Recent developments in the treatment of interstitial lung diseases

1. Recent developments in the treatment of interstitial lung diseases Milton D. Rossman, M.D. Professor of Medicine Hospital University of Pennsylvania

2. Classificiation of the Interstitial Lung Disorders (ILDs) • Drug Induced • Occupational and Environmental Exposure • Systemic Diseases • Primary Idiopathic

3. Drug Induced Interstitial lung disease • Antibiotics – nitrofurantoin • Antiarrhythmics – amiodarone • Anti-inflammatory – gold • Anticonvulsant – dilantin • Chemotherapeutic Agents – Bleomycin • Dietary Suppliments – L-Tryptophan • Dopaminergic drugs - bromocryptine • Oxygen • Radiation Therapy

4. Occupation and Environemental Induced Interstitial Lung Disease • Inorganic • Silicosis • Asbestosis • Beryllium • Organic (Hypersensitivity Pneumonitis) • Farmer’s Lung • Humidifier Lung

5. Systemic Diseases associated Interstitial Lung Disease • Granulomatous – Sarcoidosis • Vasculitis – Wegener’s granulomatosis • Genetic – Hermansky-Pudlak Syndrome • Post Infectious – ARDS • Infectious – Mycoplasma • Heart Failure

6. Primary Idiopathic Interstitial lung disorders • Acute interstitial pneumonia • Idiopathic pulmonary fibrosis • Familial idiopathic pulmonary fibrosis • Lymphocytic interstitial pulmonary fibrosis • Cryptogenic organizing pneumonia (BOOP) • Respiratory bronchiolitis interstitial lung disease (RBILD or DIP) • Non-specific interstitial pneumonia (NSIP)

7. Pathology of ILDs • Organizing pneumonia • Granuloma • Fibroblastic foci • Masson bodies • Hyaline membranes • Type II cell hyperplasia • Honeycombing

8. Model of healing in ILD Selman, King and Pardo, Ann Int Med 2001;134:136-51

9. TNF – an important early mediator in inflammatory pathways • Important role in driving cytokine cascades at sites of inflammation and granuloma formation • Mediate induction • Adhesion molecules • Angiogenic factors • Anti-TNF effective in animal models • Mouse colitis • Collagen-induced arthritis

10. TNF-a – Activation Pathways Sands. Rev Gastroentero Disorders, 2004;4 S10-S17

11. Differences between infliximab and etanercept binding to TNF-a Scallon et al. J Pharm and Exp Therapeu. 2002; 301:418-426

12. Comparison of infliximab and etanercept binding to cell surface tmTNF Scallon et al. J Pharm and Exp Therapeu. 2002; 301:418-426

13. Anti-TNF trials in ILD • Sarcoidosis • IPF • Wegener’s Granulomatosis • Chron’s Disease • Rheumatoid Arthritis

14. Etanercept for the Treatment of Stage II and III Progressive Pulmonary Sarcoidosis • Subjects with stage II or III sarcoidosis without extrapulmonary diseased that required Rx • Progressive X-ray or PFT abnormalities over 3 months • No other Rx • Prospective open-label phase II study • Etanercept 25 mgm subcu biweekly for 1 year • Outcome measurements • PFTs • Chest radiograph • Dyspnea • TNF-a levels in serum and BAL • Utz et al. Chest 2003;124: 177-85

15. Baseline characteristics of subjects entered into the study

17. Serum TNF-a increased at six months in all subjects

18. No change in spontaneous immunoreactive or bioactive TNF-a release from alveolar macrophages

19. Conclusion • Etanercept alone does not appear to be able to control TNF-a secretion in sarcoidosis and put subjects into remission

20. Double-blinded randomized placebo controlled trial of infliximab in sarcoidosis • Stage II, III or IV chest radiograph • VC > 50 < 80% of predicted despite prednisone or previous intolerance to steroids • Subjects randomized 2:1 • Infliximab 5 mgm/kg IV at weeks 0 and 2 • Evaluation of VC at 6 weeks • All subject receıved ınflıxımab at 6 and 14 weeks

21. Subject Randomized • Placebo = 6 • Infliximab = 13 • No differences in • Age, weight, height, race, number of steroid Rx • Differences • Gender (placebo males 83% vs. 38%) • Dose of corticosteroid (placebo 8 vs. 23.8 mgm)

22. Infliximab improved VC but the study was underpowered

23. Improved PFT’s and Chest X-rays at 6 weeks • Percent of subjects with > 15% improvement of predicted vital capacity • Placebo = 0% • Infliximab = 15% • Percent of subjects with improvement of chest radiograph • Placebo = 0% • Infliximab = 23%

24. Serious Adverse effects of infliximab • 5/13 had serious adverse events • Acute renal failure • Cellulitis • Decreased WBC • Elevated CPK • Pneumonia • Pulmonary emboli • Visual field defect

25. Conclusions • Infliximab may improve VC in patients with active pulmonary sarcoidosis resistant to steroids • Potential for side effects from infliximab will limit it to a second line drug.

26. Anecdotal studies suggest infliximab may be helpful in therapy resistant extrapulmonary sarcoidosis • Able to control hypercalcemia • Menon et al, Am J Med Sciences 2004;328:173-5 • Lupus Pernio • Haley et al, Brit J of Derm. 2004 ;150:146-9 • Neurosarcoidosis • Sollberger et al, J of Neurology. 2004;251:760-1 • Uveitis • Pritchard et al, Ann. of the Rheum. Dis. 2004;63:318-20,

27. Improvement of leptomeingeal lesion around the conus Sollberger et al, Journal of Neurology. 2004;251:760-1

28. Oculocutanous sarcoidosis resistant to conventional treatment responding to infliximab Roberts et al, Chest 2003;124:2028-31

29. Other interstitial lung disorders that may respond to anti-TNF-a therapy • Wegener’s Granulomatosis • Crohn’s Disease • Rheumatoid Lung • Polymyositis/Dermatomyositis • Keystone. Ann Rheum Dis 2004; 63:ii79-ii83

30. Drug Trials in IPF • Interferon-gamma • Mucomyst • Pirfenidone • On-going • Etanercept • Bosentin • Heparin

31. Interferon-gamma in IPF • Open labeled study of Interferon-g suggested dramatic improvement in IPF • Ziesche et al NEJM 1999; 341:1264-9

32. In placebo-controlled study, interferon-g did not improve pulmonary function, but may have increased survival Raghu et al, NEJM 2004; 350:125-133

33. Mucomyst in IPF • IFIGENIA trial (European) • 155 subjects with IPF • Randomized, placebo-controlled • Prednisone and azathioprine vs. prednisone, azathiprine and mucomyst

34. Mucomyst improved pulmonary function in IPF

35. Pirfenidone in IPF • Inhibits TGF-b induced collagen synthesis • Inhibits fibroblast proliferation • Open label studies suggested improvement • Nagai et al, Int. Med. 2002; 41:1118-1123 • Raghu et al, AmJ Respir Crit Care Med, 1999; 159: 1061-9

36. Trial of pirfenidone in IPF • Double blind placebo-controlled randomized 2:1 • < 10 mgm prednisone • Definite or probable IPF by HRCT • Primary end-point = change in oxygen saturation after a 6 min steady state exercise test • 109 subjects entered into study

37. Study Population • 109 entered • 2 eliminated because they violated inclusion criteria • 91 Definite UIP radiologically • 27 unable to complete 6 min walk test • 80 subjects • 55 pirfenidone • 25 placebo

38. DSMB ended the study early • Increased number of acute exacerbations in placebo group • 5/35 in placebo group • 0/72 in pirfenidone group • P = 0.0031 • Worsening otherwise unexplained • Progressive dyspnea • Radiographic infiltrates • Decrease of P02 by 10 torr

39. Pirfenidone did not improve the primary endpoint but did improve O2 saturation in the group who could complete the 6 min test.

40. Improved function in pirfenidone group at 9 months

41. Safety of pirfenidone

42. Summary • No known effective therapy for IPF • Mucomyst with prednisone and azathioprine only therapy to be shown effective • Continued drug trials in IPF necessarey