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

Pulmonary and Allergy Drugs Advisory Committee January 17, 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 Clinical relevance of the Efficacy data Application of data from these ADVAIR trials to the general COPD population Adequacy of the Safety data

Pulmonary and Allergy Drugs Advisory Committee January 17, COMBINATION DRUG PRODUCT Not approved for use in COPDApproved Relief of bronchospasm associated with COPD ADVAIR DISKUS Fluticasone propionateSalmeterol xinafoate

Pulmonary and Allergy Drugs Advisory Committee January 17, DEVELOPMENT PROGRAM

Pulmonary and Allergy Drugs Advisory Committee January 17, OBJECTIVESOBJECTIVES 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 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

Pulmonary and Allergy Drugs Advisory Committee January 17, FIXED COMBINATION DRUGS POLICY  21 CFR 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  21 CFR 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

Pulmonary and Allergy Drugs Advisory Committee January 17, 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 FEV 1 of 0.70 L OR FEV 1  0.70 L AND > 40% < 65% predicted AND FEV 1 /FVC ratio  70% 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 FEV 1 of 0.70 L OR FEV 1  0.70 L AND > 40% < 65% predicted AND FEV 1 /FVC ratio  70%

Pulmonary and Allergy Drugs Advisory Committee January 17, PATIENT POPULATION ENROLLED Mean FEV 1 across studies was 40% - 42% predicted Mean FEV 1 /FVC ratio across studies was 47% - 51% Percentage of subjects across studies with 12% improvement in FEV 1 AND >200 ml absolute change was 54% - 55% Mean FEV 1 across studies was 40% - 42% predicted Mean FEV 1 /FVC ratio across studies was 47% - 51% Percentage of subjects across studies with 12% improvement in FEV 1 AND >200 ml absolute change was 54% - 55%

Pulmonary and Allergy Drugs Advisory Committee January 17, PATIENT POPULATION ENROLLED All subjects had a history of chronic bronchitis Mean baseline symptom score on Chronic Bronchitis Symptom Questionnaire ranged [maximum possible score = 16] Dyspnea score  2 [scale 0 - 4] All subjects had a history of chronic bronchitis Mean baseline symptom score on Chronic Bronchitis Symptom Questionnaire ranged [maximum possible score = 16] Dyspnea score  2 [scale 0 - 4]

Pulmonary and Allergy Drugs Advisory Committee January 17, Percentage of Discontinuations

Pulmonary and Allergy Drugs Advisory Committee January 17, PRIMARY EFFICACY ENDPOINTS Pre-dose FEV 1  Evaluate the contribution of FP in the combination  ADVAIR vs. Salmeterol  2-hr post-dose FEV 1  Evaluate the contribution of salmeterol in the combination  ADVAIR vs. FP Pre-dose FEV 1  Evaluate the contribution of FP in the combination  ADVAIR vs. Salmeterol  2-hr post-dose FEV 1  Evaluate the contribution of salmeterol in the combination  ADVAIR vs. FP

Pulmonary and Allergy Drugs Advisory Committee January 17, EFFICACY: Pre-dose FEV 1

Pulmonary and Allergy Drugs Advisory Committee January 17, EFFICACY: 2-hr Post-Dose FEV 1

Pulmonary and Allergy Drugs Advisory Committee January 17, EFFICACY: ADVAIR vs. Placebo (Reversible and Non-reversible populations) Pre-Dose FEV 1

Pulmonary and Allergy Drugs Advisory Committee January 17, EFFICACY: ADVAIR vs. Placebo (Reversible and Non-reversible populations) 2- hour post- dose FEV 1

Pulmonary and Allergy Drugs Advisory Committee January 17, PATIENT-REPORTED OUTCOMES Evaluation of patient-related outcomes may be helpful in assessing the clinical relevance of FEV 1 changes Chronic Respiratory Disease Questionnaire [CRDQ] used in both studies Sponsor-defined Minimal Clinically Important change [MCIC] in Overall Score  10 Evaluation of patient-related outcomes may be helpful in assessing the clinical relevance of FEV 1 changes Chronic Respiratory Disease Questionnaire [CRDQ] used in both studies Sponsor-defined Minimal Clinically Important change [MCIC] in Overall Score  10

Pulmonary and Allergy Drugs Advisory Committee January 17, Chronic Respiratory Disease Questionnaire Overall Score: Treatment Difference in Change From Baseline At Endpoint

Pulmonary and Allergy Drugs Advisory Committee January 17, CRDQ: Dyspnea Domain Treatment Difference in Change from Baseline at Endpoint

Pulmonary and Allergy Drugs Advisory Committee January 17, 2002 COPD EXACERBATIONS  Severity of exacerbations  Time to first exacerbation  Time to first moderate/severe exacerbation  Number of withdrawals due to COPD exacerbations  Severity of exacerbations  Time to first exacerbation  Time to first moderate/severe exacerbation  Number of withdrawals due to COPD exacerbations

Pulmonary and Allergy Drugs Advisory Committee January 17, Percentage of Subjects with COPD Exacerbations

Pulmonary and Allergy Drugs Advisory Committee January 17, Percentage of Subjects with Moderate/Severe Exacerbations

Pulmonary and Allergy Drugs Advisory Committee January 17, Percentage of Withdrawals Due to COPD Exacerbations

Pulmonary and Allergy Drugs Advisory Committee January 17, Chronic Bronchitis Symptoms Questionnaire [CBSQ]  Cough frequency and severity  Chest discomfort  Sputum production  Sponsor-defined MCIC  1.4  Cough frequency and severity  Chest discomfort  Sputum production  Sponsor-defined MCIC  1.4

Pulmonary and Allergy Drugs Advisory Committee January 17, CBSQ GAS: Treatment Difference in Change from Baseline at Endpoint

Pulmonary and Allergy Drugs Advisory Committee January 17, Transitional Dyspnea Index (TDI): Treatment Difference at Endpoint

Pulmonary and Allergy Drugs Advisory Committee January 17, SAFETYSAFETY 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 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

Pulmonary and Allergy Drugs Advisory Committee January 17, ADVERSE EVENTS Higher percentage of subjects in ADVAIR groups reported adverse events compared to placebo ADVAIR 250/5070% Placebo64% ADVAIR 500/5078% Placebo69% Higher percentage of subjects in ADVAIR groups reported adverse events compared to placebo ADVAIR 250/5070% Placebo64% ADVAIR 500/5078% Placebo69%

Pulmonary and Allergy Drugs Advisory Committee January 17, ADVERSE EVENTS

Pulmonary and Allergy Drugs Advisory Committee January 17, ADVERSE EVENTS

Pulmonary and Allergy Drugs Advisory Committee January 17, 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 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

Pulmonary and Allergy Drugs Advisory Committee January 17, 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 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

Pulmonary and Allergy Drugs Advisory Committee January 17, 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 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

Pulmonary and Allergy Drugs Advisory Committee January 17, SUMMARY - EFFICACY No clear treatment advantage with ADVAIR for  COPD-related “quality of life”  COPD Symptoms  COPD exacerbations  Improvement in dyspnea No clear treatment advantage with ADVAIR for  COPD-related “quality of life”  COPD Symptoms  COPD exacerbations  Improvement in dyspnea

Pulmonary and Allergy Drugs Advisory Committee January 17, 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 density or ocular effects  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 density or ocular effects