1. CM-1 Clinical Transplantation Lung Howard University Hospital Department of Transplantation Clive O. Callender, MD. Arturo Hernandez, MD

2. CM-2 Objective Current Status of Lung Transplantation

3. CM-3 No of Transplanted Organs vs Waiting List 2004 Recovered Transplanted Waiting List Total 25,237 26,539 86,378 Kidney 12,575 15,671 (9,025) 57,910 PTA 2,021132504 PAK 418973 K-P879 2,410 Liver 6,4055,780 (5,457)17,133 Intestine 167 52196 Heart 2,096 1,9613,237 Lung 1,973 1,168 3,852 Heart-lung 37 171 Source: 2005 OPTN/SRTR Annual Report,

4. CM-4 Graft Survival Follow-up Period 1 Year 10 Years Tx 2002-2003 Tx 1993-2003 Kidney Deceased Donor Graft Survival 89.0% 40.5% Patient Survival 94.6% 60.7% Kidney: Living Donor Graft Survival 95.1% 56.4% Patient Survival 97.9% 76.4% Kidney-Pancreas Kidney Graft Survival 91.7% 52.5% Pancreas Graft Survival 85.8% 53.6% Liver Deceased Donor Graft Survival82.2% 52.5% Patient Survival 81.7% 67.0% Intestine Graft Survival 73.8% 22.0% Heart Graft Survival 86.8% 51.1% Lung Graft Survival 81.4% 22.1% Heart-Lung Graft Survival 55.8% 24.6% UNOS/SRTR, 2003

5. CM-5 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 is prevent bronchiolitis obliterans

6. CM-6 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

7. CM-7 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

8. CM-8 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

9. CM-9

10. CM-10 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

11. CM-11 Causes of Death Following Lung Transplantation

12. CM-12 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

13. CM-13 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:

14. CM-14 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

15. CM-15 Lymphocytic Bronchitis/Bronchiolitis

16. CM-16 Acute Rejection Acute rejection is a perivascular process diagnosed by transbronchial biopsy

17. CM-17 Separate Interventions for Separate Processes Systemic immunosuppression rejection and ongoing injury, inflammation and fibrosis ending in bronchiolitis obliterans Systemic administration to avert vascular rejection, halting lymphocytic recruitment and activation