Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee

January 17, 2002January 17, 2002

Pulmonary and Allergy Drugs Advisory Committee Meeting

Gaithersburg, Maryland January 17, 2002

Lydia I. Gilbert-McClain, MD, FCCPMedical Reviewer, DPADP

ADVAIRADVAIRTMTM DISKUS DISKUS(R)(R)

(Fluticasone propionate/salmeterol (Fluticasone propionate/salmeterol inhalation powder)inhalation powder)

2Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee

January 17, 2002January 17, 2002

CLINICAL ISSUESCLINICAL ISSUES

• Clinical relevance of the Efficacy data

• Application of data from these ADVAIR trials to the general COPD population

• Adequacy of the Safety data

3Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee

January 17, 2002January 17, 2002

COMBINATION DRUG PRODUCTCOMBINATION DRUG PRODUCT

Not approved for use in COPD Approved 1998 - Relief of bronchospasm associated with COPD

ADVAIR DISKUS

Fluticasone propionate Salmeterol xinafoate

4Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee

January 17, 2002January 17, 2002

DEVELOPMENT PROGRAMDEVELOPMENT PROGRAM

SFCA3006 SFCA3007

*TreatmentArms

Advair 500/50 Advair 250/50

FP 500 FP 250

Salmeterol 50 Salmeterol 50

Placebo Placebo

*One inhalation twice dailyFP = fluticasone propionate

5Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee

January 17, 2002January 17, 2002

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

6Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee

January 17, 2002January 17, 2002

FIXED COMBINATION DRUGS POLICYFIXED 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

7Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee

January 17, 2002January 17, 2002

ENTRY CRITERIAENTRY 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%

8Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee

January 17, 2002January 17, 2002

PATIENT POPULATION ENROLLEDPATIENT 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%

9Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee

January 17, 2002January 17, 2002

PATIENT POPULATION ENROLLEDPATIENT 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]

10Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee

January 17, 2002January 17, 2002

Percentage of DiscontinuationsPercentage of Discontinuations

0

20

40

60

80

100

ADVAIR 250/50 ADVAIR 500/50

% D

isco

ntin

uatio

ns

AdvairPlaceboSalmeterolFP

11Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee

January 17, 2002January 17, 2002

PRIMARY EFFICACY ENDPOINTSPRIMARY 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

12Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee

January 17, 2002January 17, 2002

EFFICACY: Pre-dose FEVEFFICACY: Pre-dose FEV11

ADVAIR 250/50 ADVAIR 500/50Mean FEV1 atbaseline: Advair 1.207 L 1.254 L

Mean FEV1 atbaseline: SAL 1.205 L 1.192 L

Advair - SAL atEndpoint 0.069 L 0.067 L

13Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee

January 17, 2002January 17, 2002

EFFICACY: 2-hr Post-Dose FEVEFFICACY: 2-hr Post-Dose FEV11

ADVAIR 250/50 ADVAIR 500/50Mean FEV1 atbaseline: Advair 1.207 L 1.254 L

Mean FEV1 atbaseline: FP 1.236 L 1.174 L

Advair - FP atEndpoint

0.124 L 0.129 L

14Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee

January 17, 2002January 17, 2002

EFFICACY: ADVAIR vs. Placebo EFFICACY: ADVAIR vs. Placebo (Reversible and Non-reversible populations)(Reversible and Non-reversible populations)

Pre-Dose FEVPre-Dose FEV11

Overall ITTpopulation

Reversiblepopulation

Non-Reversiblepopulation

ADVAIR250/50

0.164 L 0.211 L 0. 107 L

ADVAIR500/50

0.160 L 0.192 L 0.124 L

15Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee

January 17, 2002January 17, 2002

EFFICACY: ADVAIR vs. PlaceboEFFICACY: ADVAIR vs. Placebo(Reversible and Non-reversible populations)(Reversible and Non-reversible populations)

2- hour post- dose FEV2- hour post- dose FEV11

Overall ITTpopulation

Reversiblepopulation

Non-reversiblepopulation

ADVAIR250/50

0.223 L 0.282 L 0.150 L

ADVAIR500/50

0.233 L 0.290 L 0.167 L

16Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee

January 17, 2002January 17, 2002

PATIENT-REPORTED OUTCOMESPATIENT-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

17Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee

January 17, 2002January 17, 2002

Chronic Respiratory Disease QuestionnaireChronic Respiratory Disease QuestionnaireOverall Score: Treatment Difference in Change Overall Score: Treatment Difference in Change

From Baseline At EndpointFrom Baseline At Endpoint

CRDQ [Overall Score]ADVAIR250/50

ADVAIR500/50

Advair - Placebo 5 5Advair - SAL 3.6 2Advair - FP -0.4 5.2MCIC 10

18Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee

January 17, 2002January 17, 2002

CRDQ: Dyspnea DomainCRDQ: Dyspnea Domain Treatment Difference in Change from Baseline Treatment Difference in Change from Baseline

at Endpointat Endpoint

MCIC = 2.5ADVAIR250/50

ADVAIR500/50

Advair - Placebo 1.2 2.1Advair - SAL 0.9 1.3Advair - FP 0.1 1.8

Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee

January 17, 2002January 17, 2002

COPD EXACERBATIONSCOPD EXACERBATIONS

Severity of exacerbations

Time to first exacerbation

Time to first moderate/severe exacerbation

Number of withdrawals due to COPD exacerbations

20Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee

January 17, 2002January 17, 2002

Percentage of Subjects with COPD Percentage of Subjects with COPD ExacerbationsExacerbations

0

20

40

60

80

100

ADVAIR 250/50 ADVAIR 500/50

% S

ubje

cts

with

Exa

c.

AdvairPlaceboSalmeterolFP

21Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee

January 17, 2002January 17, 2002

Percentage of Subjects with Moderate/Severe Percentage of Subjects with Moderate/Severe ExacerbationsExacerbations

0

20

40

60

80

100

ADVAIR 250/50 ADVAIR 500/50

% S

ubje

cts

with

Mod

/Sev

Exa

c.

AdvairPlaceboSalmeterolFP

22Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee

January 17, 2002January 17, 2002

Percentage of Withdrawals Due to COPD Percentage of Withdrawals Due to COPD ExacerbationsExacerbations

0

20

40

60

80

100

ADVAIR 250/50 ADVAIR 500/50

% W

ithdr

awal

s

AdvairPlaceboSalmeterolFP

23Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee

January 17, 2002January 17, 2002

Chronic Bronchitis Symptoms Chronic Bronchitis Symptoms Questionnaire [CBSQ]Questionnaire [CBSQ]

Cough frequency and severity

Chest discomfort

Sputum production

Sponsor-defined MCIC 1.4

24Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee

January 17, 2002January 17, 2002

CBSQ GAS: Treatment Difference in Change CBSQ GAS: Treatment Difference in Change from Baseline at Endpointfrom Baseline at Endpoint

Treatment difference in CBSQ GASMCIC 1.4

ADVAIR 250/50 ADVAIR 500/50

Advair - Placebo 0.7 0.3

Advair - SAL 0.6 -0.1

Advair - FP -0.1 0.2

25Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee

January 17, 2002January 17, 2002

Transitional Dyspnea Index (TDI): Treatment Transitional Dyspnea Index (TDI): Treatment Difference at EndpointDifference at Endpoint

ADVAIR 250/50 ADVAIR 500/50

Advair - Placebo 0.7 1.7

Advair - SAL 0.1 1.2

Advair - FP 0 0.8

MCIC 1

26Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee

January 17, 2002January 17, 2002

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

27Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee

January 17, 2002January 17, 2002

ADVERSE EVENTSADVERSE 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%

28Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee

January 17, 2002January 17, 2002

ADVERSE EVENTSADVERSE EVENTSAdvair250/50

Placebo

Candidiasis 10% 1%

Hoarsness/dysphonia

5% 0

Viralrespiratoryinfections

6% 3%

29Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee

January 17, 2002January 17, 2002

ADVERSE EVENTSADVERSE EVENTSAdvair500/50

Placebo

Upper respiratorytract infection

17% 10%

Viral respiratoryinfections

8% 3%

Candidiasis 7% 1%

Hoarseness/dysphonia

3% 2%

30Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee

January 17, 2002January 17, 2002

OTHER ADVERSE EVENTSOTHER 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

31Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee

January 17, 2002January 17, 2002

SAFETY: Evaluation of HPA Axis EffectsSAFETY: 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

32Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee

January 17, 2002January 17, 2002

SUMMARY - EFFICACYSUMMARY - 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

33Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee

January 17, 2002January 17, 2002

SUMMARY - EFFICACYSUMMARY - EFFICACY

• No clear treatment advantage with ADVAIR for

COPD-related “quality of life”

COPD Symptoms

COPD exacerbations

Improvement in dyspnea

34Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee

January 17, 2002January 17, 2002

SUMMARY - SAFETYSUMMARY - 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