1 3766.01 Display 4-1: Display 4-1: Therapies that Disqualified Patients as Therapies that Disqualified Patients as Responders Responders Phototherapy (PUVA, UVB) Phototherapy (PUVA, UVB) Systemic retinoids Systemic retinoids High potency topical corticosteroids High potency topical corticosteroids Systemic corticosteroids Systemic corticosteroids Fumarates Fumarates Methotrexate, cyclosporine, azathioprine, or other systemic Methotrexate, cyclosporine, azathioprine, or other systemic immunosuppressant and immunomodulatory agents immunosuppressant and immunomodulatory agents Another investigational drug or approved therapy for Another investigational drug or approved therapy for investigational use investigational use Inappropriate use of moderate potency topical corticosteroids, Inappropriate use of moderate potency topical corticosteroids, keratolytics, coal tar, or vitamin D analogs keratolytics, coal tar, or vitamin D analogs
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1 3766.01 Display 4-1: Therapies that Disqualified Patients as Responders Phototherapy (PUVA, UVB) Systemic retinoids High potency topical corticosteroids.
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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*
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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
* 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
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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*
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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