1 3766.01 display 4-1: therapies that disqualified patients as responders phototherapy (puva, uvb) ...
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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
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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
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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
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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
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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
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
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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)
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Injection Site Reactions by SeverityInjection Site Reactions by Severity
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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
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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)
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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
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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
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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%
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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
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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
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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
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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
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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
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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
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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