13766.01

Display 4-1: Display 4-1: Therapies that Disqualified Patients as RespondersTherapies that Disqualified Patients as Responders

Phototherapy (PUVA, UVB)Phototherapy (PUVA, UVB)

Systemic retinoidsSystemic retinoids

High potency topical corticosteroidsHigh potency topical corticosteroids

Systemic corticosteroidsSystemic corticosteroids

FumaratesFumarates

Methotrexate, cyclosporine, azathioprine, or other systemic Methotrexate, cyclosporine, azathioprine, or other systemic immunosuppressant and immunomodulatory agentsimmunosuppressant and immunomodulatory agents

Another investigational drug or approved therapy for investigational useAnother investigational drug or approved therapy for investigational use

Inappropriate use of moderate potency topical corticosteroids, Inappropriate use of moderate potency topical corticosteroids, keratolytics, coal tar, or vitamin D analogskeratolytics, coal tar, or vitamin D analogs

2

Display 4-14: Proportions of Patients Responding Display 4-14: Proportions of Patients Responding in Courses 1 and 2 of Study 711in Courses 1 and 2 of Study 711

Study 711 Course 1 (a) Study 711 Course 2

Placebo IV

(Cohort 3)

7.5 mgalefacept IV

(Cohorts 1 and 2)

Placebo IV

(Cohort 2)

7.5 mgalefacept IV(Cohort 1)

Number of patients dosed 186 (100) 367 (100) 142 (100) 154 (100)

PASI 75

- 2 weeks post-treatment

- at any time (overall response)

7 ( 4)

15 ( 8)

53 ( 14)p < 0.001

102 ( 28) p < 0.001

10 ( 7)

27 ( 19)

36 ( 23)p < 0.001

57 ( 37) p < 0.001

PGA AC/C

- 2 weeks post-treatment

- at any time (overall response)

7 ( 4)

11 ( 6)

42 ( 11)p = 0.004

83 ( 23) p < 0.001

8 ( 6)

25 ( 18)

31 ( 20)p < 0.001

46 ( 30) p = 0.011

PASI 50

- 2 weeks post-treatment

- at any time (overall response)

18 ( 10)

44 ( 24)

139 ( 38)p < 0.001

204 ( 56) p < 0.001

35 ( 25)

70 ( 49)

74 ( 48)p < 0.001

99 ( 64) p = 0.002

3779.01

NOTE: Numbers in parentheses are percentages.P-values for comparisons with placebo.(a) From Display 4-5.

Placebo IV 7.5 mg Placebo IV 7.5 mgAlefacept IV Alefacept IV

(Cohort 3) (Cohorts 1 and 2) (Cohort 2) (Cohort 1)

Study 711 Course 1 (a) Study 711 Course 2

3

Display 4-15: Display 4-15: Study 711 – Proportion of Patients Study 711 – Proportion of Patients Achieving PASI 75 by CourseAchieving PASI 75 by Course

3780.01

Placebo IV (Cohort 3)

Alefacept 7.5 mg IV (Cohorts 1 and 2)

0

10

0 2 4 6 8 10 14 16 18 20 24

Pro

po

rtio

n r

esp

on

din

g (

%)

Dosing Period

20

30

0

10

20

30

0 2 4 6 8 10 14 16 18 20 24

Pro

po

rtio

n r

esp

on

din

g (

%)

Alefacept/placebo (Cohort 2)

Alefacept/alefacept (Cohort 1)

Dosing Period

Study Week Study Week

Course 1 Course 2

4

Alefacept 7.5 mg IV Weekly x12 Follow-Up 16 Weeks

600

550

500

450

400

350

300

250

Mea

n C

ou

nt

(cel

ls/µ

L)

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Weeks

T X174TetanusToxoid

CD4+ Naive

CD4+ Memory

T

Day 43Day 1 Day 99 Day 106 Day 141

Immunizations Coincided With MaximalImmunizations Coincided With MaximalCD4+ Memory T-Cell ReductionCD4+ Memory T-Cell Reduction

3444.01

5

0102030405060708090

100

% o

f P

atie

nts

Control

Alefacept

†

Immunization2nd 3rd 4th

*2 weeks after each immunization.†P=0.7299 for overall treatment difference (logistic regression model).

Percentage of Patients WithPercentage of Patients WithAnti-Anti-X174 IgG X174 IgG 30% of Total Anti-30% of Total Anti-X174 Response*X174 Response*

3446.01

6

Squamous Cell Carcinoma of Skin Squamous Cell Carcinoma of Skin by Course of Alefaceptby Course of Alefacept

* Patient also diagnosed with BCC3846.01

Baseline History

Patient ID Course 1 Course 2 Course 3 Course 4 Course 5 Total SCC SCC PUVA UVB MTX CyA

106-008111-101114-204*111-104111-114139-209128-004145-209Total: 8

212101119

030000--3

1-001---2

2--00---2

1-------1

64211111

17

X

X

XX

XX

X

X

XXX

XXXXXX

X

X

BCC

7

Incidence of Injection Site ReactionsIncidence of Injection Site Reactions

3853.01

Phase 3 IM Study

No. of Patients Dosed

No. with an injectionsite reaction

No. of injections associated with an injection site reaction

12345

Placebo 10 mg 15 mg

168 (100)

14 (8)

10 (6)4 (2)00 0

173 (100)

22 (13)

14 (8)6 (3)2 (1)00

166 (100)

31 (19)

20 (12)8 (5)003 (2)

8

Injection Site Reactions by SeverityInjection Site Reactions by Severity

3854.01

No. with an injectionsite reaction

Maximum severityMildModerateSevere

Placebo 10 mg 15 mg

14 (100)

13 (93)1 (7)0

22 (100)

18 (82)4 (18)0

31 (100)

26 (84)5 (16)0

Phase 3 IM Study

93855.01

Malignancy Rates: Invasive Squamous Cell CancersMalignancy Rates: Invasive Squamous Cell Cancers

Number of tumors per 1000 person years (p-y) exposure

Placebo0/178 p-y

Alefacept(Placebo-ControlledStudies)5/401 p-y

Alefacept(Overall)14/1056 p-y

Expected Rates

210

0

294

12.5

227

13.3

20 - 76

10 - 38 ***

* R. Stern (PUVA registry data, adjusted rates)**Estimated current rates, R. Stern (Personal communication)

10

Phase 3 IM Study

PASI 75 at 2 Weeks After Last DosePASI 75 at 2 Weeks After Last Doseby Quartiles of Weightby Quartiles of Weight

3889.01

2

97

3

22 2119

22

0

5

10

15

20

25

40-75 76-87 88-102 103-206

Weight (kg)

Pro

po

rtio

n R

esp

on

din

g (

%)

Placebo

15 mg IM

Quartiles of weight are calculated using baseline weights

n=46 n=55 n=47n=44 n=37n=45 n=27n=33

11

Baseline Characteristics of Patients Who Baseline Characteristics of Patients Who Developed SCC or BCCDeveloped SCC or BCC

No. of Patients

Male

Age (years)Median

Caucasian

History of PriorSCC or BCC

SCCBCC

Prior Treatment of:PUVAUVBMethotrexateCyclosporine

Alefacept TreatedPatients Who

Developed SCC

8 (100%)

50%

53

100%

38%

25% 13%

63% 50% 75% 0%

BaselineCharacteristics

Alefacept TreatedPatients Who

Developed BCC

6 (100%)

83%

62

67%

33%

17% 17%

50% 50% 50% 0%

Alefacept Treated Patients

1357 (100%)

69%

45

89%

3%

1% 2%

38% 45% 30% 11%

4093.01

12

Mean EAUC CD4+ Memory by Weight Quartile

Phase 3 IV Study

593 716540 657

4825 4803

4188

5093

40-75 75-87 87-12 102-206

Weight (kg)

Mea

n E

AU

C

placebo 7.5 mg IV

4210.01

13

Alefacept 7.5 mg IVAlefacept 15 mg IM

2 Weeks After Last Dose Overall Response Rate

* P<0.001† P=0.004‡ P=0.006

Efficacy Summary: IV vs IMEfficacy Summary: IV vs IM

Phase 3 Studies

Alefacept 7.5 mg IVAlefacept 15 mg IM

PASI 75 PGA AC/C PASI 50

Pro

po

rtio

n R

es

po

nd

ing

(%

)

14%

21%

11%14%

38%42%

*

*

**

†

‡

0

10

20

30

40

50

60

70

PASI 75 PGA AC/C PASI 50

Pro

po

rtio

n R

es

po

nd

ing

(%

)

28%33%

23% 24%

56%57%

**

* *

**

0

10

20

30

40

50

60

70

4218.01

14

DTH Response Converting from Positive to NegativeDTH Response Converting from Positive to Negative

Antigen Placebo 0.025 mg/kg 0.075 mg/kg 0.15 mg/kg

Tetanus 15/32 (47) 13/26 (50) 18/28 (64) 9/14 (64)Diphtheria 4/10 (40) 3/6 (50) 8/11 (73) 8/11 (73)Streptococcus 5/7 (71) 3/3 (100) 3/4 (75) 5/5 (100)

Tuberculin 7/9 (78) 7/7 (100) 12/14 (86) 9/11 (82)Candida 3/5 (60) 6/8 (75) 7/8 (88) 3/4 (75)

Trycophyton 3/3 (100) 5/7 (71) 4/6 (67) 2/2 (100)Proteus 4/11 (36) 8/15 (53) 6/13 (46) 9/13 (69)

Study 708

4269.02

Less than 30% of patients were reactive at baseline

15

DTH Response Converting from Positive to NegativeDTH Response Converting from Positive to Negative

Antigen Placebo 0.025 mg/kg 0.075 mg/kg 0.15 mg/kg

Tetanus 10/32 (31) 9/26 (35) 13/28 (46) 4/14 (29)Diphtheria 1/10 (10) 2/6 (33) 5/11 (45) 5/11 (45)Streptococcus 4/7 (57) 2/3 (67) 2/4 (50) 4/5 (80)

Tuberculin 5/9 (56) 3/7 (43) 9/14 (64) 7/11 (64)Candida 2/5 (40) 4/8 (50) 6/8 (75) 2/4 (50)

Trycophyton 0/3 3/7 (43) 3/6 (50) 1/2 (50)Proteus 2/11 (18) 4/15 (27) 3/13 (23) 5/13 (38)

Study 708

4270.02

Less than 30% of patients were reactive at baseline

16

Influence of Concomitant Medications on the Influence of Concomitant Medications on the Primary EndpointPrimary Endpoint

PASI 75 responders n (%)irrespective of use of disqualifying meds

PASI 75 responders n (%)without the use of phototherapy or other systemic therapies (pre-specified)

PASI 75 responders n (%)without the use of phototherapy or other systemic therapies (Table 28)

Placebo (n=186)

7.5 mg(n=367)

Placebo(n=168)

15 mg(n=166)

7 (4%) 55 (15%) 12 (7%) 37 (22%)

53 (14%) 9 (5%) 35 (21%)

53 (14%) 8 (5%) 33 (20%)

P< 0.001 P< 0.001

P< 0.001 P< 0.001

P< 0.001 P< 0.001

4370.01

7 (4%)

7 (4%)

Phase 3 Studies IV Study IM Study

17

Range of Memory and Naïve T-Cell Counts at Range of Memory and Naïve T-Cell Counts at BaselineBaseline

CD4+ Memory Cells (cells/L)

CD4+ Naïve Cells (cells/L)

CD8+ Memory Cells (cells/L)

CD8+ Naïve Cells (cells/L)

Phase 2 IV Study

Phase 3 IV Study

Phase 3 IM Study

81 to 1233 8 to 1084 3 to 575

24 to 700

159 to 3233 8 to 985 15 to 981

2 to 1000

143 to 1415 11 to 1351 9 to 707

25 to 1237

18

Course 1Course 1(n=1357)(n=1357)

Course 2Course 2(n=790*)(n=790*)

Course 3Course 3(n=422*)(n=422*)

Course 4Course 4(n=152*)(n=152*)

Course 5Course 5(n=116*)(n=116*)

Any SAE** n (%)Any SAE** n (%) 67 ( 5) 67 ( 5) 33 (4)33 (4) 15 (4)15 (4) 3 (2)3 (2) 2 (2)2 (2)

Multiple Course ExperienceMultiple Course Experience

* Number of patients in the 2nd through 5th course is estimated.

** The serious adverse events represent all events reported to Biogen through May 20, 2002

Estimated Incidence of Serious Adverse EventsEstimated Incidence of Serious Adverse Events

19

Changes in Lesional Skin: Histologic Responders Changes in Lesional Skin: Histologic Responders vs Nonrespondersvs Nonresponders

Nonresponder (n=5) Responder (n=8)

Number of T Cells in Epidermis

200

150

100

0

Lesional

NL

50

B Wk2 Wk6 Wk13

Number of T Cells in Lesion

600

400

300

0NL

100

B Wk2 Wk6 Wk13

500

200

Lesional

NL = non-lesional skin at baseline.B = baseline.

Epidermal Thickness (µm)

400

300

200

0NL

100

B Wk2 Wk6 Wk13

Lesional

20

NaNaïïveve MemoryMemory

CD4CD4 CD4CD4

Primary Primary ResponseResponse

Expansion of effector Expansion of effector CD4+ cells during active CD4+ cells during active

immune responseimmune response

TTememTTcmcm

Central Central MemoryMemory

––16%16%

Long-term Long-term memorymemory

Effector Effector MemoryMemory

– –50%50%

*at week 13; N=21*at week 13; N=21

PP=0.0007=0.0007

Effect of Alefacept on Circulating CD4+ T-Cell Effect of Alefacept on Circulating CD4+ T-Cell Subsets*Subsets*

21

Incidence of B Cell LymphomaIncidence of B Cell Lymphomain Nonhuman Primatesin Nonhuman Primates

Incidence Rate

Species Spontaneous SIV-Related PTLDa

Cynomolgus Monkey

<1% 33-40% 25-30% (CsA)

Rhesus Monkey

<1% 4-15% n.d.

Baboon <1% n.d. n.d.

a Post-transplant Lymphoproliferative Disorder FDA/CBER Biological Response Modifiers Advisory Comm (June 1999) PTLD-related lymphomas were detected within 28-134 days following initiation of immunosuppressive therapy