1. CM-1 Current Status of Lung Transplantation Jeff Golden, MD Professor of Clinical Medicine and Surgery Medical Director, Lung Transplantation University of California, San Francisco

2. CM-2 Current Status of Lung Transplantation Long term survival—50% die by 5 years Bronchiolitis obliterans (chronic rejection)— primary cause of poor survival Future of lung transplantation— prevent bronchiolitis obliterans

3. CM-3 Lung Transplantation Pre-Cyclosporine Era, Pre-1983 Time (days) (4) (12) (19) (28) (38) At risk: 050100150200250 0 20 40 60 80 100 % free from death

4. CM-4 Worldwide Lung Transplantation Numbers Source: International Society of Heart and Lung Transplantation (ISHLT); UNOS Lung transplants performed worldwide, by year Emphysema/COPD Idiopathic pulmonary fibrosis Cystic fibrosis Alpha-1 antitrypsin deficiency Primary pulmonary hypertension Sarcoidosis Retransplant/graft failure Other 1.8% 2.6% 4.2% 39.0% 10.4% 17.0% 16.0% 9.0% Primary diagnosis, 01/1995 - 06/2003 1342 1337 1417 1413 1410 1508 1537 1706 1655 1206 1069 902 685 408 185 80 47 1513

5. CM-5 Comparative Transplantation Survival Rates Primary lung transplant by underlying diagnosis Primary kidney, liver, and heart transplant *Kidney, liver, and heart data extrapolated from OPTN Annual Report, 2003. Chiron Briefing Document Figure 2.2-1

6. CM-6

7. CM-7 Clinical Manifestations of Chronic Rejection Two methods for the diagnosis of chronic rejection –Histologically through transbronchial biopsy (OB) –Clinically through sustained decline in pulmonary function (Bronchiolitis Obliterans Syndrome, BOS) –OB and BOS are histologic and clinical manifestations of the same process Patients develop progressive shortness of breath, graft failure, airflow obstruction, recurrent pulmonary infections Once chronic rejection develops, airway damage is progressive and irreversible –Patients die of graft failure/pneumonia

8. CM-8 Causes of Death Following Lung Transplantation

9. CM-9 Despite Best Current Systemic Treatment and Patient Management, Chronic Rejection Eventually Affects Most Patients 0 20 40 60 80 100 01234567 Years from transplant 0 20 40 60 80 100 Calcineurin inhibitors Anti-metabolitesPrednisone CsA Tac AZA MMF % of patients Plus induction, plus pulsed intensifications prn Source: ISHLT, market research Despite best available therapy % chronic rejection-free survival

10. CM-10 New Concept: Avoid Increasing Systemic Immunosuppression Infection GERD Others Infection GERD Others Immune activation Immune activation Increase systemic immune suppression Increase systemic immune suppression BOS Non Nonalloimmunefactors:

11. CM-11 Epithelial injury Inflammation Fibroblastic repair Pathway to Chronic Rejection Non-alloimmune stimuli Airway ischemia Viruses Bacterial - PSEUDOMONAS Oxidant stress Reflux Alloimmune stimuli Recurrent acute vascular rejection Lymphocytic bronchitis

12. CM-12 Lymphocytic Bronchitis/Bronchiolitis

13. CM-13 Acute Rejection Acute rejection is a perivascular process diagnosed by transbronchial biopsy

14. CM-14 Separate Interventions for Separate Processes Cyclosporine by inhalation Systemic immunosuppression Epithelial administration to avert airway rejection and ongoing injury, inflammation and fibrosis ending in bronchiolitis obliterans Systemic administration to avert vascular rejection, halting lymphocytic recruitment and activation