MEDICAL FORM Presenting Complaint Persistent cough Mild exercise intolerance No fever, chills, weight loss Medical History GERD Never smoker No significant exposures (eg, mold, bird, or drug) Medications Esomeprazole 40 mg/d oral Examination Notes BP: 130/80 Pulse: 72 Chest: Bibasilar crackles CV: Regular rate and rhythm, no M/R/G Abd: Soft, non tender, non obese Ext: No cyanosis/clubbing/or edema PFT at Presentation FVC 3.3 L 68% FEV 1 3.0 L 90% FEV 1 /FVC 0.91 TLC 4.77 64% DLCO 15.7 59% Abd: abdomen; DLCO: diffusing capacity of the lung for carbon monoxide; Ext: extremities; FEV 1 : forced expiratory volume in 1 second; FVC: forced vital capacity; GERD: gastroesophageal reflux disease; M/R/G: murmurs, rubs, and gallops; TLC: total lung capacity. Distinguishing Dyspnea: IPF Prevalence 1 3 COPD: chronic obstructive pulmonary disease; IPF: idiopathic pulmonary fibrosis. 1. Raghu G et al. Resp Crit Care Med. 2006;174:810 816. 2. Go AS et al. Circulation. 2013;127:e6 e245. 3. Wheaton AG et al. MMWR Morb Mortal Wkly Rep. 2015;64:289 295. 2

Increasing Prevalence of IPF 1 Medicare Beneficiaries Age 65 y Median survival = 3.8 years Factors associated with lower survival Age, index year, male gender 1. Raghu G et al. Lancet Respir Med. 2014;2:566 572. Classification of Diffuse Parenchymal Lung Disease 1 AIP: acute interstitial pneumonia; COP: cryptogenic organizing pneumonia; DIP: desquamative interstitial pneumonia; DPLD: diffuse parenchymal lung disease; IIP: idiopathic interstitial pneumonia; LAM: lymphangioleiomyomatosis; LCG: Langerhans cell granulomatosis; LIP: lymphocytic interstitial pneumonia; NIP: nonspecific interstitial pneumonia; RB ILD: respiratory bronchiolitis interstitial lung disease. 1. American Thoracic Society; European Respiratory Society (ATS/ERS). Am J Respir Crit Care Med. 2002;165:277 304. 3

Updated Consensus Statement: Diagnostic Requirements for IPF 1,2 Diagnosis of IPF requires 1.Exclusion of other known causes of ILD 2.Presence of UIP pattern on HRCT (in patients without surgical biopsy) 3.An HRCT pattern of definite/possible UIP with a surgical lung biopsy showing definite/probable UIP HRCT: high resolution computed tomography; UIP: usual interstitial pneumonia. 1. Raghu G et al. Am J Respir Crit Care Med. 2011;183:788 824. 2. ATS/ERS. Am J Respir Crit Care Med. 2000;161(2 Pt 1):646 664. Clinical Tools for Diagnosis 1 Clinical History and physical PFT Lab Raise suspicion that ILD is present Identify the cause of the disease Infection Systemic disorders Exposures (eg, occupational, environment, hobby) Idiopathic 1. Raghu G et al. Am J Respir Crit Care Med. 2011;183:788 824. 4

Radiographic Tools for Diagnosis 1 Radiographic HRCT: allows detailed evaluation of the lung parenchyma HRCT Features Ground glass attenuation Honeycombing/cysts Lines/reticular thickening Consolidation Nodules Decreased lung attenuation HRCT Distribution Upper Lower Central Peripheral Diffuse/bilateral 1. Raghu G et al. Am J Respir Crit Care Med. 2011;183:788 824. Role of HRCT in Diagnosing UIP 1 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/ air trapping (bilateral, in 3 lobes) Consolidation in bronchopulmonary segment(s)/lobe(s) 1. Raghu G et al. Am J Respir Crit Care Med. 2011;183:788 824. 5

Rachel: 61 Year Old Female With Persistent Cough and Dyspnea PFT at Presentation FVC 3.3 L 68% FEV 1 3.0 L 90% FEV 1 /FVC 0.91 TLC 4.77 64% DLCO 15.7 59% Test Results and Next Steps Her chest x ray is markedly abnormal The lung volumes are very small or restricted And there are reticular infiltrates that are worse on the periphery and perhaps the lower lobes For a more detailed evaluation of the lung parenchyma, we need to order a high resolution CT scan Rachel s HRCT 1 1. Image courtesy of Steven Nathan, MD. 6

Nonspecific Interstitial Pneumonia 1 1. Image courtesy of Navdeep Singh, MD. Chronic Hypersensitivity Pneumonitis 1 Mosaic Ground glass Air trapping 1. Image courtesy of Kevin Flaherty, MD. 7

Histologic Tools for Diagnosis 1,2 Histology Bronchoscopy Surgical lung biopsy UIP Pattern Marked fibrosis/architectural distortion honeycombing, predominantly subpleural/paraseptal Patchy fibrosis Fibroblastic foci Absence of features to suggest alternative diagnosis 1. Images courtesy of Steven Nathan, MD. 2. Raghu G et al. Am J Respir Crit Care Med. 2011;183:788 824. Interstitial Lung Disease Diagnostic Team Clinician Radiologist Pathologist Communication among multidisciplinary team members is essential for an accurate diagnosis 8

Having a Conversation With the Patient Newly Diagnosed With IPF Spend adequate time to explain the prognosis and assess patient's preferences and values Burden and morbidity of IPF can be emotionally overwhelming and will likely impact family members as well Each individual patient with IPF is different; consider physiology, exercise tolerance, radiology, and pathology when choosing a course of treatment Patients who are at increased risk of mortality should be referred for lung transplantation early in the course Monitoring Patients With IPF for Disease Progression Every 3 to 4 months: PFT 6MWD (distance/nadir saturation) O 2 requirement Comorbidities Consider dyspnea questionnaire (UCSD) HRCT Annually or when suspicion for clinical worsening 6MWD: 6 minute walk distance; USCD: University of California, San Diego. 9

Shared Decision Making in IPF Treatment Review of Rachel s Case 61 year old female with ILD discovered through workup for cough and dyspnea Rachel s PFT showed restrictive lung disease with decreased gas transfer Patient was diagnosed with IPF Next step: Should we consider initiating therapy for IPF? 10

Breakthroughs in the Treatment of IPF Therapy Nintedanib Pirfenidone Trial Name INPULSIS ASCEND Both therapies were FDA approved on October 15, 2014, for treatment of IPF 2015 IPF guidelines indicate Conditional recommendation for use of nintedanib and pirfenidone (moderate confidence in effect estimates) 1 1. Raghu G et al. Am J Respir Crit Care Med. 2015;192(2):e3 e19. Nintedanib: INPULSIS 1 and INPULSIS 2 Trial Design 1 SGRQ: St. George s Respiratory Questionnaire. 1. Richeldi L et al. N Engl J Med. 2014;370:2071 2082. 11

INPULSIS Primary Endpoint: Adjusted Annual Rate of Decline in FVC 1 1. Richeldi L et al. N Engl J Med. 2014;370:2071 2082. INPULSIS Secondary Endpoint: Adjusted Mean Change From Baseline in Total SGRQ Score Over 52 Weeks 1 Study Nintedanib Placebo INPULSIS 1 4.34 4.39 INPULSIS 2 2.80 5.48 Difference, Nintedanib vs Placebo (95% CI) 0.05 ( 2.50 to 2.40) 2.69 ( 4.95 to 0.43) P.97.02 1. Richeldi L et al. N Engl J Med. 2014;370:2071 2082. 12

INPULSIS: Time to First Investigator Reported Acute Exacerbation 1 INPULSIS 1 INPULSIS 2 1. Richeldi L et al. N Engl J Med. 2014;370:2071 2082. INPULSIS: Treatment Emergent Adverse Events 1 Diarrhea (~62% vs 18%) and nausea (~23% vs 6%) more common in nintedanib group than in the placebo group Event Nintedanib (n = 309) INPULSIS 1 Placebo (n = 204) Nintedanib (n = 329) INPULSIS 2 Placebo (n = 219) Any AE 96.4% 88.7% 94.5% 90.4% Any AE, excluding progression of IPF 95.8% 87.7% 94.5% 90.0% Severe AEs 26.2% 18.1% 28.3% 28.3% Serious AEs 31.1% 27.0% 29.8% 32.9% Fatal AEs 3.9% 4.9% 7.6% 9.6% AEs leading to treatment D/C 21.0% 10.8% 17.6% 15.1% 1. Richeldi L et al. N Engl J Med. 2014;370:2071 2082. 13

FDA Approval of Nintedanib 1 Approved October 15, 2014, for the treatment of IPF Liver function tests required prior to treatment and should be evaluated every 3 months in first year Dosage and administration 150 mg twice daily with food Take each dose approximately 12 h apart Adverse reactions? Consider temporary dose reduction to 100 mg, temporary interruption, or discontinuation 1. Ofev (nintedanib) Prescribing Information. http://bidocs.boehringer ingelheim.com/biwebaccess/ ViewServlet.ser?docBase=renetnt&folderPath=/ Prescribing+Information/PIs/Ofev/ofev.pdf. Accessed July 24, 2015. Effect of Nintedanib on Patients With Baseline FVC >90% 1 Annual Rate of Decline in FVC by Baseline FVC 90% Predicted Patients with marginally impaired FVC at baseline might benefit from treatment with nintedanib 1. Kolb M et al. American Thoracic Society 2015 International Conference (ATS 2015). Abstract A1021. 14

Nintedanib: Update From European Respiratory Society (ERS) International Congress 2015 1 Data from interim analysis of INPULSIS extension trial (INPULSIS ON) showed efficacy and safety of nintedanib is sustained long term (2 years) Effect of nintedanib on mean change from baseline in FVC at wk 48 of INPULSIS ON was comparable to that seen at 52 wk in INPULSIS trial: INPULSIS ON:» 87 ml for all patients» 96.4 ml for patients continuing treatment with nintedanib in extension trial» 73.1 ml for patients initiating treatment with nintedanib INPULSIS (pooled data from INPULSIS 1 and 2): 88.9 ml (nintedanib) vs 203.0 ml (placebo) 1. Crestani B et al. European Respiratory Society International Congress 2015 (ERS 2015). Abstract OA4495. Pirfenidone: ASCEND Trial Design 1 PFS: progression free survival. 1. King TE Jr et al. N Engl J Med. 2014;370:2083 2092. 15

ASCEND: Primary Efficacy Analysis 1 Absolute difference 2.5% 7.9% 12.3% 15.3% Relative difference 54.0% 58.0% 57.8% 47.9% Rank ANCOVA P <.001 <.001 <.001 <.001 ANCOVA: analysis of covariance. 1. King TE Jr et al. N Engl J Med. 2014;370:2083 2092. ASCEND: Secondary Endpoints (6MWD and PFS) 1 1. King TE Jr et al. N Engl J Med. 2014;370:2083 2092. 16

ASCEND and CAPACITY: Mortality 1 Variable Pirfenidone Placebo HR (95% CI) P ASCEND Patients, n 278 277 Death From any cause 4.0% 7.2% 0.55 (0.26 1.15).10 Related to IPF 1.1% 2.5% 0.44 (0.11 1.72).23 ASCEND and CAPACITY (pooled data) Patients, n 623 623 Death From any cause 3.5% 6.7% 0.52 (0.31 0.87).01 Related to IPF 1.1% 3.5% 0.32 (0.14 0.76).006 1. King TE Jr et al. N Engl J Med. 2014;370:2083 2092. ASCEND: Treatment Emergent Adverse Events 1 Nausea (36% vs 13%) and rash (28% vs 9%) more common in pirfenidone group than placebo group Adverse events (AEs) generally mild to moderate severity, reversible, and without clinically significant sequelae Patients Pirfenidone (n = 278) Placebo (n = 277) Any AE 99.6% 98.2% Grade 3 20.9% 22.0% Grade 4 2.9% 5.1% Any serious AE 19.8% 24.9% IPF 2.5% 9.7% Treatment emergent all cause mortality 2.9% 5.4% Any AE leading to treatment discontinuation 14.4% 10.8% 1. King TE Jr et al. N Engl J Med. 2014;370:2083 2092. 17

FDA Approval of Pirfenidone 1 Approved October 15, 2014, for the treatment of IPF Liver function tests required prior to treatment and should be evaluated every 3 months in first year Dosage and administration 801 mg 3x daily with food (three 267 mg capsules per dose) Take each dose at the same time each day Initiate with titration» Days 1 7: one capsule 3x daily» Days 8 14: two capsules 3x daily» Days 15 onward: three capsules 3x daily Adverse reactions? Consider temporary dosage reduction, treatment interruption, or discontinuation 1. Esbriet (pirfenidone) Prescribing Information. http://www.gene.com/download/pdf/esbriet_prescribing.pdf. Accessed July 24, 2015. Effect of Pirfenidone on Patients With 10% Decline in FVC in First 6 Months of Treatment a Outcomes During the Subsequent 6 Month Period After an Initial 10% Absolute Decline in %FVC 1 a Pooled data from ASCEND and CAPACITY. 1. Nathan SD et al. ATS 2015. Abstract A1016. Patients whose disease has progressed might benefit from continued treatment with pirfenidone 18

Pirfenidone: Update From ERS International Congress 2015 1 Kaplan Meier Plot of Treatment Emergent All Cause Mortality Through End of Study of All Randomized Patients 1. Nathan SJ et al. European Respiratory Society International Congress 2015 (ERS 2015). Abstract 852820. Engaging in a Shared Decision Making Process With Rachel, a 61 Year Old Patient With IPF 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 Rachel s preferences and concerns Focus on symptom control and management of comorbidities Set treatment expectations Look at the option of lung transplantation 19

Improving Comorbidity Management and Quality of Life Throughout the IPF Disease Continuum Will: 57 Year Old With Comorbid Disease 57 year old male Diagnosed with IPF ~3 y ago (CT scan and open lung biopsy) Medical history significant for depression, GERD, and pulmonary hypertension 20

IPF Comorbidities 1 Pulmonary Parenchymal lung disease Lung cancer COPD or emphysema Infections, such as aspergillomas Pulmonary vascular disease (eg, pulmonary embolus, PH) Other (eg, sleep apnea) Extrapulmonary Cardiac (eg, HFpEF, CAD) Endocrine (eg, diabetes mellitus, hypogonadism) Hematologic (eg, anemia, polycythemia) GI (eg, GERD) Psychiatric Musculoskeletal (eg, osteoporosis, deconditioning) Medications HFpER: heart failure with preserved ejection fraction; PH: pulmonary hypertension. 1. King C, Nathan SD. Curr Opin Pulm Med. 2013;19:466 737. GERD Treatment and Survival 1 Suggests that GERD could contribute to the rate of decline in patients with IPF 1. Lee JS et al. Am J Respir Crit Care Med. 2011;184:1390 1394. 21

GERD Management in IPF: ATS/ERS Recommendation IPF guidelines suggest that clinicians use regular antacid treatment for patients with IPF (conditional recommendation, very low confidence in effect estimates) 1 1. Raghu G et al. Am J Respir Crit Care Med. 2015;192(2):e3 e19. Prevalence of Pulmonary Hypertension in IPF 1 Concomitant PH and IPF significantly increases the likelihood of mortality or lung transplant RHC: right heart catheterization; RVSP: right ventricular systolic pressure. 1. Nathan SD, Cottin V. Eur Respir Monogr. 2012;57:148 160. 22

Treat IPF Patients for PH? 1 Ambrisentan, bosentan, and macitentan have been found nonefficacious or harmful STEP IPF Trial (Sildenafil) In patients with advanced IPF, the primary outcome variable (proportion of patients with 6MWD increase >20%) was not met However, arterial oxygenation, DLCO, dyspnea, and quality of life improved ATS/ERS guidelines suggest that clinicians not use sildenafil, for treatment of IPF (conditional recommendation against, moderate confidence in estimates of effect) 2 1. Zisman DA et al. N Engl J Med. 2010;363:620 628. 2. Raghu G et al. Am J Respir Crit Care Med. 2015;192(2):e3 e19. Treat IPF Patients for PH? IPF patients should NOT be routinely treated for PH ATS/ERS Recommendation for PH Management 1 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 lowquality evidence) In patients with moderate to severe PH (mpap >35 mmhg) documented by RHC, a trial of vasomodulatory therapy may be indicated 2015 updated guidelines note that reassessment of the previous recommendation was deferred 2 Is IPF with PH a distinct clinical phenotype (IPF PH)? Regardless, mortality risk is higher and lung transplantation should be discussed early mpap: mean pulmonary arterial pressure. 1. Raghu G et al. Am J Respir Crit Care Med. 2011;183:788 824. 2. Raghu G et al. Am J Respir Crit Care Med. 2015;192(2):e3 e19. 23

IPF Impairs Patient s Quality of Life 1 Symptoms Dyspnea limited activity Fatigue/exhaustion Cough Dry, nagging, never satisfying Look for evidence of reflux and treat, as this may improve severe cough Outlook Hopeless, abandoned Frustrated, uneducated, embarrassed 1. http://www.heartfailurematters.org/en_gb/understanding heart failure/shortness of breath. Accessed July 22, 2015. Enroll patients in pulmonary rehabilitation and support groups Supportive Care for Patients With IPF Supportive Care Options Educate patients Refer to reliable sources Treatment of comorbid illness PH, GERD, OSA, CAD Prescribe O 2 Screen for resting/ nocturnal/exertional requirement Close monitoring of symptoms and pulmonary function Exercise Pulmonary rehabilitation OSA: obstructive sleep apnea. 24

Patient Centered Management 1 Informed, activated, participatory patient and family Patient centered, communicative healthcare provider Accessible, well organized, responsive healthcare system Improved communication Improved health outcomes 1. Epstein RM, Street RL Jr. National Cancer Institute, NIH Publication No. 07 6225. Bethesda, MD: 2007. Will: Overcoming Barriers to Optimal IPF Management Initiate treatment An Action Plan for Will Notify if change in status/new symptoms occur Monitor oxygen desaturation to see if he needs supplemental oxygen Get educated Discuss transplant options and potential next steps Consider a support group Focus on things that he can still do Stay active, weight loss program if overweight Consider a pulmonary rehabilitation program Adhere to management plan, explaining his other options if he progresses Other medications Clinical trials Engaging the patient, his family, and his clinician in his care can lead to the best possible outcome 25