Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 OutlineOutline History of development programHistory of development program –Dr. Carol Bosken Introduction to efficacy resultsIntroduction to efficacy results Dr. Carol BoskenDr. Carol Bosken Efficacy results Efficacy results Ms. Feng Zhou Ms. Feng Zhou Safety results and summary – Dr. Carol Bosken History of development programHistory of development program –Dr. Carol Bosken Introduction to efficacy resultsIntroduction to efficacy results Dr. Carol BoskenDr. Carol Bosken Efficacy results Efficacy results Ms. Feng Zhou Ms. Feng Zhou Safety results and summary – Dr. Carol Bosken

Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 Outline of Presentation Statistical methods Results –Mortality – SCO30003 Dropout issue SFC compared to components US vs. Non-US –Exacerbations SFCB3024 SCO30003 –Multiplicity issues US vs. Non-US Statistical methods Results –Mortality – SCO30003 Dropout issue SFC compared to components US vs. Non-US –Exacerbations SFCB3024 SCO30003 –Multiplicity issues US vs. Non-US

Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 Statistical Methods Agreed with sponsor’s statistical methods and results –Mortality (SCO30003) Log-Rank test, stratified by smoking status Other pre-specified supportive analyses –Exacerbations (SFCB3024, SCO30003) Negative Binomial model Poisson model Andersen Gill model Agreed with sponsor’s statistical methods and results –Mortality (SCO30003) Log-Rank test, stratified by smoking status Other pre-specified supportive analyses –Exacerbations (SFCB3024, SCO30003) Negative Binomial model Poisson model Andersen Gill model

Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 All-Cause Mortality Results Study SCO30003 SFC vs. PLA: ∆ = 2.6% HR=0.82 (0.68, 1.00) p=0.052 Death rates at 3 yrs:

Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 Factors Affecting Interpretation of Results Study SCO30003 Dropout Low risk vs. High risk US vs. Non-US Dropout Low risk vs. High risk US vs. Non-US

Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 Percentage of Dropouts Overall and by Primary Reason Study SCO30003

Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 Dropout Issue Addressed dropout issue in 2 ways: –Dropouts for low and high risk subgroups Risk profile defined by baseline characteristics where low risk is defined by: –No history of myocardial infarction & –No COPD exacerbation during the year previous to baseline & –% predicted post-bron. FEV1 > 40% Mortality results by risk groups –On-treatment mortality Addressed dropout issue in 2 ways: –Dropouts for low and high risk subgroups Risk profile defined by baseline characteristics where low risk is defined by: –No history of myocardial infarction & –No COPD exacerbation during the year previous to baseline & –% predicted post-bron. FEV1 > 40% Mortality results by risk groups –On-treatment mortality

Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 Percentage of Dropouts by Subgroups

Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 All-Cause Mortality Hazard Ratios (95% CI) for SFC vs. PLA by Selected Risk Groups

Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 All-Cause Mortality by Risk Profile (SFC vs. PLA) Low Risk (26%) High Risk (74%) Death rates: 12.1% – PLA 7.9% - SFC ∆ = 4.2% HR = % CI (0.40, 0.99) Death rates: 16.1% – PLA 14.3% - SFC ∆ = 1.8% HR = % CI (0.71, 1.09)

Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 All-Cause Mortality (SFC vs. PLA) On-Treatment Deaths Overall Deaths All-Cause Mortality (SFC vs. PLA) On-Treatment Deaths Overall Deaths Death rates: 15.2% - PLA 12.6%- SFC ∆ = 2.6% HR = %CI (0.7, 0.99) Death rates: 10.5% - PLA 8.1% - SFC ∆ = 2.4% HR = %CI (0.6, 1.01)

Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 Relationship of Risk Profile to Dropout & to Outcome Low risk patients remained on study longer than high risk patients regardless of randomized treatment Low risk patients show greater benefit from SFC over placebo compared to high risk patients –Supported by favorable on-treatment mortality results Dropouts in both treatment groups were at a higher risk of dying than patients remaining on treatment Low risk patients remained on study longer than high risk patients regardless of randomized treatment Low risk patients show greater benefit from SFC over placebo compared to high risk patients –Supported by favorable on-treatment mortality results Dropouts in both treatment groups were at a higher risk of dying than patients remaining on treatment

Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 All-Cause Mortality SFC vs. PLA and Components SAL50 == SFC50/500 ?

Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 COPD-related Mortality SFC vs. PLA and Components Death rate at 3 years: 6.3% - PLA, 6.4% - SAL, 7.3% - FP, 4.9% - SAL

Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 All-cause Mortality By Region SFC vs. PLA

Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 All-Cause Mortality (SFC vs. PLA) US Population (23%) Non-US Population (77%) Death rates: 13.9% - PLA 12.3% - SFC ∆ = 1.6% HR = % CI (0.58, 1.32) Death rates: 15.5% - PLA 12.7% - SFC ∆ = 2.8% HR = % CI (0.65, 1.00)

Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 All-Cause Mortality US Population (23%) Non-US Population (77%) HR: SFC vs. SAL=0.83 (p=0.4) SFC vs. FP=0.91 (p=0.7) HR: SFC vs. SAL=0.96 (p=0.8) SFC vs. FP=0.74 (p=0.006)

Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 Summary of Mortality Result SFC showed a marginal survival benefit over placebo (∆=2.6%, p=0.052) and comparable results to SAL (∆=0.9%) SFC showed a smaller survival benefit in US (∆=1.6%) compared to other countries (∆=2.8%) SFC showed a greater survival benefit for low risk patients (∆=4.2%) compared to higher risk patients (∆=1.8%) SFC showed a marginal survival benefit over placebo (∆=2.6%, p=0.052) and comparable results to SAL (∆=0.9%) SFC showed a smaller survival benefit in US (∆=1.6%) compared to other countries (∆=2.8%) SFC showed a greater survival benefit for low risk patients (∆=4.2%) compared to higher risk patients (∆=1.8%)

Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 COPD Exacerbation Endpoints

Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 SCO30003 Study - Multiplicity (proposed in SAP in 1/06) All-cause mortality SFC vs. PLA Stop Exacerbation SFC vs. PLA Stop Exacerbation SFC vs. SAL p <= 0.05 p > 0.05 SGRQ SFC vs. PLA SFC vs. SAL Stop p > 0.05 p <= 0.05 p = 0.052

Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 Exacerbation Endpoint for SFCB3024 Moderately Severe and Severe

Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 Exacerbation Endpoint for SCO30003 Moderate and Severe

Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 COPD Exacerbation Endpoints - Moderate/Severe Subjects had previous exacerbation history

Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 Exacerbation Endpoint for SCO30003 Moderate and Severe by Region (SFC vs. PLA)

Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 Moderate/Severe Exacerbation Study SCO30003 – US vs. Non-US

Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 Summary of COPD Exacerbation No statistical adjustments for multiple comparisons were made for this secondary endpoint. SFC showed a benefit in reduction for COPD moderate/severe exacerbation compared to placebo in both studies The comparison of SFC to SAL and FP showed a similar trend in both studies; however, comparisons are only significant in Study SCO30003 SFC showed a smaller benefit in US population compared to Non-US population in Study SCO30003 No statistical adjustments for multiple comparisons were made for this secondary endpoint. SFC showed a benefit in reduction for COPD moderate/severe exacerbation compared to placebo in both studies The comparison of SFC to SAL and FP showed a similar trend in both studies; however, comparisons are only significant in Study SCO30003 SFC showed a smaller benefit in US population compared to Non-US population in Study SCO30003

Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 Thank You! ****