FLOVENT ® DISKUS ® NDA 20-833, S004 GlaxoSmithKline

1. FLOVENT® DISKUS®NDA 20-833, S004GlaxoSmithKline Pulmonary-Allergy Drugs Advisory Committee January 17, 2002 Charles E. Lee, M.D. Medical Reviewer Division of Pulmonary and Allergy Drug Products CDER/FDA

2. Proposed Indication “FLOVENT DISKUS is indicated for the long-term, twice-daily maintenance treatment of COPD (including emphysema and chronic bronchitis).”

3. Proposed Dose “The starting dosage for adults is 1 inhalation (250 mcg) twice daily. For patients who do not respond adequately to the starting dose, increasing the dose to 500 mcg twice daily may provide additional control.”

4. Introduction • Efficacy • Pivotal studies • Safety • Pivotal studies • Supportive studies

5. Overview • Efficacy • Small changes in primary and secondary efficacy endpoints • Majority of patients had reversibility with bronchodilator • Safety concerns • Respiratory infections • Systemic effects • Adrenal • Bone

6. Questions for Consideration • Efficacy • Clinical interpretation of the primary efficacy endpoint results • Higher percentage of reversibility in COPD population than generally found • All patients had chronic bronchitis, could have self-reported emphysema • Safety • Adequacy of long-term safety database • Risk versus benefit

7. Pivotal Studies

8. Efficacy Assessment • Primary efficacy variable • Pre-dose FEV1 • Secondary efficacy variables • CBSQ, BDI/TDI • PEFR, albuterol use • COPD exacerbations • Patient Reported Outcomes • CRDQ

9. Safety Assessment • AEs, SAEs, Withdrawals • Vital signs, physical examination, oropharyngeal exam • ECG • Hematology and chemistry studies • Serum cortisol (FLTA3025) • Cosyntropin stimulation (SFCA3006, SFCA3007)

10. DemographicsPivotal Studies

11. Demographics FLTA3025 SFCA3006 SFCA3007 Gender, %M 69 66 63 Mean age, yr 64 63 64 Race, %C 94 94 93 Race, %B 4 5 4 Race, %O 1 2 3 ICS use, % 31 25 25 Current smokers, % 45 48 47

12. ReversibilityPercent of Population Reversible % FLTA3025 59 SFCA3006 54 SFCA3007 55 Reversible: Increase in FEV1 12% and 0.2 L

13. Mean Response to Bronchodilator % Change in FEV1 Reversible Non Overall Reversible % % % FLTA3025 32 9 23 SFCA3006 30 9 20 SFCA3007 30 9 20 Reversible: Increase in FEV1 12% and 0.2 L

14. EfficacyPivotal Studies

15. Mean Change From Baseline in Pre-dose FEV1, LitersDifference from Placebo *p <0.05

16. Secondary Endpoints and Patient Reported Outcomes • Small differences from placebo group • CBSQ • BDI/TDI • COPD Exacerbations • AM PEFR • Albuterol use • CRDQ

17. COPD Exacerbations% of Patients with 1 Exacerbation

18. Daily Albuterol UseMean Change From Baseline Difference from Placebo Baseline: 4.5 to 5.7 puffs/day

19. CRDQChange from Baseline in Overall Score Difference from Placebo MCIC = 10.0 Baseline: 83.6 to 88.8

20. Subgroup AnalysisNon-reversible Group Non-reversible: Increase in FEV1 <12% or <0.2 L

21. Subgroup Analysis, Non-reversible Group Mean Change From Baseline in Pre-dose FEV1 Difference from Placebo

22. Efficacy, Pivotal Studies • Primary efficacy endpoint • Statistically significant and replicated for FP 500 • Not replicated for FP 250 • Smaller effect in the non-reversible group • Secondary endpoints and patient reported outcomes • Small differences from the placebo group

23. Safety Pivotal Studies

24. Notable AEs, Pivotal Studies

25. Notable AEs, Pivotal Studies

26. Adrenal Effects • Serum cortisol • FLTA3025 • Cosyntropin stimulation testing • SFCA3006, SFCA3007

27. FLTA3025: Serum Cortisol Percent Difference from Placebo

28. Cosyntropin Stimulation Testing • SFCA3006, SFCA3007 • No evidence of adrenal insufficiency • Insensitive test for less than complete adrenal insufficiency

29. Safety Other Studies

30. FLTA1003 • Phase 1 PK and PD study • Single center, open label, randomized, single dose, 4-way crossover design • 1000 mcg of FP administered with Diskus • Washout of 5 days between periods

31. FLTA1003Mean 24 Hour Urinary Cortisol Excretion

32. FLIT78 • Multicenter, double blind, randomized, placebo controlled, parallel group study • Flovent MDI, 500 mcg BID for 3 years • COPD • “ISOLDE” • Burge PS, et. al. BMJ 2000;320:1297-1303

33. Notable AEs, FLIT78

34. Notable AEs, FLIT78

35. FLIT98 • Multicenter, randomized, double blind, placebo controlled, parallel group study • 1000 mcg BID of FP MDI for 4 weeks • Patients with acute COPD exacerbation • N = 249 (126 FP, 123 pbo) • One FP-treated patient had SAE for decreased cortisol

36. Bone Mineral Density • 2-year studies • FLTA3001 • FLTA3017 • Asthma patients • Ages 18-50 years • Females were premenopausal • Study population at lower risk for osteoporosis than the population proposed in this NDA

37. Bone Mineral Density • FLTA3001 • FP MDI 88 mcg BID, 440 mcg BID • N = 160 • Small decrease at lumbar spine for FP 440 mcg, but increase for FP 88 mcg and placebo • No changes for proximal femur or total body • FLTA3017 • FP Rotadisk 500 mcg BID • N = 64 • Decrease at femoral neck • No changes for lumbar spine or total body

38. Conclusions • Primary efficacy endpoint • Replication for FP 500 only, not for FP 250 • Small differences from placebo from secondary endpoints • Majority of patients were reversible • Safety concerns • Respiratory infections • Adrenal effects • Bone density • Risk versus benefit