Agenda

1
Agenda

• Overview
• Burt Adelman MD
• Efficacy and Pharmacodynamics
• Akshay Vaishnaw MD, PhD
• Safety
• Gloria Vigliani MD
• Alefacept Risk Benefit Profile
• Mark Lebwohl MD

2
Safety Overview

• Size of database
• Adverse Events
• Serious Adverse Events
• Deaths
• Infection
• Malignancy
• Immunogenicity

3
Safety Database
4
Comparison of Placebo vs. Alefacept Experience
1200
1056 p-y
Placebo- controlled experience
1000
800
Person-years (p-y) exposure
600
401 p-y
400
178 p-y
200
0
Placebo
Alefacept
Total Alefacept
n 413
n 876
n 1357
5
Safety Overview Placebo-Controlled Studies
Placebo (n413)
Alefacept(n 876)
Event Category


Any AE
79
83
SAE
5
5
Discontinuations
1
2
Death
0
lt1
6
Safety Overview by Course
Course 1 (n1357)
Course 2 (n756)
Course 3 (n199)
Course 4 (n81)
Course 5 (n46)
Event category ()





Any AE
83
74
64
72
61
SAE
5
4
5
0
2
Discontinuations
2
lt1
1
1
0
Death
lt1
lt1
lt1
0
0
7
Adverse Events ?5 IncidencePlacebo-Controlled
Studies
Placebo (n413)
Alefacept (n876)
83
79
Percentage with an event
Event Headache Accidental Injury Pharyngitis
Infection Pruritis Rhinitis Flu
Syndrome Viral Infection Asthenia Chills Pain
Diarrhea Dizziness Arthralgia Nausea
18 13 13 11 8 10 9 7 7 1 5 5 3 6 3
17 15 15 11 11 11 9 6 6 6 6 5 5 5 5
8
Serious Adverse Events
9
Most Frequent Serious Adverse Events
Placebo-Controlled First Course Experience
Alefacept (n876)
Placebo (n413)
42 (5)
19 (5)
Any SAE N ()
2 (lt1) 4 (lt1) 3 (lt1) 3 (lt1) 2 (lt1) 2 (lt1) 2
(lt1) 2 (lt1) 2 (lt1) 2 (lt1)
6 (1) 0 0 0 0 0 1 (lt1) 0 0 1 (lt1)
Psoriasis Coronary Artery Disorder Cellulitis
Myocardial Infarction Accidental
Injury Carcinoma Chest Pain Diabetes
Mellitus Gastroenteritis Pancreatitis
Events occurring in gt1 alefacept patient
10
Most Frequent Serious Adverse Events
Multiple Course Experience
Course 1 (n1357)
Course 2 (n756)
Course 3 (n199)
Course 4 (n81)
Course 5 (n46)
Any SAE N ()
67 ( 5)
30 (4)
9 (5)
0
1 (2)
Accidental Injury Psoriasis Cellulitis Coro
nary Artery Disorder Skin Carcinoma Chest
Pain Cholelithiasis Diabetes Mellitus Myocardia
l Infarct Asthma Carcinoma Gastroenteritis Her
nia Infection Infection Bacterial Pancreatitis
Suicide Attempt
1 ( lt1) 0 0 0 0 0 0 0 1 ( lt1) 1 ( lt1) 0 0 0 1 (
lt1) 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
5 ( lt1) 5 ( lt1) 4 ( lt1) 4 ( lt1) 4 ( lt1) 3 ( lt1) 3
( lt1) 3 ( lt1) 3 ( lt1) 2 ( lt1) 2 ( lt1) 2 ( lt1) 2
( lt1) 2 ( lt1) 2 ( lt1) 2 ( lt1) 2 ( lt1)
5 ( lt1) 0 0 0 1 ( lt1) 0 4 ( lt1) 0 0 0 1 ( lt1) 1
( lt1) 0 2 ( lt1) 0 0 0
0 0 0 0 0 0 0 0 1 (2) 0 0 0 0 0 0 0 0
Events occurring in more than 1 patient included.
11
Deaths
12
Deaths
Causeof Death
Age/ gender
Underlyingfactors
Alefacept Received
Suicide
34M
Psoriasis, family history of suicide
Yes
Myocardial infarction
47M
CAD, HT, obesity, smoker
Yes
Myocardial infarction
52M
CAD, HT
No
Esophageal carcinoma
53M
Diaphragmatic hernia, Barretts esophagus
Yes
Lung carcinoma
46M
Smoker
Yes
Life-long history of seizures
43M
Yes
Seizure
13
Infections
14
Infections ?5 Incidence
Placebo-Controlled First Course Experience
Placebo n413
Alefacept n876
Percentage with an infection
43
45
Event Pharyngitis Nasopharyngitis Flu
syndrome Viral infection
10 7 5 7
10 8 7 6
15
Infections by CD4 T Cell Counts
Placebo-Controlled First Course Experience
Alefacept
Placebo
CD4?250 (n411)
CD4lt250 (n90)
CD4 ? 250 (n786)
Number with an infection n () Event n
() Pharyngitis Nasopharyngitis Flu
syndrome Viral infection Infection
fungal Sinusitis Urinary tract
infection Accidental injury Bronchitis Conjunct
ivitis Fungal dermatitis Skin
infection Periodontal abscess
174 (42) 40 (10) 28 (7) 21 (5) 27
(7) 5 (1) 15 (4) 5 (1) 1
(lt1) 9 (2) 5 (1) 0 5 (1)
4 (lt1)
22 (24) 8 (9) 5 (6) 4 (4) 3 (3) 2 (2) 2
(2) 2 (2) 1 (1) 1 (1) 1 (1) 1 (1) 1 (1) 1
(1)
359 (46) 80 (10) 57 (7) 58 (7) 47 (6)
10 (1) 26 (3) 6 (lt1) 1 (lt1) 18 (2)
10 (1) 6 (lt1) 6 (lt1) 14 (2)
Only infections which occurred after the onset
of CD4 T cell count lt 250 cells/uL are included
16
Serious Infections
Placebo-Controlled First Course Experience
17
Serious Skin Infections - All Studies
Description
Skin Infections Facial cellultis 12 50
M Obesity, DM, recurrent 343 Cont. Rx otitis
externa Pre-septal cellulitis 10 44 F Sty
manipulation 600 (placebo) Leg cellulitis 1 52
M DM, CAD, COPD, edema, 312 Withdrew erythema
around plaque Finger abscess 8 43 M Olecranon
bursitis 720 Cont. Rx Peri-orbital
infection 23 50 M Herpes simplex
superinfection 868 N.A. Burn infection 5 55
M Obesity, 18x24 cm burn, DM 1014 Cont. Rx Toxic
shock 6 56 F Cellulitis, renal and
respiratory 673 Withdrew failure - full
recovery Post-surgical Wound Infections Post-op
infection 17 58 M DM, rotator cuff
repair 616 Cont. Rx Post-op infection 11 26
M Open tibial fracture repair 289 Cont.
Rx Post-op infection 12 32 M Post-appendiceal
rupture 491 Cont. Rx
18
Infection Conclusions

• Similar incidence alefacept vs. placebo
• Low CD4 T cell counts not a risk factor
• No increase by course
• Uncomplicated clinical course and outcome
• No opportunistic infections
• No TB
• No deaths due to infections

19
Functional Integrity of Immune System

• Preservation of naïve T cells
• Partial effect against memory T cells,
  preservation of antibody responses
• Redundancy of immune system

20
Malignancy
21
Incidence of Malignancies
Placebo-Controlled First Course Experience
Placebo (n413)
Alefacept (n876)
Number with a malignancy N () Event N
() Non-melanoma skin cancer Carcinoma Prosta
tic carcinoma Skin melanoma
2 (lt1) 1 (lt1) 0 1 (lt1) 0
10 (1) 6 (lt1) 2 (lt1) 1 (lt1) 1 (lt1)
One case each of testicular and renal cell cancer
22
Incidence of Malignancies
Multiple Course Experience
Course 5 n46
Course 1 n1357
Course 2 n756
Course 3 n199
Course 4 n81
Number With a Malignancy n () Event n () Skin
Carcinoma Carcinoma Skin Melanoma Prostatic
Carcinoma Carcinoma of Lung Gastrointestinal
Carcinoma GI Neoplasia
1 ( 1) 1 ( 1) 0 0 0 0 0
0
1 ( 2) 1 ( 2) 0 0 0 0 0
0
4 (lt1) 2 (lt1) 1 (lt1) 0 0 0 1
(lt1) 0
4 ( 2) 2 ( 1) 0 0 0 1
(lt1) 1 (lt1) 1 (lt1)
16 ( 1) 11 (lt1) 2 (lt1) 2 (lt1) 1
(lt1) 0 0 0
One case each of adenocarcinoma of colon and
esophagus
Benign colonic polyp
23
Single case of B cell lymphoma

• 68 yr old female
• Long-standing psoriasis, previous MTX and PUVA
• During third course of alefacept (total 20
  injections)
• Isolated 2 cm node
• Follicular B cell Non-Hodgkins lymphoma
• No other lymphoid/bone marrow involvement
• Features consistent with sporadic B cell NHL and
  not with immunotherapy-related lesion

24
Overall Malignancy Rates
Incidence Rate Per 1000 Person Years (p-y)
Exposure
32.1
13
Alefacept (Overall) 22/1056 p-y
20.8
Expected Rate (Psoriasis population)
36
23
29
Margolis (2001)
25
Malignancy Conclusions

• No evidence of increase in malignancy
• Majority skin cancers
• Observed rates for skin and total malignancies
  within expected rates

26
Percentage Testing Positivefor Anti-Alefacept
Antibodies
Course of Alefacept
First
Second
Third
Fourth
Fifth
Number ofpatients dosed
1357
756
199
81
46
Baseline
lt1
lt1
2
0
0
During course
2
2
lt1
0
0
27
Safety Conclusions

• Alefacept has a favorable safety profile
• Similar incidence of adverse events alefacept vs.
  placebo
• No convincing evidence of increased risk of
  infection or malignancy
• No correlation between rates of malignancy,
  infections and CD4 T cell counts
• Low immunogenicity

28
Plans for Extended Long-Term Safety Evaluation

• Approximately 800 patients in ongoing
  safety-extension studies
• Alefacept safety registry
• powered to specifically evaluate increase in risk
  of adverse events of interest

29
Alefacept Conclusions

• Selective and novel approach targeting memory T
  cells
• T-cell effects correlate with efficacy but not
  with adverse safety outcomes
• Clinically meaningful benefit in the majority of
  patients
• Significant duration of remission
• Improvements in disease activity associated with
  QOL benefit
• Well-tolerated
• First systemic disease-remittive agent

30
Agenda

• Overview
• Burt Adelman MD
• Efficacy and Pharmacodynamics
• Akshay Vaishnaw MD, PhD
• Safety
• Gloria Vigliani MD
• Alefacept Risk Benefit Profile
• Mark Lebwohl MD