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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 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
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2 Display 4-14: Proportions of Patients Responding in Courses 1 and 2 of Study 711 3779.01 NOTE: Numbers in parentheses are percentages. P-values for comparisons with placebo. (a) From Display 4-5. Placebo IV7.5 mgPlacebo IV7.5 mgAlefacept IVAlefacept IV (Cohort 3)(Cohorts 1 and 2)(Cohort 2)(Cohort 1) Study 711 Course 1 (a)Study 711 Course 2
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3 Display 4-15: Study 711 – Proportion of Patients Achieving PASI 75 by Course 3780.01 Placebo IV (Cohort 3) Alefacept 7.5 mg IV (Cohorts 1 and 2) 0 10 02468 1416182024 Proportion responding (%) Dosing Period 20 30 0 10 20 30 02468101416182024 Proportion responding (%) Alefacept/placebo (Cohort 2) Alefacept/alefacept (Cohort 1) Dosing Period Study Week Course 1Course 2
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4 Alefacept 7.5 mg IV Weekly x12Follow-Up 16 Weeks 600 550 500 450 400 350 300 250 Mean Count (cells/µL) 0246810121416182022242628 Weeks T X174 Tetanus Toxoid CD4+ Naive CD4+ Memory T Day 43 Day 1 Day 99Day 106Day 141 Immunizations Coincided With Maximal CD4+ Memory T-Cell Reduction 3444.01
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5 0 10 20 30 40 50 60 70 80 90 100 % of Patients Control Alefacept † Immunization 2nd3rd4th *2 weeks after each immunization. † P=0.7299 for overall treatment difference (logistic regression model). Percentage of Patients With Anti- X174 IgG 30% of Total Anti- X174 Response* 3446.01
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6 Squamous Cell Carcinoma of Skin by Course of Alefacept * Patient also diagnosed with BCC 3846.01 Baseline History Patient IDCourse 1Course 2Course 3Course 4Course 5Total SCCSCCPUVAUVBMTXCyA 106-008 111-101 114-204* 111-104 111-114 139-209 128-004 145-209 Total: 8 212101119212101119 030000--3030000--3 1-001---21-001---2 2--00---22--00---2 1-------11-------1 6 4 2 1 17 XXXX XXXXXXXXXX XXXXXXXX XXXXXXXXXXXX X X BCC
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7 Incidence of Injection Site Reactions 3853.01 Phase 3 IM Study No. of Patients Dosed No. with an injection site reaction No. of injections associated with an injection site reaction 1 2 3 4 5 Placebo10 mg15 mg 168(100) 14(8) 10 (6) 4 (2) 0 173(100) 22(13) 14 (8) 6 (3) 2 (1) 0 166(100) 31(19) 20 (12) 8 (5) 0 3 (2)
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8 Injection Site Reactions by Severity 3854.01 No. with an injection site reaction Maximum severity Mild Moderate Severe Placebo10 mg15 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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9 3855.01 Malignancy Rates: Invasive Squamous Cell Cancers Number of tumors per 1000 person years (p-y) exposure Placebo 0/178 p-y Alefacept (Placebo-Controlled Studies) 5/401 p-y Alefacept (Overall) 14/1056 p-y Expected Rates 21 0 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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10 Phase 3 IM Study PASI 75 at 2 Weeks After Last Dose by Quartiles of Weight 3889.01 2 9 7 3 22 21 19 22 0 5 10 15 20 25 40-7576-8788-102103-206 Weight (kg) Proportion Responding (%) Placebo 15 mg IM Quartiles of weight are calculated using baseline weights n=46n=55 n=47n=44n=37n=45n=27n=33
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11 Baseline Characteristics of Patients Who Developed SCC or BCC No. of Patients Male Age (years) Median Caucasian History of Prior SCC or BCC SCC BCC Prior Treatment of: PUVA UVB Methotrexate Cyclosporine Alefacept Treated Patients Who Developed SCC 8 (100%) 50% 53 100% 38% 25% 13% 63% 50% 75% 0% Baseline Characteristics Alefacept Treated Patients Who Developed BCC 6 (100%) 83% 62 67% 33% 17% 50% 0% Alefacept Treated Patients 1357 (100%) 69% 45 89% 3% 1% 2% 38% 45% 30% 11% 4093.01
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12 Mean E AUC CD4+ Memory by Weight Quartile Phase 3 IV Study 593 716 540 657 4825 4803 4188 5093 40-7575-8787-12102-206 Weight (kg) Mean EAUC placebo7.5 mg IV 4210.01
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13 Alefacept 7.5 mg IV Alefacept 15 mg IM 2 Weeks After Last Dose Overall Response Rate * P<0.001 † P=0.004 ‡ P=0.006 Efficacy Summary: IV vs IM Phase 3 Studies Alefacept 7.5 mg IV Alefacept 15 mg IM PASI 75 PGA AC/C PASI 50 Proportion Responding (%) 14% 21% 11% 14% 38% 42% * * * * † ‡ 0 10 20 30 40 50 60 70 PASI 75 PGA AC/C PASI 50 Proportion Responding (%) 28% 33% 23% 24% 56% 57% * * * * * * 0 10 20 30 40 50 60 70 4218.01
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14 DTH Response Converting from Positive to Negative AntigenPlacebo0.025 mg/kg0.075 mg/kg0.15 mg/kg Tetanus15/32 (47)13/26 (50)18/28 (64)9/14 (64) Diphtheria4/10 (40)3/6 (50)8/11 (73) Streptococcus5/7 (71)3/3 (100)3/4 (75)5/5 (100) Tuberculin7/9 (78)7/7 (100)12/14 (86)9/11 (82) Candida3/5 (60)6/8 (75)7/8 (88)3/4 (75) Trycophyton3/3 (100)5/7 (71)4/6 (67)2/2 (100) Proteus4/11 (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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15 DTH Response Converting from Positive to Negative AntigenPlacebo0.025 mg/kg0.075 mg/kg0.15 mg/kg Tetanus10/32 (31)9/26 (35)13/28 (46)4/14 (29) Diphtheria1/10 (10)2/6 (33)5/11 (45) Streptococcus4/7 (57)2/3 (67)2/4 (50)4/5 (80) Tuberculin5/9 (56)3/7 (43)9/14 (64)7/11 (64) Candida2/5 (40)4/8 (50)6/8 (75)2/4 (50) Trycophyton0/33/7 (43)3/6 (50)1/2 (50) Proteus2/11 (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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16 Influence of Concomitant Medications on the Primary 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 4370.01 7 (4%) Phase 3 Studies IV StudyIM Study
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17 Range of Memory and Naïve T-Cell Counts at Baseline 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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18 Course 1 (n=1357) Course 2 (n=790*) Course 3 (n=422*) Course 4 (n=152*) Course 5 (n=116*) Any SAE** n (%) 67 ( 5) 33 (4) 15 (4) 3 (2) 2 (2) Multiple 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 Events
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19 Changes in Lesional Skin: Histologic Responders vs Nonresponders Nonresponder (n=5) Responder (n=8) Number of T Cells in Epidermis 200 150 100 0 Lesional NL 50 BWk2Wk6Wk13 Number of T Cells in Lesion 600 400 300 0 NL 100 BWk2Wk6Wk13 500 200 Lesional NL = non-lesional skin at baseline. B = baseline. Epidermal Thickness (µm) 400 300 200 0 NL 100 BWk2Wk6Wk13 Lesional
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20 Naïve Memory CD4 CD4 Primary Response Expansion of effector CD4+ cells during active immune response T em T cm Central Memory –16% Long-term memory EffectorMemory –50% –50% *at week 13; N=21 P=0.0007 Effect of Alefacept on Circulating CD4+ T-Cell Subsets*
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21 Incidence of B Cell Lymphoma in Nonhuman Primates
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