Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 OutlineOutline History of development programHistory…

Pulmonary-Allergy Drugs Advisory CommitteePulmonary-Allergy Drugs Advisory CommitteeMay 1, 2007May 1, 2007

OutlineOutline• History of development program History of development program

– Dr. Carol BoskenDr. Carol Bosken• Introduction to efficacy results Introduction to efficacy results

• Dr. Carol BoskenDr. Carol Bosken Efficacy results Efficacy results

Ms. Feng ZhouMs. Feng Zhou• Safety results and summary

– Dr. Carol Bosken


Outline of PresentationOutline 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 MethodsStatistical 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


80

82

84

86

88

90

92

94

96

98

100

0 84 168 252 336 420 504 588 672 756 840 924 1008 1092Treatment Days

Surv

ival

Per

cent

age

(%)

Placebo - 15.2%SAL 50 - 13.5%FP 500 - 16.0%SFC 50/500 - 12.6%

All-Cause Mortality ResultsAll-Cause Mortality ResultsStudy SCO30003Study SCO30003

SFC vs. PLA: ∆=2.6%

HR=0.82 (0.68, 1.00) p=0.052

Death rates at 3 yrs:


Factors Affecting Interpretation of Results Factors Affecting Interpretation of Results Study SCO30003Study SCO30003

• Dropout• Low risk vs. High risk• US vs. Non-US


Percentage of Dropouts Percentage of Dropouts Overall and by Primary ReasonOverall and by Primary Reason

Study SCO30003 Study SCO30003

PLA SAL FP SFC N 1524 1521 1534 1533 Dropout Rate 44% 36% 38% 34%

Adverse event 24% 20% 23% 19%

Lack of efficacy 7% 4% 3% 2%


Dropout IssueDropout 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


Percentage of DropoutsPercentage of Dropoutsby Subgroupsby Subgroups

0

10

20

30

40

50

CS Naïve(41%)

CS (59%)

Low Risk(26%)

High Risk(74%)

Age <= 65(44%)

Age > 65(56%)

Perc

enta

ge o

f Dis

coun

tined

Pat

ient

s

Placebo SAL50 FP500 SFC50/500


All-Cause MortalityAll-Cause MortalityHazard Ratios (95% CI) for SFC vs. PLAHazard Ratios (95% CI) for SFC vs. PLA

by Selected Risk Groups by Selected Risk Groups

0.4

0.6

0.8

1.0

1.2

1.4

<65(44%)

>=65(56%)

No(93%)

Yes(7%)

=0 (43%)

>=1(57%)

> 40%(60%)

≤ 40%(40%)

Haza

rd R

atio

and

95%

CI Age Myocardial

infarctionCOPD exac in pre-year

BL %pred post-br FEV1


80

82

84

86

88

90

92

94

96

98

100

0 84 168 252 336 420 504 588 672 756 840 924 1008 1092

Survival Proba

bility (%

)

80

82

84

86

88

90

92

94

96

98

100

0 84 168 252 336 420 504 588 672 756 840 924 1008 1092

Survival Proba

bility (%

)All-Cause Mortality by Risk ProfileAll-Cause Mortality by Risk Profile

(SFC vs. PLA)(SFC vs. PLA)Low Risk (26%) High Risk (74%)Low Risk (26%) High Risk (74%)

Death rates:

12.1% – PLA

7.9% - SFC

∆ = 4.2%

HR = 0.63

95% CI (0.40, 0.99)

Death rates:

16.1% – PLA

14.3% - SFC

∆ = 1.8%

HR = 0.88

95% CI (0.71, 1.09)


All-Cause Mortality All-Cause Mortality (SFC vs. PLA)(SFC vs. PLA)

On-Treatment Deaths Overall Deaths On-Treatment Deaths Overall Deaths

80

82

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98

100

0 84 168 252 336 420 504 588 672 756 840 924 1008 1092

Treatment Days

Survival Percentage (%

)

80

82

84

86

88

90

92

94

96

98

100

0 84 168 252 336 420 504 588 672 756 840 924 1008 1092Treatment Days


)

Death rates:

15.2% - PLA

12.6%- SFC

∆ = 2.6%

HR = 0.82

95%CI (0.7, 0.99)

Death rates:

10.5% - PLA

8.1% - SFC

∆ = 2.4%

HR = 0.77

95%CI (0.6, 1.01)


Relationship of Risk Profile Relationship of Risk Profile to Dropout & to Outcometo 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


0.4

0.6

0.8

1

1.2

1.4

SFC vs. PLA SFC vs. SAL SFC vs. FP SAL vs. PLA FP vs. PLA

Haza

rd R

atio

and

95%

CI

All-Cause MortalityAll-Cause MortalitySFC vs. PLA and ComponentsSFC vs. PLA and Components

SAL50 == SFC50/500 ?


COPD-related MortalityCOPD-related Mortality SFC vs. PLA and Components SFC vs. PLA and Components

Death rate at 3 years:

6.3% - PLA, 6.4% - SAL, 7.3% - FP, 4.9% - SAL

0.4

0.6

0.8

1

1.2

1.4

SFC vs.PLA

SFC vs.SAL

SFC vs. FP SFC vs.PLA

SFC vs.SAL

SFC vs. FP

Haza

rd R

atio

and

95%

CI

All-cause MortalityDeath Rate at 3 Years:

PLA-15%, SAL-14%, FP-16%, SFC-13%

COPD-related MortalityDeath Rate at 3 Years:

PLA-6%, SAL-6%, FP-7%, SFC-5%


All-cause Mortality By RegionAll-cause Mortality By RegionSFC vs. PLASFC vs. PLA

0.4

0.6

0.8

1.0

1.2

1.4

US (n=694, 23%)

Asia Pacific (n=376, 12%)

E. Europe (n=578, 19%)

W. Europe(n=952, 31%)

Other (n=457,15%)

MITT (n=3057)

Haz

ard

Rat

io a

nd 9

5% C

I


80

82

84

86

88

90

92

94

96

98

100

0 84 168 252 336 420 504 588 672 756 840 924 1008 1092

Survival Percentage (%)

80

82

84

86

88

90

92

94

96

98

100

0 84 168 252 336 420 504 588 672 756 840 924 1008 1092


)All-Cause MortalityAll-Cause Mortality

(SFC vs. PLA)(SFC vs. PLA)US Population (23%) Non-US Population (77%)US Population (23%) Non-US Population (77%)

Death rates:

13.9% - PLA

12.3% - SFC

∆ = 1.6%

HR = 0.87

95% CI (0.58, 1.32)

Death rates:

15.5% - PLA

12.7% - SFC

∆ = 2.8%

HR = 0.81

95% CI (0.65, 1.00)


80

82

84

86

88

90

92

94

96

98

100

0 84 168 252 336 420 504 588 672 756 840 924 1008 1092

Survival Percentag

e (%

)

80

82

84

86

88

90

92

94

96

98

100

0 84 168 252 336 420 504 588 672 756 840 924 1008 1092

Survival Percentag

e (%

)All-Cause MortalityAll-Cause Mortality

US Population (23%) Non-US Population (77%)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)


Summary of Mortality ResultSummary 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%)


COPD Exacerbation EndpointsCOPD Exacerbation Endpoints

Study SFCB3024 SCO30003 N 1462 6112 Duration 1 year 3 years US population 0% 23% Exacerbation history 100% 57% Endpoint – primary Pre-dose FEV1 All-cause mortality

- secondary Exacerbation Exacerbation Multiplicity adjustment No Yes


SCO30003 Study SCO30003 Study - - Multiplicity (proposed in SAP in 1/06)Multiplicity (proposed in SAP in 1/06)

All-cause mortalitySFC vs. PLA Stop

ExacerbationSFC vs. PLA Stop

StopExacerbationSFC vs. SAL

p <= 0.05

p <= 0.05

p > 0.05

p > 0.05

p > 0.05

SGRQSFC vs. PLASFC vs. SAL

Stopp > 0.05

p <= 0.05

p = 0.052


Exacerbation Endpoint for SFCB3024 Exacerbation Endpoint for SFCB3024 Moderately Severe and SevereModerately Severe and Severe

0.4

0.6

0.8

1

1.2

1.4

SFCvsPLA SFCvsSAL SFCvsFP SALvsPLA FPvsPLATreatment Comparison

Rate

Rat

io a

nd 9

5% C

I


Exacerbation Endpoint for SCO30003 Exacerbation Endpoint for SCO30003 Moderate and SevereModerate and Severe

0.4

0.6

0.8

1

1.2

1.4

SFCvsPLA SFCvsSAL SFCvsFP SALvsPLA FPvsPLATreatment Comparison

Rate

Rat

io a

nd 9

5% C

I


COPD Exacerbation EndpointsCOPD Exacerbation Endpoints- Moderate/Severe- Moderate/Severe

Subjects had previous exacerbation historySubjects had previous exacerbation history

0.4

0.6

0.8

1

1.2

1.4

SFCvsPLA SFCvsSAL SFCvsFP SFCvsPLA SFCvsSAL SFCvsFP

Treatment Comparison

Rate

Rat

io a

nd 9

5% C

I

SCO30003 - 3 Years - Subgroup of patients (57%)

SFCB3024 - 1 Year


Exacerbation Endpoint for SCO30003 Exacerbation Endpoint for SCO30003 Moderate and SevereModerate and Severe

by Region (SFC vs. PLA)by Region (SFC vs. PLA)

0.4

0.6

0.8

1

1.2

1.4

US Asia E.Europe W.Europe Other

Regions

Rate

Rat

io a

nd 9

5% C

I


Moderate/Severe ExacerbationModerate/Severe ExacerbationStudy SCO30003Study SCO30003 – US vs. Non-US – US vs. Non-US

0.4

0.6

0.8

1

1.2

1.4

SFCvsPLA SFCvsSAL SFCvsFP SFCvsPLA SFCvsSAL SFCvsFP

Treatment Comparison

Rate

Rat

io a

nd 9

5% C

I

US (23%) Non-US (77%)


Summary of COPD ExacerbationSummary 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


Thank You!Thank You!

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Documents

Pulmonary-Allergy Drugs Advisory Committee May 1, 2007 OutlineOutline History of development programHistory…