Display 4-1: Therapies that Disqualified Patients as Responders

1
Display 4-1 Therapies that Disqualified
Patients as Responders

• Phototherapy (PUVA, UVB)
• Systemic retinoids
• High potency topical corticosteroids
• Systemic corticosteroids
• Fumarates
• Methotrexate, cyclosporine, azathioprine, or
  other systemic immunosuppressant and
  immunomodulatory agents
• Another investigational drug or approved therapy
  for investigational use
• Inappropriate use of moderate potency topical
  corticosteroids, keratolytics, coal tar, or
  vitamin D analogs

3766.01
2
Display 4-14 Proportions of Patients Responding
in Courses 1 and 2 of Study 711
Study 711 Course 1 (a) Study 711 Course 2
Placebo IV 7.5 mg Placebo IV 7.5 mg Alefacept
IV Alefacept IV (Cohort 3) (Cohorts 1 and
2) (Cohort 2) (Cohort 1)
NOTE Numbers in parentheses are
percentages. P-values for comparisons with
placebo. (a) From Display 4-5.
3779.01
3
Display 4-15 Study 711 Proportion of Patients
Achieving PASI 75 by Course
Course 1
Course 2
30
30
20
20
Proportion responding ()
Proportion responding ()
10
10
0
0
Dosing Period
Dosing Period
0
2
4
6
8
10
14
16
18
20
24
0
2
4
6
8
10
14
16
18
20
24
Study Week
Study Week
Placebo IV (Cohort 3)
Alefacept/placebo (Cohort 2)
Alefacept 7.5 mg IV (Cohorts 1 and 2)
Alefacept/alefacept (Cohort 1)
3780.01
4
Immunizations Coincided With MaximalCD4 Memory
T-Cell Reduction
600
CD4 Memory
550
CD4 Naive
500
450
Mean Count (cells/µL)
400
350
300
250
TetanusToxoid
Alefacept 7.5 mg IV Weekly x12
Follow-Up 16 Weeks
?
?X174
T
?
?
?
?
T
Day 43
Day 1
Day 99
Day 106
Day 141
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
Weeks
3444.01
5
Percentage of Patients WithAnti-?X174 IgG ?30
of Total Anti-?X174 Response
100
90

80
70
Control
60
of Patients
50
Alefacept
40
30
20
10
0
2nd
3rd
4th
Immunization
2 weeks after each immunization.P0.7299 for
overall treatment difference (logistic regression
model).
3446.01
6
Squamous Cell Carcinoma of Skin by Course of
Alefacept
Baseline History
Patient ID
Course 1
Course 2
Course 3
Course 4
Course 5
Total SCC
SCC
PUVA
UVB
MTX
CyA
BCC
106-008 111-101 114-204 111-104 111-114 139-209 1
28-004 145-209 Total 8
2 1 2 1 0 1 1 1 9
0 3 0 0 0 0 - - 3
1 - 0 0 1 - - - 2
2 - - 0 0 - - - 2
1 - - - - - - - 1
6 4 2 1 1 1 1 1 17
X X
X X X X X
X X X X
X X X X X X
X
X
Patient also diagnosed with BCC
3846.01
7
Incidence of Injection Site Reactions
Phase 3 IM Study
Placebo
10 mg
15 mg
No. of Patients Dosed No. with an injectionsite
reaction No. of injections associated with an
injection site reaction 1 2 3 4 5
168 (100) 14 (8) 10 (6) 4 (2) 0 0 0
173 (100) 22 (13) 14 (8) 6 (3) 2 (1) 0 0
166 (100) 31 (19) 20 (12) 8 (5) 0 0 3
(2)
3853.01
8
Injection Site Reactions by Severity
Phase 3 IM Study
Placebo
10 mg
15 mg
No. with an injectionsite reaction Maximum
severity Mild Moderate Severe
14 (100) 13 (93) 1 (7) 0
22 (100) 18 (82) 4 (18) 0
31 (100) 26 (84) 5 (16) 0
3854.01
9
Malignancy Rates Invasive Squamous Cell Cancers
Number of tumors per 1000 person years (p-y)
exposure
Placebo 0/178 p-y
0
21
0
Alefacept (Placebo-Controlled Studies) 5/401 p-y
29
4
12.5
Alefacept (Overall) 14/1056 p-y
22
7
13.3
10 - 38

Expected Rates
20 - 76

R. Stern (PUVA registry data, adjusted
rates) Estimated current rates, R. Stern
(Personal communication)
3855.01
10
PASI 75 at 2 Weeks After Last Doseby Quartiles
of Weight
Phase 3 IM Study
25
22
22
21
19
20
15
Placebo
Proportion Responding ()
9
15 mg IM
10
7
3
5
2
n46
n55
n47
n44
n37
n45
n27
n33
0
40-75
76-87
88-102
103-206
Weight (kg)
Quartiles of weight are calculated using baseline
weights
3889.01
11
Baseline Characteristics of Patients Who
Developed SCC or BCC
BaselineCharacteristics
No. of Patients Male Age (years) Median Caucasian
History of PriorSCC or BCC SCC BCC Prior
Treatment of PUVA UVB Methotrexate Cyclospori
ne
4093.01
12
Mean EAUC CD4 Memory by Weight Quartile
Phase 3 IV Study
5093
4825
4803
4188
Mean EAUC
716
657
593
540
40-75
75-87
87-12
102-206
Weight (kg)
placebo
7.5 mg IV
4210.01
13
Efficacy Summary IV vs IM
Phase 3 Studies
Overall Response Rate
2 Weeks After Last Dose
Alefacept 7.5 mg IV
Alefacept 7.5 mg IV
Alefacept 15 mg IM
Alefacept 15 mg IM

70
70

57
56
60
60

42

50
50
38

40
40
33

Proportion Responding ()
Proportion Responding ()

28


24
30
30
23
21


14
14
20
20

11
10
10
0
0
PASI 75
PASI 50
PGA AC/C
PASI 75
PASI 50
PGA AC/C
Plt0.001 P0.004 P0.006
4218.01
14
DTH Response Converting from Positive to Negative
Study 708
Antigen
Placebo
0.025 mg/kg
0.075 mg/kg
0.15 mg/kg
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)
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)
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)
Less than 30 of patients were reactive at
baseline
4269.02
15
DTH Response Converting from Positive to Negative
Study 708
Antigen
Placebo
0.025 mg/kg
0.075 mg/kg
0.15 mg/kg
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)
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)
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)
Less than 30 of patients were reactive at
baseline
4270.02
16
Influence of Concomitant Medications on the
Primary Endpoint
IV Study
IM Study
Phase 3 Studies
7.5 mg (n367)
Placebo (n168)
15 mg (n166)
Placebo (n186)
7 (4)
55 (15)
12 (7)
37 (22)
PASI 75 responders n () irrespective of use of
disqualifying meds
Plt 0.001
Plt 0.001
PASI 75 responders n () without the use of
phototherapy or other systemic therapies
(pre-specified)
7 (4)
53 (14)
9 (5)
35 (21)
Plt 0.001
Plt 0.001
PASI 75 responders n () without the use of
phototherapy or other systemic therapies (Table
28)
53 (14)
8 (5)
33 (20)
7 (4)
Plt 0.001
Plt 0.001
4370.01
17
Range of Memory and Naïve T-Cell Counts at
Baseline
Phase 2 IV Study
Phase 3 IV Study
Phase 3 IM Study
CD4 Memory Cells (cells/?L) CD4 Naïve Cells
(cells/?L) CD8 Memory Cells (cells/?L) CD8
Naïve Cells (cells/?L)
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
Estimated Incidence of Serious Adverse Events
Multiple Course Experience
Course 5 (n116)
Course 1 (n1357)
Course 2 (n790)
Course 3 (n422)
Course 4 (n152)
Any SAE n ()
67 ( 5)
33 (4)
15 (4)
3 (2)
2 (2)
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
19
Changes in Lesional Skin Histologic Responders
vs Nonresponders
NL non-lesional skin at baseline. B baseline.
20
Effect of Alefacept on Circulating CD4 T-Cell
Subsets
Expansion of effector CD4 cells during active
immune response
Naïve
Memory
Primary Response
CD4
CD4
Long-term memory
Central Memory 16
Effector Memory 50
P0.0007
at week 13 N21
21
Incidence of B Cell Lymphomain Nonhuman Primates