1. Food and Drug Administration Division of Pulmonary and Allergy Drug Products Endocrine and Metabolic Drugs Advisory Committee Meeting - Human Recombinant Inhaled Insulin (Exubera) Pulmonary Safety Review Sally Seymour, M.D. Medical Officer Division of Pulmonary and Allergy Drug Products September 8, 2005

2. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 2 Why is pulmonary safety a concern?  Administered via inhalation  Novel drug substance and excipients for inhalation  Chronic administration  Insulin is a polypeptide associated with immune response  Insulin has growth promoting properties

3. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 3 Agenda  Pulmonary Safety Database  Respiratory Adverse Events  Pulmonary Function Tests  FEV 1 and DLCO  Imaging  CXR  High resolution computed tomography (HRCT)  Underlying Lung Diseases  Asthma and COPD  Conclusions

4. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 4 Agenda  Pulmonary Safety Database  Respiratory Adverse Events  Pulmonary Function Tests  FEV 1 and DLCO  Imaging  CXR and HRCT  Underlying Lung Diseases  Asthma and COPD  Conclusions

5. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 5 Pulmonary Safety Database - Controlled Studies in Type 1 DM INH – Inhaled insulin; COMP – Comparator; AE - Adverse Event; PFT – Pulmonary Function Test; HRCT – High Resolution Computed Tomography; CXR – Chest X-ray

6. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 6 Pulmonary Safety Database - Controlled Studies in Type 2 DM INH – Inhaled insulin; COMP – Comparator; AE - Adverse Event; PFT – Pulmonary Function Test; HRCT – High Resolution Computed Tomography; CXR – Chest X-ray

7. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 7 Agenda  Pulmonary Safety Database  Respiratory Adverse Events  Pulmonary Function Tests  FEV 1 and DLCO  Imaging  CXR and HRCT  Underlying Lung Diseases  Asthma and COPD  Conclusions

8. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 8 Respiratory Serious Adverse Events (SAEs)

9. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 9 Respiratory Adverse Events in Type 1 DM

10. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 10 Respiratory Adverse Events - Discontinuation

11. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 11 Cough  Majority mild in severity  Duration longer in inhaled insulin group  Cough questionnaire  Mild in severity, non-productive  Frequently noted within seconds to minutes of inhaled insulin administration

12. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 12 Respiratory Adverse Events  Lung neoplasm – 5 cases  4 malignant 3 in controlled studies 2 inhaled insulin, 1 comparator 1 in extension study in inhaled insulin group  Pulmonary fibrosis  Pleural Effusion  Sarcoidosis

13. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 13 Agenda  Pulmonary Safety Database  Respiratory Adverse Events  Pulmonary Function Tests  FEV 1 and DLCO  Imaging  CXR and HRCT  Underlying Lung Diseases  Asthma and COPD  Conclusions

14. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 14 Approach to Pulmonary Function Test (PFT) Analyses  Individual studies  Pooled controlled phase 2 and 3 studies by diabetes type  Reversal of effect  Long term exposure  Uncontrolled extension Studies 111 and 1036

15. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 15 Change from Baseline FEV1 in Type 1 Pooled Phase 2 and 3 Studies (Mean +/- SD)

16. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 16 Reversal of Effect on FEV 1 in Type 1  Study 1027  12 wks on treatment then 12 wks off inhaled insulin  Limitations Only 12 weeks exposure to inhaled insulin No treatment group difference at 12 weeks  Study 111  Uncontrolled extension study amended to include randomized withdrawal of inhaled insulin  Limitations Self-selected population Varying lengths of exposure to inhaled insulin  Available data not conclusive

17. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 17 Change from Baseline FEV1 in Type 1 in Study 1027 (Mean +/- SD)

18. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 18 Reversal of Effect of FEV1 in Type 2  Study 1001-1002  24 wk treatment extended to 104 wks  104 wks on treatment, 12 wks off inhaled insulin  Provides data following long term (2 yrs) exposure  Data suggests some reversal of effect of inhaled insulin on FEV 1

19. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 19 Change from Baseline FEV1 in Type 2 in Study 1001-1002 (Mean +/- SD)

20. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 20 Summary – Inhaled Insulin and FEV 1  Inhaled insulin associated with greater decline in FEV 1 than comparator  Effect noted within first few wks  Treatment group difference of ~40mL does not appear to progress out to 2 yrs  Results comparable in type 1 and type 2  Reversal of effect  Data not conclusive in type 1  Data from Study 1001-1002 suggest some reversal of effect after 2 years exposure in type 2

21. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 21 Change from Baseline DLCO in Type 1 Pooled Phase 2 and 3 Studies (Mean +/- SD)

22. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 22 Change from Baseline DLCO in Type 2 Pooled Phase 2 and 3 Studies (Mean +/- SD)

23. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 23 Change from Baseline DLCO in Type 1 in Study 1027 (Mean +/- SD)

24. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 24 Change from Baseline DLCO in Type 2 in Study 1001-1002 (Mean +/- SD)

25. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 25 Summary – Inhaled Insulin and DLCO Type 1  Inhaled insulin associated with greater decline in DLCO than comparator  Effect noted within first few wks  Treatment group difference of ~0.5 to 0.6 mL/min/mmHg did not progress out to 2 yrs  Reversal  Data from Study 1027 suggest reversal of effect of inhaled insulin on DLCO after short term (12 wk) exposure

26. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 26 Summary – Inhaled Insulin and DLCO Type 2  Both treatment groups demonstrated similar decline in DLCO at 2 yrs  Maximum treatment group difference was ~0.5mL/min/mmHg during treatment

27. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 27 Agenda  Pulmonary Safety Database  Respiratory Adverse Events  Pulmonary Function Tests  FEV 1 and DLCO  Imaging  CXR and HRCT  Underlying Lung Diseases  Asthma and COPD  Conclusions

28. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 28 Imaging  Chest X-ray  More significant CXR changes noted in the inhaled insulin group  Notable changes included nodular density, opacity, nodule, atelectasis, and cardiomegaly  High Resolution Computed Tomography (HRCT)  Two year HRCT data does not suggest an increase in abnormal findings associated with inhaled insulin use

29. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 29 Agenda  Pulmonary Safety Database  Respiratory Adverse Events  Pulmonary Function Tests  FEV 1 and DLCO  Imaging  CXR and HRCT  Underlying Lung Diseases  Asthma and COPD  Conclusions

30. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 30 Pulmonary Safety Database – Controlled Studies in Asthma & COPD INH – Inhaled insulin; COMP – Comparator; AE - Adverse Event; PFT – Pulmonary Function Test; HRCT – High Resolution Computed Tomography; CXR – Chest X-ray

31. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 31 Study 1028 - Asthma  139 subjects treated (goal 250)  Respiratory AEs  Cough -14% INH, 3% comp  Respiratory tract infection - 43% INH, 33% comp  3 discontinuations due to respiratory AEs All in inhaled insulin group  Asthma AEs more common in comp group  Non-severe asthma exacerbation and severe asthma exacerbation more common in inhaled insulin group  Asthma Control Questionnaire

32. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 32 Change from Baseline FEV1 in Study 1028 – Asthma (Mean +/- SD)

33. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 33 Change from Baseline DLCO in Study 1028 – Asthma (Mean +/- SD)

34. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 34 Study 1030 - COPD  Respiratory AEs  Cough – 8.6% INH, 3.1% comp  Dyspnea – 11.4% INH, 6.3% comp  One discontinuation due to respiratory AE COPD exacerbation in inhaled insulin group  Non-severe COPD exacerbation (protocol defined) 10 subjects with 14 events (INH) 4 subjects with 9 events (comp)  Severe COPD exacerbation (protocol defined) One event in INH, none in comparator

35. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 35 Change from Baseline FEV1 in Study 1030 - COPD (Mean +/- SD)

36. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 36 Change from Baseline DLCO in Study 1030- COPD (Mean +/- SD)

37. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 37 Summary - Underlying Lung Disease  Limited data at 52 weeks  Asthma (Study 1028)  Separation of treatment groups for FEV1 and DLCO after week 39, favoring comparator  COPD (Study 1030)  FEV1 – 30mL greater decline in FEV1 in inhaled insulin group at 52 weeks  DLCO – inhaled insulin with increase in DLCO at 52 weeks

38. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 38 Agenda  Pulmonary Safety Database  Respiratory Adverse Events  Pulmonary Function Tests  FEV 1 and DLCO  Imaging  CXR and HRCT  Underlying Lung Diseases  Asthma and COPD  Conclusions

39. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 39 Conclusions – Inhaled Insulin  Increase in respiratory adverse events  Cough  Decline in pulmonary function  Effect occurs within first few weeks  Not progressive out to 2 years  Some evidence for reversal of effect after discontinuation of inhaled insulin, but not conclusive in type 1 DM  No increase HRCT findings at 2 years  Limited controlled data in asthma & COPD

40. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 40 Questions to the Committee  5. Are there sufficient data to assess the pulmonary safety profile of Exubera ® in patients without underlying lung disease?  A. If yes, do the data suggest an acceptable pulmonary safety profile in patients without underlying lung disease?  B. If no, what additional information is needed?

41. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 41 Questions to the Committee  6. Are there sufficient data to assess the pulmonary safety of Exubera® in patients with underlying lung disease?  A. If yes, do the data suggest an acceptable pulmonary safety profile in patients with underlying lung disease?  B. If no, what additional information is needed?

42. Food and Drug Administration Division of Pulmonary and Allergy Drug Products September 8, 2005 EMDAC Meeting 42 Division of Pulmonary and Allergy Drug Products Parklawn Building, Room 10B-45 5600 Fishers Lane, HFD-570 Rockville, MD 20857 Phone: 301-827-1050 Fax: 301-827-1271