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Ganesh Raghu, MD, FCCP, FACP

Ganesh Raghu, MD, FCCP, FACP. Professor of Medicine and Laboratory Medicine (Adjunct) University of Washington, Seattle, WA, USA Chief, Chest Clinic Director, Interstitial Lung Disease, Sarcoid and Pulmonary Fibrosis Program Medical Director, Lung Transplant Program

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Ganesh Raghu, MD, FCCP, FACP

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  1. Ganesh Raghu, MD, FCCP, FACP Professor of Medicine and Laboratory Medicine (Adjunct) University of Washington, Seattle, WA, USA Chief, Chest Clinic Director, Interstitial Lung Disease, Sarcoid and Pulmonary Fibrosis Program Medical Director, Lung Transplant Program University of Washington Medical Center Seattle, WA, USA

  2. Interstitial lung disease Medical Treatment -current trends

  3. Interstitial Lung Disease(Immunocompetent Host) Interstitial Lung Disease Unique Entities* Collagen- Vascular Diseases Iatrogenic/ Drug-induced Conditions Granulo- matous Diseases** Occupational/ Environmental Exposures Inherited Conditions*** Idiopathic Interstitial Pneumonia (IIP) * Langerhans’ cell granulomatosis, lymphangioleimyomatosis, alveolar proteinosis, idiopathic pulmonary capillaritis ** Sarcoidosis, hypersensitivity pneumonitis *** Tuberous sclerosis, Hermansky-Pudlak Syndrome, neruofibromatosis, metabolic storage disorders, familial IPF

  4. Interstitial Lung Disease(Immunocompetent Host) Idiopathic Interstitial Pneumonia (IIP) Idiopathic Pulmonary Fibrosis (UIP) Non-IPF IIP LIP RBILD (DIP) COP (BOOP) NSIP AIP Eosinophilic pneumonia

  5. Interstitial Lung DiseaseClinical Response to Currently Available Therapeutic Agents • Sarcoidosis • Acute hypersensitivity pneumonitis • Drug induced (acute) • Environmental • Acute pulmonary capillaritis • Idiopathic BOOP • Respiratory bronchiolitis associated ILD • Chronic eosinophilic pneumonia • Primary alveolar proteinosis • Acute radiation pneumonitis • Lymphocytic interstitial pneumonia Generally Favorable

  6. Interstitial Lung DiseaseClinical Response to Currently Available Therapeutic Agents Generally Unfavorable • IPF • Chronic secondary, and advanced pulmonary fibrosis • Pulmonary fibrosis co-existing/associated with pulm. HTN • Chronic idiopathic BOOP (subset of idiopathic BOOP) • BOOP associated with collagen vascular diseases • Chronic pulmonary hemorrhage syndromes • Pulmonary venoocclusive disease

  7. Interstitial Lung DiseaseClinical Response to Currently Available Therapeutic Agents Generally Unfavorable • Obliterative bronchiolitis with or without associated ILD • Acute interstitial pneumonia of unknown etiology • Langerhan cell granulomatosis • Lymphangioleiomyomatosis • Tuberous sclerosis • Pulmonary fibrosis associated with other inherited disorders • Familial idiopathic pulmonary fibrosis

  8. Idiopathic Interstitial Pneumonia (IIP) IIP IPF (UIP) Non-IPF Relentlessly Progressive NSIP LIP COP Eosinophilic pneumonia RBILD DIP AIP NSIP-f NSIP-c Subgroup Subgroup (small) Slow progression (+ adjunct immunosuppressive) Death (~ 3 years) Steroid response (vast majority) Death (several years ?)

  9. Idiopathic Pulmonary Fibrosis:Clinical Course/Subgroups* IPF Rapidly Progressive Stable Slowly progressive Progression slowed by Rx Death ? trigger Slowly progressive Acute deterioration (? exacerbation) Continued progression Rx Complication Respiratory insufficiency Respiratory insufficiency Cor pulmonale (2 Pulm hypertension) Progressive Death secondary to other cause Cor pulmonale (2 Pulm hypertension) Death Death Modified from Raghu: Chest 1987; 92:148-54

  10. Idiopathic Pulmonary Fibrosis-ATS Statement Guidelines for Diagnosis and Treatment Treatment • Usual course: • Often insidious • Relentlessly progressive • No spontaneous remissions • Treatment: • No data to support specific therapy, duration, dosage, timing • Combined corticosteroids and azathioprine or cyclophosphamide in all patients who do not have contraindications • Initiate ‘early’ in the clinical course AJRCCM Feb 2000

  11. Idiopathic Pulmonary Fibrosis- ATS Statement Guidelines for Diagnosis and Treatment Treatment: Duration • 6 Months minimum, in the absence of complications or adverse effects At 6 months and 12 months Improved Stable Worse Continue low dose prednisone Switch to alternative therapy or different cytotoxic Rx or stop Rx Continue therapy AJRCCM Feb 2000

  12. Idiopathic Pulmonary fibrosis-predictors of survival • Dyspnea score(1,6) • CRP score (2) • Composite physiologic index (3,4) • Change in PFTs [FVC,DLCO,P(A-a)O2] (5,6) • Walk test - 6 min walk (7) - modified [ timed walk test-(8) ] distance/velocity to desaturate 1)Schwartz et al,1994; 2)Watters et al,1986; 3)Wells et al,2003; 4) Latsi et al,2003;5) Flaherty et al,2003; 6)Collard etal,2003; 7) Lama et al,2003 ;8) Hallstrand et al,2005

  13. Idiopathic Pulmonary Fibrosis Treatment Longstanding “Awareness” • Currently available treatment regimen “ineffective” • Myth or fact?

  14. Case Reports/Series Retrospective Prospective Data Gathering Observations: provocative, positive, suggestive Concepts, Hypothesis Further Clinical Studies (Prospective) Idiopathic Pulmonary FibrosisRole of Pilot Studies “Pilot” Studies – Initial study following an anecdotal observation

  15. Prospective Clinical Studies Open Label Phase II Randomized Control Trials (RCT) Proof of Concept Phase II Positive Data Idiopathic Pulmonary Fibrosis: TreatmentRole of Pilot Studies “Pilot” Studies with Positive Observations

  16. Idiopathic Pulmonary Fibrosis: TreatmentPilot Studies Evolution to Clinical Trials Positive Data Well Designed, Phase III RCT Endpoints for Improved Outcome Positive 1° Endpoint Negative 1° Endpoint Clinical Relevance and Significance Negative 2° and Negative Signals in Subgroups, Exploratory Analysis Positive 2° and Positive Signals in Subgroups &/or Exploratory Analyses Evidence No Evidence for Treatment

  17. Winterbauer et al. 1978 Double blind RCT, placebo controlled. Raghu et al 1999 Prednisone + Azathioprine “Std of care”, guided by Int’l Consensus 2000 despite no evidence • Colchicine Douglas 1993 Retrospective Douglas 1997 RCT Prospective Douglas 1998 No evidence for clinical benefit • N-acetyl Cysteine (NAC) Behr et al. 1997 Multicenter,DBRCT, IFIGENIA (Europe) prednisone + AZA + NAC vs pred + AZA FVC and DLCO better with adjunct NAC compared to pred+AZA : ? New standard of care ..need further studies Idiopathic Pulmonary Fibrosis: TreatmentPilot Studies → Evolution to Clinical Studies Treatment Pilot Further Studies Current Status 1/2007 • Prednisone Azathioprine Prednisone + Azathioprine

  18. g-interferon Ziesche et al. 1999 Multicenter, double-blind, RCT (DBRCT), placebo controlled GIPF-001 (phase III) Raghu et al. 2004. DBRCT phase III survival studies completed • Pirfenidone Raghu et al. 1999 Phase II double-blind RCT. Azuma et al. 2005. Phase III completed in Japan;ongoing western world • Etanercept Niden et al. ATS 2002 Proof of concept, DBRCT, placebo controlled trial Results presented Raghu :CHEST,11/05 ERS,9/06 • Anticoagulation Kubo et al, CHEST 05(RCT) needed ? Treatment role Need further studies Idiopathic Pulmonary Fibrosis: TreatmentPilot Studies → Evolution to Clinical Trials Treatment Pilot Further Studies Current Status 4/2007

  19. High Dose N-acetylcysteine in Idiopathic Pulmonary Fibrosis: the IFIGENIA-Trial* • Multinational, double-blind, randomized, placebo-controlled, parallel-group trial • Prednisone + Azathioprine + NAC vs. Prednisone + Azathioprine * Maurits Demedts et al NEJM 2005

  20. High Dose N-acetylcysteine in Idiopathic Pulmonary Fibrosis: the IFIGENIA-Trial* Primary endpoint : VC (L) P = 0.02 NAC (n=) Placebo (n=) 80 75 63 60 55 51 * Maurits Demedts et al NEJM 2005

  21. High Dose N-acetylcysteine in Idiopathic Pulmonary Fibrosis: the IFIGENIA-Trial* Primary endpoint : DLCO (mmol/min/kPa) P= 0.003 NAC (n=) Placebo (n=) 79 74 58 59 48 47 * Maurits Demedts et al NEJM 2005

  22. Idiopathic Pulmonary Fibrosis: Results of the European Trial (IFIGENIA STUDY)*            Prednisone plus Azathioprine +/- N-Acetyl Cysteine (NAC) Survival within one year NACPlacebo Mortality 9% (7/80) 11% (8/75) Time to death 144* (46-276 days) 71 (57-132) * Median (quartiles) *M.Demedts et al,NEJM,2005

  23. Adverse Events (AE) Occurring in at least 5% of Patients NAC Placebo Patient Patient AE n 322 6 6 6 5 3 3 4 3 3 1 AE n 303 1 2 6 1 10 5 6 5 5 4 4 Total number of patients Total AE Blood alkaline phos increased Blood lactate dehydrogenase inc. Back pain Respiratory failure Bone marrow toxicity Edema Headache Asthenia Influenza like illness Muscle cramp Tremor n 80 72 6 6 6 5 3 3 3 3 3 1 % 100 90 8 8 8 6 4 4 4 4 4 1 n 75 67 1 2 5 1 10 5 6 5 5 4 4 % 100 89 1 3 7 1 13 7 8 7 7 5 5 P=0.03 * Demedts et al NEJM 2005; 353: 229-42

  24. High Dose N-acetylcysteine in Idiopathic Pulmonary Fibrosis: the IFIGENIA-Trial* Conclusions • Therapy with NAC 600 mg TID added to prednisone and azathioprine, preserves VC and DLCO in IPF better than prednisone and azathioprine (standard therapy) * Demedts et al NEJM,2005

  25. Idiopathic Pulmonary Fibrosis Treatment with Antifibrotic Agents Am J Respir Crit Care Med 1999; 159:1061-9

  26. Idiopathic Pulmonary FibrosisTreatment with Pirfenidone

  27. Idiopathic Pulmonary Fibrosis (IPF)Treatment with Pirfenidone in IPFOpen label, Phase 2, Compassionate Use Study (UWMC, Seattle, WA)(Raghu et al,AJRCCM 1999) Raghu G et al. AJRCCM 1999

  28. Idiopathic Pulmonary Fibrosis:Treatment with Pirfenidone (prospective,double blind placebo controlled,clinical trial in Japan)* • Arata Azuma, MD (Tokyo) • Toshihiro Nukiwa, MD (Sendai) • Eiyasuu Tsuboi, MD (Tokyo) • Moritaka Suga, MD (Kumamoto) • Shosaku Abe, MD (Sapporo) • Koichiro-Nakata, MD (Tokyo) • Yoshio Taguchi, MD (Tenri) • Sonoko Nagai, MD (Kyoto) • Harumi Itoh, MD (Fukui) • Motoharu Ohi, MD (Osaka) • Atsuhiko Sato, MD (Kyoto) • Shoji Kudoh, MD (Tokyo) • Ganesh Raghu, MD (Seattle, WA, USA) *Sponsor: Shionogi & Co., Ltd. Osaka, Japan Azuma et al,AJRCCM,2005

  29. Pirfenidone: Treatment for IPFDouble-Blind, Placebo Controlled Clinical Trial in Japan* Results I. Primary Endpoint • Lowest SpO2 during 6MET higher in the subset of pirfenidone group of patients completing the 6 minute walk at 6 months (p=0.0069), 9 months (p=0.0305) - a positive trend(p =0.07) was seen in all the patients in the pirfenidone group(full analysis set) Azuma et al. AJRCCM (2005)

  30. Pirfenidone treatment in IPF : Current Status(April 2007) • Experimental anti fibrotic agent • Only available for use in patients enrolled/participating in clinical studies and not for routine use in patients • Phase III study began last Nov 2005 in Japan- results announced as a press release by Shionogi(Dec 21st 2006) indicates a positive study(final results for scientific review awaited) • Phase III study in North America and Europe just begun • Until results of these studies are available for the scientific community,unknown if effective for IPF

  31. A Randomized Placebo-Controlled Trial Assessing the Efficacy and Safety of Etanercept in Patients with Idiopathic Pulmonary Fibrosis Data presented at CHEST : Nov,2005 and at ERS,Sep,2006 G Raghu*,1 JA Lasky,2U Costabel*,3KK Brown*,4 V Cottin,5RM du Bois*,6 M Thomeer,7J Utz*,8 L McDermott9 1University of Washington Medical Center, Seattle, WA 2Tulane University Medical Center , New Orleans, LA 3Ruhrlandklinik Essen-Heidhausen, Essen, Germany 4National Jewish Center, Denver, CO 5Center for Orphan Lung Diseases, Lyon, France 6Royal Brompton Hospital, London, UK, 7Universitaire Ziekenhuizen KULeuven, Leuven, Belgium 8Mayo Clinic, Rochester, MN 9Wyeth Research, Collegeville, PA Sponsor: Wyeth Research *Consultants/Advisors

  32. 4 weeks 48 weeks Screen Etanercept 25 mg 2x/week S/C Placebo 2x/week S/C Proof of Concept Study : Etanercept in IPF(datapresented Raghu et al CHEST NOV,05 and ERS Sept,06) • 48 week, double-blind, placebo-controlled, randomized, parallel, multi-center international study • 88 IPF patients enrolled • 85 in efficacy population, 87 in safety population • Primary comparison between groups: Baseline versus 48 weeks, LOCF

  33. Proof of Concept Study : Etanercept in IPF(data presented at CHEST NOV,05 and ERS Sep.06)Conclusions • Efficacy • Primary and Secondary Endpoints not met • Trend in favor of etanercept for • Multiple physiologic endpoints • Functional measures (6MWD, QoL) • Post Hoc Analyses • Trend toward improved progression-free survival • Highest treatment differences for tertile of patients with entry FVC < 57% • Safety • No significant difference in the overall incidence of adverse event, serious adverse events or infections between treatment groups

  34. BUILD 1* • A double-blind randomized placebo controlled multicenter study to assess the efficacy, tolerability, and safety of bosentan in patients with idiopathic pulmonary fibrosis (IPF) * Sponsor : Actelion

  35. BUILD 1 :Bosentan did not improve 6MWD up to 12 months (Primary Endpoint)(data presented at ATS* and ERS meeting 5/06 and 9/06) : King*,Behr,Brown,Dubois** and Raghu) -18 (20) -17 0.226 *Or earlier if premature discontinuation

  36. BUILD 1 Predefined Population:In biopsy proven IPF, Bosentan delayed time to disease progression or death(data presented at ATS*/ERS** meetings, 5 and 9/06: King*,Behr,Brown,Dubois** and Raghu ) 100 Bosentan 90 80 p=0.009 70 60 Patients without event (%) 50 Placebo 40 30 20 10 0 0 3 6 9 12 15 Months treatment 50 47 42 36 24 0 Placebo 49 47 42 41 22 0 Bosentan Patients at risk

  37. BUILD 1: Summary and Conclusions data presented at ATS* and ERS** meetings 5 and 9/06 : (King*,Behr,Brown,Dubois** and Raghu) • Bosentan did not improve the primary endpoint of 6MWD • Bosentan showed a trend to delayed time to disease progression or death • In the predefined population with biopsy proven IPF, treatment effect was more pronounced • Bosentan was well tolerated, with no unexpected adverse events • These promising results will be investigated in a larger study (BUILD 3)

  38. BUILD 1 : Dyspnea & QoL Conclusions of Results(Raghu et al,ERS Sep.06) • QoL in IPF patients is severely compromised at baseline • Treatment with bosentan resulted in significant QoL improvements at month 6; favorable trend observed at month 12 • Bosentan improved the overall well-being of IPF patients, especially in the biopsy-proven IPF subpopulation • These results concur with the observed delay in time to death or disease progression in the bosentan group1 • Results will be further investigated in the long-term morbidity/mortality BUILD 3 study 1du Bois RM, et al. Bosentan in IPF patients, BUILD 1 study [poster]. Presented at ERS; Munich, Germany; 4 September 2006.

  39. Idiopathic Pulmonary Fibrosis:Anticoagulant Therapy* • Prospective randomized study in Japan • 56 IPF patients • Randomization: • Prednisolone alone or • Prednisolone plus oral warfarin in the outpatient setting and low molecular weight heparin in hospitalized patients with progressive respiratory failure • Overall survival and hospitalization-free periods were assessed * Kubo et al. Chest 2005; 128:1475-82

  40. Idiopathic Pulmonary Fibrosis:Anticoagulant Therapy* P=0.049 P=0.3 * Kubo et al. Chest 2005; 128:1475-82

  41. Idiopathic Pulmonary Fibrosis:Anticoagulant Therapy* • Poorly design study • Decision/Need for hospitalisation arbitrary • All hospitalisations may not have had true acute exacerbations . • Differential drop outs Limitations * Kubo et al. Chest 2005; 128:1475-82

  42. IPF: Treatment with g-Interferon Does it work ?

  43. IPF: Treatment with g-Interferon Raghu et al, NEJM , 2004; 350:125-133

  44. IPF: Treatment with g-Interferon Raghu et al, NEJM , 2004; 350:125-133

  45. INSPIRE • Large multicenter trial designed to determine if IFN- provides survival benefits in patients with mild-to-moderate IPF • Tested signals of survival benefits from post hoc analysis in an earlier phase III trial that failed to show benefits on primary composite outcome of progression-free survival(Raghu et al. N Engl J Med. 2004;350:125-133.) Raghu G. Eur Respir J. 2006;28:463-465.

  46. INSPIRE • Study Terminated on March 05 2007* • No survival benefits associated with Interferon-gamma * InterMune press Release.

  47. Insights from Recent Clinical Trials Raghu G. Eur Respir J. 2006;28:463-465.

  48. Idiopathic Pulmonary Fibrosis Clinical Course * Martinez et al. AIM 2005; 142:963-7

  49. New Insights on Disease Progression From Recent Clinical Trials • Rapid decline of respiratory status precedes death in otherwise stable patients • Remarkable stability without treatment in many patients • Importance of acute exacerbations • Very low mortality during 1-yr follow-up in patients with well-established IPF • Trials with true placebo-arm may be possible based on observed stability without treatment Raghu G. Eur Respir J. 2006;28:463-465.

  50. 1999 yr → Idiopathic Pulmonary Fibrosis (Mild/Moderate):Treatment • No differences in chosen primary endpoints between treatment groups • b interferon (Raghu et al. data presented ATS 2000) • g interferon (Raghu et al. NEJM 2004;InterMune press release March 2007) • Pirfenidone (Azuma et al. AJRCCM 2005) • Etanercept (Raghu et al. Chest Meeting Nov 05 and ERS meeting Sep 06) • Bosentan (King et al. ATS, May 23, 2006) • N-acetylcysteine (NAC) added to prednisone and azathioprine preserved VC and DLCO better than prednisone + azathioprine (Demedts et al. NEJM 2005) • Pirfenidone improves VC (Shionogi Press Release,Dec 06)

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