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RaptivaTM (efalizumab) Efficacy

Lee Kaiser, PhD

DirectorClinical Biostatistics

Genentech, Inc.

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Phase III Studies

StudyNumber Study Design

Number ofPatients

Randomized

2390 Placebo-controlled Double-blind Randomized 556

2600 Placebo-controlled Double-blind Randomized 686

2058 Placebo-controlled Double-blind Randomized 498

2059 Placebo-controlled Double-blind Randomized 597

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Conclusions About Raptiva Efficacy

• Significant efficacy at Week 12

• Onset of efficacy by Week 4

• Psoriasis returns when Raptiva stopped

• Significant efficacy on retreatment

• Efficacy improves with continuous treatment past 12 weeks

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Study 2390:Pivotal Phase III Efficacy Study

RandomizationDay 0

Screen

Primary AnalysisWeek 12 (Day 84)

Placebo (n = 187)

Raptiva 1 mg/kg (n = 369)

Entrance criteria• Plaque psoriasis ≥ 6 months• BSA ≥ 10%• PASI ≥ 12• Candidate for, or history of, systemic therapy

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Study 2390: Primary Efficacy Variable, the Psoriasis Area and Severity Index

• Physician-performed assessment • Extent of psoriasis and the degree of plaque

erythema, thickness, and scaling• Index ranges from 0 to 72, higher scores worse

Primary analysis based on rate of PASI-75 response

• PASI-75 responder: A patient with a PASI percent improvement from baseline of ≥ 75%

• PASI-75 nonresponder: A patient with a PASI percent improvement from baseline of < 75%

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Study 2390: Secondary Efficacy Endpoints

• Physician-derived assessments– PASI-50– PASI % improvement from baseline– Physician’s Global Assessments as given in

briefing book• Patient-reported assessments

– DLQI: Dermatology Life Quality Index• 10 items, each rated 0=Not at All, 1=A Little,

2=A Lot, 3=Very Much, or Not Relevant – Others as given in briefing book

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Placebo(n = 187)

Raptiva 1 mg/kg(n = 369)

Age, mean (range), yr 45 (20-75) 45 (18-75)

≥ 65 yrs 7% 6%

Sex Male 71% 68%Female 29% 32%

Race White 89% 90%

Nonwhite 11% 10%

Study 2390: Demographics

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Placebo(n = 187)

Raptiva 1 mg/kg(n = 369)

Duration of psoriasis, mean sd, yr 19 11 19 12

History of systemic therapy 59% 60%

Baseline PASI, mean sd 19 7 19 8

Baseline BSA, mean sd, % 27 16 28 17

Study 2390: Baseline Characteristics

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4

27

0

5

10

15

20

25

30

35Placebo Raptiva 1 mg/kg

% o

f pat

ient

s w

ith P

AS

I-75

Study 2390

*

n = 187 n = 369

Significant Effect on the Primary Endpoint:Rate of PASI-75 at Week 12

* Fisher’s exact test, Raptiva vs. placebo, ITT analysis

* p < 0.001

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PASI = 45 PASI = 295% improvement

Baseline Week 12

A PASI-75 Response

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A PASI-50 Response

PASI = 43 PASI = 1467% improvement

Baseline Week 12

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14

59

01020304050607080

Placebo Raptiva 1 mg/kg

% o

f pat

ient

s w

ith P

AS

I-50

*

n = 187 n = 369

Study 2390

Significant Effect on Rate of PASI-50 at Week 12

* Fisher’s exact test, Raptiva vs. placebo, ITT analysis

* p < 0.001

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1.6

5.6

0

1

2

3

4

5

6

7Placebo Raptiva 1 mg/kg

Mea

n D

LQI I

mpr

ovem

ent

*

Study 2390

* Wilcoxon rank-sum test, Raptiva vs. placebo

Significant Effects on Dermatology Life Quality Index at Week 12

Note: Mean baseline DLQI = 12 in each treatment group

* p < 0.001

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0

20

40

60

80Baseline Week 12Raptiva 1 mg/kg

Dermatology Life Quality Index Item

% o

f pat

ient

sPercent of Patients with DLQI Problems Rated ‘A Lot’ or ‘Very Much’Study 2390

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Study

PASI-75 Rates at Week 12 in Placebo-Controlled Studies: Raptiva Superior to Placebo in Each Study

4 3 2 5

2724

39

22

0

10

20

30

40

50Placebo Raptiva 1 mg/kg

% o

f pat

ient

s w

ith P

AS

I-75

*

***

* Fisher’s exact test, Raptiva vs. placebo, ITT analysis

2390 (n = 556)

2059 (n = 354)

2058 (n = 332)

2600 (n = 686)

* p < 0.001

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Study

PASI-75 Rates at Week 12 in Placebo-Controlled Studies: Raptiva Superior to Placebo in Each Study

4 3 2 5

2724

39

2227 28

0

10

20

30

40

50Placebo Raptiva 1 mg/kg Raptiva 2 mg/kg

% o

f pat

ient

s w

ith P

AS

I-75

*

* ** * *

2390 (n = 556)

2059 (n = 597)

2058 (n = 498)

2600 (n = 686)

* Fisher’s exact test, Raptiva vs. placebo, ITT analysis

* p < 0.001

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PASI-50 Rates at Week 12Raptiva Superior to Placebo in Each Study

14 14 15 16

5952

615251

57

0

20

40

60

80Placebo Raptiva 1 mg/kg Raptiva 2 mg/kg

% o

f pat

ient

s w

ith P

AS

I-50

** ** **

2390 (n = 556)

2059 (n = 597)

2058 (n = 498)

2600 (n = 686)

* Fisher’s exact test, Raptiva vs. placebo, ITT analysis

Study

* p < 0.001

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Conclusions About Raptiva Efficacy

• Significant efficacy at Week 12

• Onset of efficacy by Week 4

• Psoriasis returns when Raptiva stopped

• Significant efficacy on retreatment

• Efficacy improves with continuous treatment past 12 weeks

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Study 2390

* Hierarchical t-test, Raptiva vs. placebo

Mean PASI % Improvement Over Time

Study Week

0

10

20

30

40

50

60

0 2 4 6 8 10 12

Placebo Raptiva 1 mg/kg

*

**

* *

Mea

n ±

SE %

impr

ovem

ent

from

bas

elin

e

* p < 0.001

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* Hierarchical rank-sum test, Raptiva vs. placebo

Mean DLQI Improvement Over TimeStudy 2390

Study Week

0

2

4

6

8

0 4 8 12

Placebo Raptiva 1 mg/kg

*

* *

Mea

n ±

SE D

LQI i

mpr

ovem

ent

* p < 0.001

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Conclusions About Raptiva Efficacy

• Significant efficacy at Week 12

• Onset of efficacy by Week 4

• Psoriasis returns when Raptiva stopped

• Significant efficacy on retreatment

• Efficacy improves with continuous treatment past 12 weeks

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RandomizationDay 0

Study 2058: First 12 Weeks of Treatment, Observation, and Retreatment

Week 12 (Day 84)

ScreenPlacebo

Raptiva 1 or 2 mg/kg

ObservationPeriod

PASI 75

Placebo

Raptiva

Retreatment for 12 weeks

Relapse *

* Relapse was the loss of at least half of a patient’s PASI improvement at Week 12 of the treatment period.

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Time to Relapse for Subjects with PASI-75 Response after 12 Weeks of Treatment

0.0

0.2

0.4

0.6

0.8

1.0

0 84 12 242016Weeks Since Last Dose

Pro

porti

on R

elap

sed

Study 2058, Observation Period (n = 107)

Relapse is the loss of 50% of the PASI improvement at Week 12

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Raptiva is Effective upon Retreatment PASI Response Rates after 12 weeks of Retreatment in Relapsing Patients with a Previous PASI-75 Response

0

1931

67

0

20

40

60

80

100

PASI-75 Response PASI-50 Response

Placebo (n = 27) Raptiva (n = 55)

% o

f Pat

ient

s

*

** p < 0.001

* Fisher’s exact test, Raptiva vs. placebo, ITT analysis

Study 2058, Retreatment Period

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Conclusions About Raptiva Efficacy

• Significant efficacy at Week 12

• Onset of efficacy by Week 4

• Psoriasis returns when Raptiva stopped

• Significant efficacy on retreatment

• Efficacy improves with continuous treatment past 12 weeks

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RandomizationDay 0

Screen

Week 12(Day 84)

Placebo(n = 187)

Raptiva 1 mg/kg (n = 369)

Studies 2390 and 2391

Raptiva 1 mg/kg

Raptiva 1 mg/kg

Week 24(Day 168)

Study 2390 Study 2391

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% o

f Pat

ient

s

0

20

40

60

80

100

Week 12 Week 24

≥75 50-75

59%

44%

66%

27%

Week 12 and 24 rates each based on 369 patients randomized to Raptiva on Day 0 of Study 2390

PASI Response:

Studies 2390 and 2391

Continued Treatment with Raptiva 1 mg/kg:PASI Response Rates at Weeks 12 and 24

*

*

* McNemar’s test, Week 24 vs. Week 12

* p ≤ 0.002

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Efficacy of Raptiva - Summary

• Significant efficacy of Raptiva at 1 mg/kg for 12 weeks– PASI-75 response rate of 27% – PASI-50 response rate of 59% – Quality of life and patient-reported symptoms improved

• Efficacy demonstrated at 4 weeks

• Median time to relapse approximately 2 months

• Raptiva is effective on retreatment

• Improved efficacy with continuous treatment past 12 weeks– PASI-75 response rate of 44% at Week 24