ADVAIR TM DISKUS (R) (Fluticasone propionate/salmeterol inhalation powder)

1. ADVAIRTM DISKUS(R)(Fluticasone propionate/salmeterol inhalation powder) Pulmonary and Allergy Drugs Advisory Committee Meeting Gaithersburg, Maryland January 17, 2002Lydia I. Gilbert-McClain, MD, FCCPMedical Reviewer, DPADP

2. CLINICAL ISSUES • Clinical relevance of the Efficacy data • Application of data from these ADVAIR trials to the general COPD population • Adequacy of the Safety data

3. COMBINATION DRUG PRODUCT ADVAIR DISKUS Fluticasone propionate Salmeterol xinafoate Not approved for use in COPD Approved 1998 - Relief of bronchospasm associated with COPD

4. DEVELOPMENT PROGRAM

5. OBJECTIVES 1.Efficacy of ADVAIR 250/50 bid and ADVAIR 500/50 bid 2. Safety of ADVAIR 250/50 bid and ADVAIR 500/50 bid 3.The “ quality of life” in COPD subjects receiving ADVAIR 250/50 bid and ADVAIR 500/50 bid

6. FIXED COMBINATION DRUGS POLICY • 21 CFR 300.50 -Two or more drugs may be combined in a single dosage form when: • Each component makes a contribution to the claimed effects • The combination is safe and effective • SFCA3006, SFCA3007 adequately designed to fulfill the efficacy requirements of the policy

7. ENTRY CRITERIA • Diagnosis of COPD [ATS definition] • Must have a history of cough productive of sputum on most days for at least 3 months of the year for at least 2 years that was not attributable to another disease process • Baseline FEV1 of < 65% predicted but > 0.70 L OR • FEV1 0.70 L AND > 40% < 65% predicted • AND FEV1/FVC ratio  70%

8. PATIENT POPULATION ENROLLED • Mean FEV1 across studies was 40% - 42% predicted • Mean FEV1/FVC ratio across studies was 47% - 51% • Percentage of subjects across studies with 12% improvement in FEV1 AND >200 ml absolute change was 54% - 55%

9. PATIENT POPULATION ENROLLED • All subjects had a history of chronic bronchitis • Mean baseline symptom score on Chronic Bronchitis Symptom Questionnaire ranged 6.9 - 7.5 [maximum possible score = 16] • Dyspnea score  2 [scale 0 - 4]

10. Percentage of Discontinuations

11. PRIMARY EFFICACY ENDPOINTS • Pre-dose FEV1 • Evaluate the contribution of FP in the combination • ADVAIR vs. Salmeterol • 2-hr post-dose FEV1 • Evaluate the contribution of salmeterol in the combination • ADVAIR vs. FP

12. EFFICACY: Pre-dose FEV1

13. EFFICACY: 2-hr Post-Dose FEV1

14. EFFICACY: ADVAIR vs. Placebo (Reversible and Non-reversible populations)Pre-Dose FEV1

15. EFFICACY: ADVAIR vs. Placebo(Reversible and Non-reversible populations)2- hour post- dose FEV1

16. PATIENT-REPORTED OUTCOMES • Evaluation of patient-related outcomes may be helpful in assessing the clinical relevance of FEV1 changes • Chronic Respiratory Disease Questionnaire [CRDQ] used in both studies • Sponsor-defined Minimal Clinically Important change [MCIC] in Overall Score 10

17. Chronic Respiratory Disease QuestionnaireOverall Score: Treatment Difference in Change From Baseline At Endpoint

18. CRDQ: Dyspnea Domain Treatment Difference in Change from Baseline at Endpoint

19. COPD EXACERBATIONS Severity of exacerbations Time to first exacerbation Time to first moderate/severe exacerbation Number of withdrawals due to COPD exacerbations

20. Percentage of Subjects with COPD Exacerbations

21. Percentage of Subjects with Moderate/Severe Exacerbations

22. Percentage of Withdrawals Due to COPD Exacerbations

23. Chronic Bronchitis Symptoms Questionnaire [CBSQ] • Cough frequency and severity • Chest discomfort • Sputum production • Sponsor-defined MCIC 1.4

24. CBSQ GAS: Treatment Difference in Change from Baseline at Endpoint

25. Transitional Dyspnea Index (TDI): Treatment Difference at Endpoint

26. SAFETY • Incidence of Cardiovascular events similar across treatment groups • No clinically significant change in heart rate • No drug-related QTc changes • Holter monitoring - One case of heart block with ADVAIR 500/50

27. ADVERSE EVENTS • Higher percentage of subjects in ADVAIR groups reported adverse events compared to placebo ADVAIR 250/50 70% Placebo 64% ADVAIR 500/50 78% Placebo 69%

28. ADVERSE EVENTS

29. ADVERSE EVENTS

30. OTHER ADVERSE EVENTS • Fractures rarely reported • No cataracts reported • Two reports of ocular pressures disorders in the ADVAIR 500/50 group and one in the placebo group • Elevated blood glucose [ > 175 mg/dl] similar in ADVAIR and placebo groups

31. SAFETY: Evaluation of HPA Axis Effects • Mean AM cortisol levels comparable in ADVAIR and placebo groups on Treatment Day 1 and Endpoint • No adrenal insufficiency observed with ACTH [Cosyntropin] stimulation testing • ACTH stimulation insensitive test for less than complete adrenal insufficiency

32. SUMMARY - EFFICACY • ADVAIR 250/50 and ADVAIR 500/50 meet efficacy criteria for combination drugs in the primary endpoints • Similar efficacy for ADVAIR 250/50 and ADVAIR 500/50 • Numerically, effect size in “Reversible” subjects > effect size of “Non-reversible” subjects

33. SUMMARY - EFFICACY • No clear treatment advantage with ADVAIR for • COPD-related “quality of life” • COPD Symptoms • COPD exacerbations • Improvement in dyspnea

34. SUMMARY - SAFETY • Higher incidence of candidiasis, viral respiratory infections and hoarseness/dysphonia with ADVAIR • No adrenal insufficiency observed with ACTH [Cosyntropin] stimulation testing • Studies not designed to evaluate bone mineral densityor ocular effects