Therapies for Idiopathic Pulmonary Fibrosis Pharmacologic, Non-Pharmacologic

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2 Therapies for Idiopathic Pulmonary Fibrosis Pharmacologic, Non-Pharmacologic Amy Olson, MD, MSPH Associate Professor, Division of Pulmonary and Critical Care Medicine National Jewish Health, Denver, CO

3 Learning Objectives Describe best practices for diagnosing IPF based on the most recent evidence-based guidelines Develop a comprehensive assessment and diagnosis strategy to differentiate IPF from other interstitial lung diseases Develop a comprehensive approach to management of IPF based on the most recent clinical data to include pharmacologic and non-pharmacologic therapies Determine appropriate strategies for the multidisciplinary healthcare team to effectively educate patients with IPF about their disease and address quality of life issues

4 Learning Objectives Review Guidelines for the Treatment of IPF Overview of IPF Pathophysiology Review the two FDA-approved anti-fibrotic therapies for IPF Proposed mechanism of action Outcomes from the clinical trials Management Expectations Side Effects Review recommended non-pharmacologic therapies Lung Transplant Oxygen therapy Pulmonary Rehabilitation Co-morbidities (?)

5 Guidelines for the Treatment of IPF Raghu G, et al. Am J Respir Crit Care Med. 2015;192:

6 Strong vs. Conditional Recommendations Raghu G, et al. Am J Respir Crit Care Med. 2015;192:

7 Conventional Pharmacological Therapies Treatment Lung Transplantation Long-term oxygen for hypoxemia Pulmonary Rehabilitation Comorbidity Therapy GERD Pirfenidone Nintedanib (TKI multiple targets) Sildenafil (PDE-5 inhibitor) Macitentan/Bosentan (Dual ERA) NAC alone NAC/Azathioprine/Prednisone Corticosteroids Warfarin (Anticoagulation) Ambrisentan (Selective ERA) Imatinib (TKI one target) Strong For Conditional For Weak Against Strong Against Raghu G, et al. Am J Respir Crit Care Med. 2011;183: Raghu G, et al. Am J Respir Crit Care Med. 2015;192:

8 Pathophysiology of IPF This image has been adapted and reprinted with permission of the American Thoracic Society. Copyright 2017 American Thoracic Society. Ahluwalia N, et al./2014/new Therapeutic Targets in Idiopathic Pulmonary Fibrosis/Am J Respir Crit Care Med/190/ The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.

9 IPF Histopathology Courtesy of Steve Groshong, MD, NJH.

10 Anti-Fibrotic Therapies Treatment Lung Transplantation Long-term oxygen for hypoxemia Pulmonary Rehabilitation Comorbidity Therapy GERD Pirfenidone Nintedanib (TKI multiple targets) Sildenafil (PDE-5 inhibitor) Macitentan/Bosentan (Dual ERA) NAC alone NAC/Azathioprine/Prednisone Corticosteroids Warfarin (Anticoagulation) Ambrisentan (Selective ERA) Imatinib (TKI one target) Strong For Conditional For Weak Against Strong Against Raghu G, et al. Am J Respir Crit Care Med. 2011;183: Raghu G, et al. Am J Respir Crit Care Med. 2015;192:

11 Pharmacologic Therapies - Pirfenidone Anti-fibrotic Anti-inflammatory Anti-oxidant

12 Pathophysiology of IPF This image has been adapted and reprinted with permission of the American Thoracic Society. Copyright 2017 American Thoracic Society. Ahluwalia N, et al./2014/new Therapeutic Targets in Idiopathic Pulmonary Fibrosis/Am J Respir Crit Care Med/190/ The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.

13 Capacity I & II: Pirfenidone Based on this data, the FDA did not approve Pirfenidone and a 3 rd study was required (Ascend) Mean change from baseline in percentage predicted FVC in study 004 (A), study 006 (B), and the pooled population (C) FVC=forced vital capacity. *Pirfenidone 2403 mg/day versus placebo. Rank ANCOVA (pirfenidone 2403 mg/day vs placebo). 95% CIs were only calculated for absolute differences for the week 72 timepoint in study 004 (0 7 to 9 1) and study 006 ( 3 5 to 4 7). Reprinted from The Lancet, 377, Nobel PW, et al., Pirfenidone in patients with Idiopathic Pulmonary Fibrosis (CAPACITY): two randomised trials, , Copyright 2011, with permission from Elsevier.

14 Ascend: Pirfenidone Primary Endpoint Was Achieved Patients with 10% FVC Decline or Death (%) Mean Change in FVC from Baseline 235 ml vs. 428 ml* 48% Relative Reduction. * For deaths, FVC = 0. From The New England Journal of Medicine, King TE, et al., A Phase 3 Trial of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis, 370, Copyright 2014 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society

15 Side Effects Adverse Event Pirfenidone (N=278) Placebo (N=277) Nausea 36% 13.4% Rash 28.1% 8.7% Dyspepsia % 6.1% GERD 11.9% 6.5% In addition to nausea and dyspepsia, subjects on therapy also had an increased incidence of anorexia, vomiting, and decrease in weight The rash is typically a photosensitivity rash that results in a macular-type exanthema with flaking plaques, and can be extremely pruritic Discontinuation due to side effects was 14.4% King TE, et al. N Engl J Med. 2014;370: Koulelidis A, et al.

16 Pharmacologic Therapies - Nintedanib Triple Tyrosine Kinase Inhibitor Vascular Endothelial Growth Factor (VEGF) Platelet Derived Growth Factor (PDGF) Fibroblast Growth Factor (FGF)

17 Pathophysiology of IPF This image has been adapted and reprinted with permission of the American Thoracic Society. Copyright 2017 American Thoracic Society. Ahluwalia N, et al./2014/new Therapeutic Targets in Idiopathic Pulmonary Fibrosis/Am J Respir Crit Care Med/190/ The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.

18 INPULSIS 1 & 2: Nintedanib Primary Endpoint Was Achieved 52% Relative Reduction 45% Relative Reduction From The New England Journal of Medicine, Richeldi, et al., Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis, 370, Copyright 2014 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society

19 Side Effects: Gastrointestinal Discontinuation due to side effects was 21%. Adverse Event * Nintedanib (N=309) Placebo (N=204) Any 96% 89% Diarrhea 62% 19% Nausea 23% 6% * Adverse event data from INPULSIS 1; similar to INPULSIS 2. Richeldi L, et al. N Engl J Med ;370:

20 Side Effects: Bleeding Theoretical risk with nintedanib given inhibition of PDGF and VEGF Patients on anticoagulation were excluded from INPULSIS studies Bleeding Events Epistaxis Contusion Serious Bleeding Nintedanib 10.3% 4.1% 1.6% 1.3% Placebo 7.8% 3.1% 0.9% 1.4% Corte T, et al. Respiratory Research. 2015; 16:116.

21 Side Effects: Additional Myocardial Infarction Fatal adverse cardiac events INPULSIS I INPULSIS II Nintedanib 0.3% (n=1) 0.6% (n=2) Placebo 1% (n=2) 1.8% (n=4) Other cardiovascular events were similar between the treatment and placebo groups. Richeldi L, et al. N Engl J Med ;370:

22 Side Effects - Liver Toxicity Pirfenidone Pirfenidone vs. Placebo AST/ALT > 3 x upper limits of normal (2.9% vs. 0.7%) All elevations were reversible Lead to discontinuation in 1% of patients Monitoring LFTs q month x 6 months LFTs q 3 months Nintedanib Nintedanib vs. Placebo AST/ALT > 3 x upper limits of normal INPULSIS 1 (4.9% vs. 0.5%) INPULSIS 2 (5.2% vs. 0.9%) Monitoring LFTs q month x 3 months LFTs q 3 months

23 Management of Side Effects Patient Education Adjunctive Medications/Food Diarrhea with Nintedanib Loperamide Nausea with Pirfenidone Ensure medications taken within the meal If a side effect occurs, adjust dose If it persists, temporary interrupt therapy Once resolved, slow re-escalation Permanent discontinuation for recurrent or severe side effects

24 Management of Expectations These anti-fibrotics MAY Slow down progression of disease Cause significant side-effects These anti-fibrotics WON T Make a patient feel better May or may not make a patient live longer Thus, the conditional recommendation

25 Mr. Slide H Has Title Been Newly Diagnosed With IPF. What Is His Likely Response? 1. Mr. H may not want to take pirfenidone due to the phototoxocity. 2. Mr. H may not want to take pirfenidone due to the number of pills/frequency of dosing. 3. Mr. H may not want to take nintedanib due to his cardiac history. 4. Mr. H may not want to take nintedanib due to concerns for diarrhea. 5. All of the above.

26 Mr. Slide H Has Title Been Newly Diagnosed With IPF. What Is His Likely Response? 1. Mr. H may not want to take pirfenidone due to the phototoxocity. 2. Mr. H may not want to take pirfenidone due to the number of pills/frequency of dosing. 3. Mr. H may not want to take nintedanib due to his cardiac history. 4. Mr. H may not want to take nintedanib due to concerns for diarrhea. 5. All of the above.

27 Conventional Non-Pharmacological Therapies Treatment Lung Transplantation Long-term oxygen for hypoxemia Pulmonary Rehabilitation Comorbidity Therapy GERD Pirfenidone Nintedanib (TKI multiple targets) Sildenafil (PDE-5 inhibitor) Macitentan/Bosentan (Dual ERA) NAC alone NAC/Azathioprine/Prednisone Corticosteroids Warfarin (Anticoagulation) Ambrisentan (Selective ERA) Imatinib (TKI one target) Strong For Conditional For Weak Against Strong Against Raghu G, et al. Am J Respir Crit Care Med. 2011;183: Raghu G, et al. Am J Respir Crit Care Med. 2015;192:

28 Lung Transplantation The only therapy that prolongs survival in IPF IPF is now the number one diagnosis for transplant Five-year survival is ~ 50% Many centers are transplanting older patients (>65) Chambers DC, et al. J Heart Lung Transplant Oct;36(10): King TE Jr, et al. Lancet. 2011;378:

29 Lung Transplantation: When To Refer At the time of diagnosis Evaluation (due to unpredictable course) As disease progresses Listing (based on Lung Allocation Score) Chambers DC, et al. J Heart Lung Transplant Oct;36(10): Reprinted from The Lancet, 378, King TE Jr, et al., Idiopathic Pulmonary Fibrosis, , Copyright 2011, with permission from Elsevier.

30 Oxygen Therapy Ensure oxygen saturations are > 90% at all times Rest, Ambulation, Exercise, Sleep Obstructive Sleep Apnea (OSA) is common in IPF Patients may not present with typical symptoms Untreated OSA may be associated with worse prognosis Mortality & Clinical Progression While this is a Strong Recommendation, limited data No proven survival benefit Evidence does exist that it may improve exercise capacity/reduces dyspnea At present, Ongoing studies Calls for more research Raghu G, et al. Am J Respir Crit Care Med. 2011;183: Bosi M, et al. Lung Jul 3. [Epub ahead of print]. Dowman LM, et al. Respirology. 2017;22:

31 Pulmonary Rehabilitation Most programs meet 2-3 times per week for 4 to 12 weeks or more... Improves quality of life Increases walk distance Decreases breathlessness Decreases depression Duration of benefit? Image from: ATS Patient Information Series. Dowman L, et al. Cochrane Database Sys Rev Oct 6;(10). Olson AL, et al. Patient Relat Outcome Meas May 17; Raghu G, et al. Am J Respir Crit Care Med. 2011;183:

32 Comorbidities: Gastroesophageal Reflux Disease (GERD) Higher prevalence in IPF Distal GER reported as high as 88% of patients Proximal GER reported as high as 71% of patients May be silent Hypothesized to play a role in progressive lung fibrosis IPF treatment recommendations Conditional for the treatment of reflux Lee JS, et al. Am J Respir Crit Care. 2011;184:

33 Pathophysiology of IPF This image has been adapted and reprinted with permission of the American Thoracic Society. Copyright 2017 American Thoracic Society. Ahluwalia N, et al./2014/new Therapeutic Targets in Idiopathic Pulmonary Fibrosis/Am J Respir Crit Care Med/190/ The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.

34 Other Comorbidities Comorbidities Relative Risk (95% CI) Pulmonary Hypertension ( )* Pulmonary Embolism 6.97 ( )* Pulmonary Infections 4.20 ( )* Heart Failure 3.83 ( )* Sleep Apnea 3.65 ( )* Lung Cancer 2.83 ( )* Myocardial Infarction 2.13 ( )* Coronary Artery Disease 1.86 ( )* Depression 1.40 ( )* Collard H, et al. J Med Econ. 2012;15:

35 IPF Future We have no known pharmacologic therapy to halt disease Still much work to be done Consider discussing with patients a referral for a clinical trial

36 Summary For patients with IPF Two FDA approved anti-fibrotic therapies are available Equipoise on the efficacy Shared decision making between the physician and patient regarding treatment/agent Keeping patients on therapy requires Expectation management Side effect management Remember the non-pharmacologic therapies & to identify and treat comorbidities Always consider ongoing clinical trials in IPF

37 For additional resources and IPF patient education materials, please visit