Pulmonary and Allergy Drugs Advisory Committee Meeting

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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

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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

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COMBINATION DRUG PRODUCT

ADVAIR DISKUS

Fluticasone propionate
Salmeterol xinafoate
Not approved for use in COPD
Approved 1998 - Relief of bronchospasm associated
with COPD
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DEVELOPMENT PROGRAM
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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

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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

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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 lt 65 predicted but gt 0.70 L OR
• FEV1 ? 0.70 L AND gt 40 lt 65 predicted
• AND FEV1/FVC ratio ? 70

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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 gt200 ml absolute change
  was 54 - 55

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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

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Percentage of Discontinuations
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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

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EFFICACY Pre-dose FEV1
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EFFICACY 2-hr Post-Dose FEV1
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EFFICACY ADVAIR vs. Placebo (Reversible and
Non-reversible populations)Pre-Dose FEV1
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EFFICACY ADVAIR vs. Placebo(Reversible and
Non-reversible populations)2- hour post- dose
FEV1
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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

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Chronic Respiratory Disease QuestionnaireOverall
Score Treatment Difference in Change From
Baseline At Endpoint
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CRDQ Dyspnea Domain Treatment Difference in
Change from Baseline at Endpoint
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COPD EXACERBATIONS

• Severity of exacerbations
• Time to first exacerbation
• Time to first moderate/severe exacerbation
• Number of withdrawals due to COPD exacerbations

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Percentage of Subjects with COPD Exacerbations
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Percentage of Subjects with Moderate/Severe
Exacerbations
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Percentage of Withdrawals Due to COPD
Exacerbations
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Chronic Bronchitis Symptoms Questionnaire CBSQ

• Cough frequency and severity
• Chest discomfort
• Sputum production
• Sponsor-defined MCIC ?1.4

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CBSQ GAS Treatment Difference in Change from
Baseline at Endpoint
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Transitional Dyspnea Index (TDI) Treatment
Difference at Endpoint
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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

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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

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ADVERSE EVENTS
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ADVERSE EVENTS
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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 gt 175 mg/dl similar in
  ADVAIR and placebo groups

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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

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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
  gt effect size of Non-reversible subjects

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SUMMARY - EFFICACY

• No clear treatment advantage with ADVAIR for
• COPD-related quality of life
• COPD Symptoms
• COPD exacerbations
• Improvement in dyspnea

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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