IPF AND OTHER FIBROSING LUNG DISEASE: WHAT DRUGS MIGHT WORK AND ON WHOM DO THEY W ORK?

Transcription

1 IPF AND OTHER FIBROSING LUNG DISEASE: WHAT DRUGS MIGHT WORK AND ON WHOM DO THEY W ORK? KEVIN K. BROWN, MD PROFESSOR AND VICE CHAIRMAN, DEPARTMENT OF MEDICINE NATIONAL JEWISH HEALTH DENVER, CO Kevin K. Brown, MD, is a Professor and Vice Chairman in the Department of Medicine at National Jewish Health. He has had a long-standing interest in the clinical and biologic aspects of fibrosing lung disease and has directed National Jewish s Interstitial Lung Disease Program for two decades. Dr. Brown has leadership positions in a number of national and international pulmonary organizations, and serves on the steering and protocol development committees of multiple national and international multi-centered treatment trials in lung fibrosis. Named as one of the nation s top physicians for more than a decade, he has an active clinical practice as well as an NIH-funded translational research program focused on the development, progression, and control of fibrosing lung diseases. OBJECTIVES: Participants should be better able to: 1. To classify and distinguish among causes of pulmonary fibrosis; 2. To diagnose Idiopathic Pulmonary Fibrosis (IPF); 3. To assess the newly available treatments for IPF. FRIDAY, MARCH 13, :30 AM 1

2 IPF and other Fibrosing Lung Diseases: What Drugs Might Work and On Whom Do They Work? Kevin K. Brown, MD Professor and Vice Chair Department of Medicine National Jewish Health Denver, CO NAMDRC 2015 March 15, 2015 Scottsdale, AZ DISCLOSURE Dr. Brown has received research grants from NHLBI, Actelion, Amgen, Gilead and participates in consulting and speakers bureau activities for Actelion, Almiral, Altitude Pharma, Amgen, Astra Zeneca, Bayer, Biogen/Stromedix, Boehringer Ingelheim, Celgene, Centocor, Fibrogen, Galecto, Gilead, GlaxoSmith Kline, Medmmune, Novartis, Pfizer, Promedior, Roche/Genentech, Sanofi/Genzyme, Veracyte, but these do not create a conflict related to the following presentation. 2

3 The problem 3

4 4

5 The interstitial lung diseases include a wide variety of pulmonary disorders that diffusely affect all anatomic compartments of the lung. 5

6 The interstitial lung diseases include a wide variety of pulmonary disorders that diffusely affect all anatomic compartments of the lung. The final diagnosis often requires information from a number specialties Chest imaging pattern Clinical context Pathologic pattern 6

7 Chest imaging pattern Clinical context Pathologic pattern Diagnosis 7

8 Significant pulmonary fibrosis occurs in which of the following clinical contexts? 1. Drug-induced Lung Disease 2. Hypersensitivity Pneumonitis 3. Uncharacterized Connective Tissue Disease 4. All of the above Significant pulmonary fibrosis occurs in which of the following clinical contexts? 1. Drug-induced Lung Disease 2. Hypersensitivity Pneumonitis 3. Uncharacterized Connective Tissue Disease 4. All of the above 0% 0% 0% 0%

9 Clinical context Chest imaging pattern Pathologic pattern Interstitial Lung Disease Infection Systemic Disorders Idiopathic disorders Exposures Genetic Conditions 9

10 Interstitial Lung Disease Atypical Pneumonia Infection Mycoplasma Chlamydia Viral Pneumocystis Mycobacterial Interstitital Lung Disease Infection Familial Interstitial Pneumonia Hermansky Pudlak Genetic Conditions 10

11 Infection Interstitial Lung Disease Systemic Disorders Sarcoidosis Connective Tissue Disease Immunodeficiency Malignancy Genetic Conditions Survival is shortened in RA Solomon et al, submitted 11

12 ExRA shortens survival in RA Solomon et al, submitted ILD shortens survival in RA Solomon et al, submitted 12

13 ILD shortens survival in RA Solomon et al, submitted Pulmonary Fibrosis shortens survival in RA Solomon JJ et al, Resp Med

14 Infection Interstitial Lung Disease Medications/Drugs/Tobacco Systemic Disorders Occupational Avocational Environmental Accidental Exposures Genetic Conditions Fibrosis predicts mortality in HP median survival > 20 yrs median survival 7.1 yrs p = Vourlekis et al, Am J Med

15 Interstitial Lung Disease Alveolar Proteinosis (PAP) Infection Lymphangioleiomyomatosis (LAM) Systemic Disorders Pulmonary Langerhans Cell Histiocytosis (PLCH) Exposures Idiopathic disorders Genetic Conditions Idiopathic interstitial pneumonias (IIP) Idiopathic Pulmonary Fibrosis (IPF) Nonspecific Interstitial Pneumonia (NSIP) Cryptogenic Organizing Pneumonia (COP) Desquamative Interstitial Pneumonia/ Respiratory Bronchiolitis-ILD (DIP/RBILD) Acute Interstitial Pneumonia (AIP) 15

16 Raghu et al, Am J Respir Crit Care Med : In most patients, which of the following is not required for a definitive diagnosis of IPF? 1. High-resolution CT scan of the chest 2. Surgical Lung Biopsy 3. Exclusion of competing causes of pulmonary fibrosis 4. All of the above are required 16

17 In most patients, which of the following is not required for a definitive diagnosis of IPF? 1. High-resolution CT scan of the chest 2. Surgical Lung Biopsy 3. Exclusion of competing causes of pulmonary fibrosis 4. All of the above are required 0% 0% 0% 0% In 2015 the diagnosis of IPF requires: 1. Exclusion of other known causes of interstitial lung disease (e.g., domestic exposures, connective tissue disease, and drug toxicity). 2. The presence of a UIP chest imaging pattern on HRCT in patients not subjected to surgical lung biopsy. 3. Specific combinations of HRCT chest imaging patterns and pathologic patterns in patients who undergo a surgical lung biopsy. 17

18 Is this IPF? Identifiable cause/association? No Yes UIP pattern HRCT pattern Not UIP Surgical lung biopsy Not UIP UIP pattern IPF Not IPF The problem with IPF 18

19 Survival in IPF is short Median survival years King et al, Am J Respir Crit Care Med 2000 Quality of life with IPF is poor Martinez TY et al, Chest

20 Functional Status in IPF is impaired Olson A et al, submitted Hospital admissions have increased 5%/year Navaratnam V et al, Chest

21 Which of the following is the most frequent cause of death in IPF patients? 1. Acute exacerbation of disease 2. Gradual disease progression with respiratory failure 3. Pneumonia 4. Ischemic heart disease Which of the following is the most frequent cause of death in IPF patients? 1. Acute exacerbation of disease 2. Gradual disease progression with respiratory failure 3. Pneumonia 4. Ischemic heart disease 1. 0% 0% 0% 0%

22 IPF patients die from their disease Olson et al, Am J Respir Crit Care Med 2007 Specific causes of death King, et al Lancet

23 Specific causes of death King, et al Lancet 2009 Specific causes of death Daniels, et al Eur Respir J 2008; 32:

24 Mortality Rate per 1,000,000 Mortality Rate per 1,000,000 Mortality Rates with Lung Cancer Age-Adjusted Mortality Rates With Lung Cancer per 1,000, Men - Lung Cancer Women - Lung Cancer The age-adjusted mortality rates with lung cancer: In men decreased by 21% In women increased by 7% Year Mortality Rates with COPD 1992 through 2003 Age-Adjusted Mortality Rates for Decedents with COPD per 1,000, through Men - COPD Women - COPD The age-adjusted mortality rates with COPD: In men decreased by 7% In women increased by 27% Year 24

25 From , rates have increased by 55% From 1992 to 2003, the age-adjusted mortality rates increased. In men increased by 28% from 48 per 1,000,000 to 62 per 1,000,000 In women increased by 40% from 40 per 1,000,000 to 56 per 1,000,000 Olson et al, Am J Respir Crit Care Med 2007 The clinical course is unpredictable 25

26 Untreated IPF progresses Carrington CB. NEJM, 1978 Untreated IPF progresses Carrington CB. NEJM,

27 Untreated IPF progresses Carrington CB. NEJM, 1978 Better Disease severity Worse Time (years) 27

28 Am J Respir Crit Care Med Vol 176. pp , 2007 How to think about treatment 28

29 Recent trial results have been disappointing Summary of Selected Multi-centered Trials 29

30 Summary of Selected Multi-centered Trials Trial N Primary Endpoint Result Summary of Selected Multi-centered Trials Trial N Primary Endpoint Result Interferon-beta (1999) 167 Progression free survival time Negative 30

31 Summary of Selected Multi-centered Trials Trial N Primary Endpoint Result Imatinib Mesylate 120 Progression free survival Negative Bosentan (BUILD-3) 132 Change in 6MW distance Negative Etanercept 100 Change in DL CO, FVC Negative Interferon-gamma (007) 826 Survival time Negative Interferon-beta (1999) 167 Progression free survival time Negative Summary of Selected Multi-centered Trials Trial N Primary Endpoint Result Pirfenidone (CAPACITY 1) 344 Change in FVC Negative Pirfenidone (CAPACITY 2) 435 Change in FVC Positive Imatinib Mesylate 120 Progression free survival Negative Bosentan (BUILD-3) 132 Change in 6MW distance Negative Etanercept 100 Change in DL CO, FVC Negative Interferon-gamma (007) 826 Survival time Negative Interferon-beta (1999) 167 Progression free survival time Negative 31

32 Summary of Selected Multi-centered Trials Trial N Primary Endpoint Result Ambrisentan (ARTEMIS-IPF) 492 Time to disease progression Potentially Harmful Pirfenidone (CAPACITY 1) 344 Change in FVC Negative Pirfenidone (CAPACITY 2) 435 Change in FVC Positive Imatinib Mesylate 120 Progression free survival Negative Bosentan (BUILD-3) 132 Change in 6MW distance Negative Etanercept 100 Change in DL CO, FVC Negative Interferon-gamma (007) 826 Survival time Negative Interferon-beta (1999) 167 Progression free survival time Negative Summary of Selected Multi-centered Trials Trial N Primary Endpoint Result Coumadin (ACE) 145 Time to disease progression Harmful Ambrisentan (ARTEMIS-IPF) 492 Time to disease progression Potentially Harmful Pirfenidone (CAPACITY 1) 344 Change in FVC Negative Pirfenidone (CAPACITY 2) 435 Change in FVC Positive Imatinib Mesylate 120 Progression free survival Negative Bosentan (BUILD-3) 132 Change in 6MW distance Negative Etanercept 100 Change in DL CO, FVC Negative Interferon-gamma (007) 826 Survival time Negative Interferon-beta (1999) 167 Progression free survival time Negative 32

33 Summary of Selected Multi-centered Trials Trial N Primary Endpoint Result Pred/Aza/N-acetylcysteine (PANTHER) 155 Change in FVC Harmful Coumadin (ACE) 145 Time to disease progression Harmful Ambrisentan (ARTEMIS-IPF) 492 Time to disease progression Potentially Harmful Pirfenidone (CAPACITY 1) 344 Change in FVC Negative Pirfenidone (CAPACITY 2) 435 Change in FVC Positive Imatinib Mesylate 120 Progression free survival Negative Bosentan (BUILD-3) 132 Change in 6MW distance Negative Etanercept 100 Change in DL CO, FVC Negative Interferon-gamma (007) 826 Survival time Negative Interferon-beta (1999) 167 Progression free survival time Negative IPFnet, N Engl J Med 2012;366:

34 IPFnet, N Engl J Med 2012;366:

35 IPFnet, N Engl J Med 2012;366: King et al, New Engl J Med

36 ASCEND Baseline Characteristics King et al, New Engl J Med 2014 Change in FVC over 52 weeks King et al, New Engl J Med

37 Linear slope analysis of FVC change from baseline to week 52 King et al, New Engl J Med 2014 Patients with >10% decline in FVC or death at 52 weeks King et al, New Engl J Med

38 Mean change from baseline in 6-minute walk test distance King et al, New Engl J Med 2014 Patients with decline in FVC, 6mwd or death at 52 weeks King et al, New Engl J Med

39 Categorical change baseline to week 52 in UCSD SOBQ score King et al, New Engl J Med 2014 All-cause mortality in pooled study populations King et al, New Engl J Med

40 Adverse events King et al, New Engl J Med 2014 Adverse events King et al, New Engl J Med

41 Richeldi et al, New Engl J Med 2014 INPULSIS baseline characteristics Richeldi et al, New Engl J Med

42 INPULSIS I primary end point: annual rate of decline in FVC Richeldi et al, New Engl J Med 2014 INPULSIS II primary end point: annual rate of decline in FVC Richeldi et al, New Engl J Med

43 INPULSIS I and II: adjusted annual rate of decline in FVC INPULSIS I Richeldi et al, New Engl J Med 2014 INPULSIS I and II: adjusted annual rate of decline in FVC INPULSIS I INPULSIS II Richeldi et al, New Engl J Med

44 BIBF 1120: Incidence of AE per 12 months Richeldi et al, New Engl J Med 2011 Incidence of investigator-reported AEs within 52 weeks Richeldi et al, New Engl J Med

45 Time to first investigator-reported AE (pooled data) Richeldi et al, New Engl J Med 2014 Time to first adjudicated AE (pooled data) Richeldi et al, New Engl J Med

46 BIBF1120: SGRQ responders ( 4-point decrease) Richeldi et al, New Engl J Med 2011 Change from baseline in SGRQ total score over 52 weeks INPULSIS I Richeldi et al, New Engl J Med

47 Change from baseline in SGRQ total score over 52 weeks INPULSIS I INPULSIS II Richeldi et al, New Engl J Med 2014 Change from baseline in SGRQ over 52 weeks (pooled) Richeldi et al, New Engl J Med

48 Time to death in INPULSIS -1 and INPULSIS -2 (pooled) Richeldi et al, New Engl J Med 2014 Adverse events Richeldi et al, New Engl J Med

49 Adverse events Richeldi et al, New Engl J Med 2014 IPFnet, New Engl J Med

50 PANTHER baseline characteristics IPFnet, New Engl J Med 2014 Changes in FVC and Subgroups before and after the Alert IPFnet, New Engl J Med

51 Changes in FVC and Subgroups before and after the Alert IPFnet, New Engl J Med 2014 Shulgina L, et al. Thorax 2013;68:

52 Co-trimoxazole trial: Kaplan-Meier plots of time until death Intention-to-treat population Per-protocol population Shulgina L, et al. Thorax 2013;68: Which of the following interventions has been shown to have an effect on mortality in patients with IPF? 1. Supplemental oxygen 2. Bosentan 3. Prednisone, Azathioprine, and N-acetyl cysteine 4. Interferon - g 52

53 Which of the following interventions has been shown to have an effect on mortality in patients with IPF? 1. Supplemental oxygen 2. Bosentan 3. Prednisone, Azathioprine, and N-acetyl cysteine 4. Interferon - g 0% 0% 0% 0% Summary Progressive pulmonary fibrosis is a significant clinical problem and occurs in a variety of clinical contexts IPF is a specific and well characterized form of pulmonary fibrosis New treatments are available for IPF 53