**AMEVIVE^®^**

(alefacept)

##### BRIEFING DOCUMENT {#briefing-document .unnumbered}

######## AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION {#available-for-public-disclosure-without-redaction .unnumbered}

Prepared by Biogen, Inc for the

**Dermatologic and Ophthalmic Drugs**

**Advisory Committee Meeting**

**23 May 2002**

**EXECUTIVE SUMMARY**

####### Proposed Indication and Dose {#proposed-indication-and-dose .unnumbered}

The data presented in this briefing document demonstrate that AMEVIVE^®^
(alefacept) administered intramuscularly (IM) or intravenously (IV) has
an acceptable benefit-risk profile to support the following proposed
indication:

Alefacept is indicated for the treatment of patients with chronic plaque
psoriasis who are candidates for phototherapy or systemic therapy.

The intended dose and dose regimen are:

-   Alefacept administered as a once-weekly IM injection of 15 mg or as
    a once-weekly IV bolus dose of 7.5 mg for 12 weeks.

-   Retreatment with alefacept may be initiated as needed provided that
    total lymphocyte and CD4+ T cell counts are within the normal range
    and a minimum of 12 weeks has passed between courses of treatment.

####### Major Findings {#major-findings .unnumbered}

-   In two pivotal studies, significantly more patients treated with a
    fixed dose of alefacept IM or IV weekly for 12 weeks achieved
    clinical response than those who received placebo, as measured by
    multiple outcome measures of efficacy, including

```{=html}
<!-- -->
```
-   a 75% or greater improvement in the Psoriasis Area and Severity
    Index (PASI 75),

-   a 50% or greater improvement in the Psoriasis Area and Severity
    Index (PASI 50),

-   a Physician's Global Assessment of "almost clear" or "clear" (PGA
    AC/C), and

-   quality of life as measured by the Dermatology Life Quality Index
    (DLQI).

```{=html}
<!-- -->
```
-   The clinical response following treatment with alefacept is durable.
    Repeat administration of alefacept provides cumulative efficacy such
    that some patients who did not demonstrate clinical response after
    one course respond to treatment with a second course.

-   Alefacept targets the reduction of CD4+ and CD8+ memory T cells.
    These memory cells play a critical role in the pathogenesis of
    chronic plaque psoriasis.

-   The clinical response seen with alefacept treatment is related to
    its pharmacodynamic effect on lymphocytes. The maximum reduction in
    T cells and their subsets typically occurs within 6 weeks of
    initiation of treatment with alefacept, at which time the rate of
    reduction decreases and T cell counts stabilize. Recovery of T cells
    occurs after withdrawal of treatment. A second course of alefacept
    showed no cumulative reduction in T cells.

-   Treatment with alefacept is well-tolerated. Over 1350 patients have
    received a course of alefacept in clinical trials. The incidence of
    adverse events, including serious adverse events, was comparable in
    patients receiving alefacept or placebo. Despite the effect of
    alefacept on T cell counts, the incidence of infections, including
    serious infections, was low and comparable to that in
    placebo-treated patients. No patient experienced an opportunistic
    infection. Patients responding to alefacept therapy do not
    experience rebound of disease requiring hospitalization.

-   The safety profile over multiple courses of alefacept therapy was
    similar to that defined for the first course.

-   The combined data validate memory T cells as a novel pharmacologic
    target in the treatment of chronic plaque psoriasis.

#######  {#section .unnumbered}

####### Unmet Need {#unmet-need .unnumbered}

Patients with moderate to severe psoriasis have a chronic disease that
results in severe social and physical disabilities associated with major
deficits in quality of life including depression and suicide. Since
topical therapies are rarely adequate, patients generally require
treatment with phototherapy (e.g., PUVA and UVB) or systemic
immunosuppressant therapy (e.g., methotrexate and cyclosporine).
Patients respond to these therapies, but all of the therapies have
limitations. Treatment with phototherapy is associated with an increased
risk for skin cancers. The systemic immunomodulatory therapies are
limited by their organ system toxicities such as hepatotoxicity or renal
toxicity. Withdrawal of these drugs is often associated with flare or
rebound of disease activity. These factors determine that no single
long-term therapies exist, so patients are required to undergo
sequential or rotational treatment. Thus, new therapies for the
treatment of patients with psoriasis are needed.

#######  {#section-1 .unnumbered}

####### Scientific Rationale for Alefacept {#scientific-rationale-for-alefacept .unnumbered}

T cells, particularly the memory T cells (CD45RO+), have a central role
in the pathogenesis of psoriasis. Immunohistochemical staining of
psoriatic lesions demonstrate the predominance of activated memory T
cells in the dermis and epidermis. The ligand, CD2, is upregulated in
CD4+ and CD8+ memory T cells. Alefacept is a fully-human dimeric protein
with the extra-cellular domain of lymphocyte functional antigen 3
(LFA-3) fused to the hinge and constant regions of the human IgG~1~
heavy chain. Alefacept has two mechanisms of action. Firstly, binding of
LFA-3 to its ligand, CD2, prevents binding of antigen-presenting cells
(APC) and activation of T cells. Secondly, the Fc domain of alefacept
binds to a receptor on natural killer (NK) cells and macrophages. The
release of pro-apoptotic mediators by these cells results in targeted
cell apoptosis of CD2-bearing cells, especially memory T cells.

#######  {#section-2 .unnumbered}

####### Summary of Efficacy {#summary-of-efficacy .unnumbered}

The efficacy of alefacept has been demonstrated in two pivotal, Phase 3,
placebo-controlled studies in 1060 patients with chronic plaque
psoriasis.

Study 712 evaluated a single course of 10 and 15 mg alefacept IM
compared to placebo. A course comprised 12 weeks of once weekly dosing
with a minimum of 12 weeks of follow-up. Of the 507 patients enrolled,
168, 173, and 166 patients received placebo, 10 mg alefacept IM, and 15
mg alefacept IM, respectively.

Study 711 evaluated the efficacy of a single and repeat course of 7.5 mg
alefacept IV in 553 patients randomized to, and dosed in, three
treatment cohorts:

-   two courses of alefacept (183 patients),

-   one course of alefacept followed by one course of placebo (184
    patients),

-   one course of placebo followed by one course of alefacept (186
    patients).

Compared to patients who received placebo, a greater proportion of
patients treated with either 7.5 mg IV, 10 mg IM, or 15 mg IM alefacept
experienced a clinical response as measured by PASI 75 two weeks after
completion of treatment, the primary endpoint of each study. The
differences between 7.5 mg IV and placebo IV, and between 15 mg IM and
placebo IM were statistically significant (p \< 0.001 in each case).

Support for clinical benefit is provided by other pre-specified
assessments of clinical response at 2 weeks after treatment: a PGA AC/C
and PASI 50 (Display 1). Both these analyses demonstrated significant
benefit with either 7.5 mg IV or 15 mg IM alefacept treatment compared
to placebo.

![](media/image5.wmf)Display 1 Response rates at 2 weeks after dosing in
the first course of treatment

Further support for clinical benefit is provided by pre-specified
assessments of clinical response at any time during a course of therapy
(analogous to an overall response rate). These assessments include PASI
75, PASI 50, and PGA AC/C. All of these analyses demonstrated
significant benefit with either 7.5 mg IV or 15 mg IM alefacept
treatment compared to placebo (Display 2).

####### ![](media/image5.wmf)Display 2 Overall response rates in the first course of treatment {#display-2-overall-response-rates-in-the-first-course-of-treatment .unnumbered}

In addition to the measurements of cutaneous responses, assessment of
the patient's quality of life using DLQI demonstrated significant
improvement in the patients' quality of life after treatment with
alefacept. The improvement in quality of life as measured by DLQI
correlates with clinical response as measured by PASI 75, PASI 50, and
PGA AC/C.

Clinical response to treatment with alefacept is durable. Indeed, the
median duration of response, defined as maintenance of at least a 50%
reduction in baseline PASI in those patients who achieved PASI 75, was
long: 216 days (more than 7 months). This result is in marked contrast
to the clinical experience with cyclosporine or methotrexate where
cessation of treatment is associated with disease flare or disease
rebound.

Treatment with two courses of alefacept provides cumulative efficacy:
patients who received a second course of alefacept continued to
demonstrate clinical response, and some patients who did not achieve
PASI 75 with a single course did so with a second course of alefacept.

The clinical response seen with alefacept correlated with its targeted
reduction of CD4+ and CD8+ memory T cells. The maximum reduction of T
cells typically occurred after approximately 6 weeks of treatment and
corresponded to detection of clinical response. A second course of
alefacept showed no cumulative reduction in T cells.

**Summary of Safety**

The consolidated safety database consists of 1357 patients with
psoriasis who have received a course of alefacept. Safety extension
studies are ongoing. Up to 46 patients have received 5 courses of
treatment. Review of the safety database indicates that treatment with
alefacept is well tolerated. The overall incidence of adverse events
reported by alefacept- and placebo-treated patients was comparable.

The safety profiles of 7.5 mg alefacept IV and 15 mg alefacept IM were
similar although patients who received 15 mg alefacept IM reported more
pruritus, infections, asthenia, and injection site events than those who
received 7.5 mg alefacept IV, while patients administered 7.5 mg
alefacept IV experienced more rhinitis, chills, and accidental injuries
than those who received 15 mg alefacept IM.

The rate of serious adverse events was comparable between alefacept- and
placebo-treated patients (5%). No serious event was seen in 1% or more
of alefacept-treated patients and the incidence of serious events did
not increase with increased exposure to alefacept following multiple
courses.

Despite the reduction in lymphocytes with alefacept treatment, a similar
incidence of infections was observed between alefacept- and
placebo-treated patients (45% *vs* 43%). The most frequently occurring
infections in both treatment groups involved primarily the upper
respiratory system, e.g., nasopharyngitis, pharyngitis, flu syndrome. In
addition, the number of patients diagnosed with serious infections was
low (8/876 (\<1%) *vs* 2/413 (\<1%), alefacept *vs* placebo,
respectively) and the incidence did not increase with additional
courses. Some patients treated with alefacept experienced CD4+ T cell
counts \<250 cells/μL, but there was no evidence that these patients
were at greater risk for infection. No patient was diagnosed with an
opportunistic infection. There was no impact of alefacept treatment on
antibody responses following immunization.

The rate of malignancies in the safety database was low in both
alefacept- and placebo-treated patients (10/876 (1%) *vs* 2/413 (\<1%),
alefacept *vs* placebo, respectively). The incidence of malignancies did
not increase with repeat courses of alefacept. The incidence rate of
malignancies was 20.8 per 1000 person-years and is consistent with that
reported in the literature (29 per 1000 patient-years). In the first
course of placebo-controlled studies, the incidence of squamous cell
carcinoma of the skin was slightly higher in alefacept-treated patients
compared to placebo (4/876 (\<1%) *vs* 0/413 (0%), respectively).
However, the observed rate per person-years exposure is consistent with
the rate expected in this population.

Many of the current immunosuppressant therapies are associated with
disease flare or rebound after cessation of treatment that sometimes
requires hospitalization. The most common serious adverse event was
hospitalization for psoriasis with an incidence rate higher in
placebo-treated patients (6/413 (1%)) than those treated with alefacept
(2/876 (\<1%)). No patient who responded to alefacept experienced
rebound of disease requiring hospitalization.

**TABLE OF CONTENTS**

**[PAGE]{.underline}**

1 INTRODUCTION 13

1.1 Clinical Background 13

1.2 Pathophysiology of Psoriasis: The Role of T cells 16

1.3 Alefacept -- Mechanism of Action 16

1.4 Intended Use of Alefacept 17

2 NONCLINICAL PHARMACOLOGY AND TOXICOLOGY 19

2.1 Nonclinical Pharmacokinetics 19

2.2 Toxicology 19

3 OVERVIEW OF CLINICAL EXPERIENCE and design of phase 3 studies 21

3.1 Phase 2, Dose-response Study and the Rationale for Fixed Dosing 23
Designs of the Phase 3 Studies and Their Extensions 23

3.2.1 Placebo-controlled Study of IM Administration of Alefacept (Study
712) and Extension Study (Study 717) 25

3.2.2 Placebo-controlled Study of Two Courses of IV Administration of
Alefacept (Study 711) and Extension Study (Study 724) 27

4 CLINICAL EFFICACY 29

4.1 Measurement of Disease Activity in Chronic Plaque Psoriasis 29

4.2 Endpoints in Phase 3 Studies 30

4.3 Statistical Methods 31

4.4 Study Populations in Phase 3 31

4.4.1 Accounting of Patients 31

4.4.2 Demographic and Baseline Disease Characteristics 32

4.5 Modification of Exposure to Alefacept 34

4.6 Clinical Response following One Course of Alefacept 34

4.6.1 Analyses of Response by PASI 75, PASI 50, and PGA AC/C 35

4.6.2 Analysis of Clinical Effect by Subgroups 39

4.6.3 Analysis of Quality of Life 41

4.7 Duration of Clinical Response Following One Course of Alefacept 42

4.8 Clinical Response with Two Courses of Alefacept 44

4.9 Preliminary Findings in Psoriatic Arthritis 48

4.10 Summary of Clinical Efficacy 50

**[PAGE]{.underline}**

5 CLINICAL PHARMACOLOGY 51

5.1 Pharmacokinetics 51

5.2 Pharmacodynamic Effects on Peripheral T Cell Counts 51

5.2.1 Pharmacodynamics following One Course of Treatment in Patients
with Chronic Plaque Psoriasis 51

5.2.2 Pharmacodynamic Effects following Additional Courses of Therapy 55

5.3 Correlations between Reductions in T Cells and Efficacy 57

5.4 Action of Alefacept on Cutaneous T Cells 59

5.5 Implications of Reductions in T Cells on Immune Function 59

5.6 Summary of Clinical Pharmacology 62

6 CLINICAL SAFETY 63

6.1 Non-serious Adverse Events 64

6.2 Deaths, Serious Adverse Events, and Adverse Events Leading to
Discontinuation of Study Drug 67

6.2.1 Deaths 67

6.2.2 Serious Adverse Events 67

6.2.3 Discontinuations from Study Drug due to Adverse Events 71

6.3 Infections 72

6.3.1 All Infections 72

6.3.2 Serious Infections 74

6.3.3 The Lack of Relationship between Infections and Low T Cell Counts
75

6.4 Malignancies 76

6.5 Immunogenicity 78

6.6 Laboratory Test Abnormalities 79

6.7 Summary of Clinical Safety 79

7 BENEFITS AND RISKS 80

7.1 Benefits 80

7.2 Risks 80

7.3 Conclusion 82

8 REFERENCES 83

APPENDIX 1: PASI, PGA, and DLQI 86

APPENDIX 2: Calculation of E~AUC~ 88

appendix 3: publication of phase 2 dose-response study (708): Ellis CN,
Krueger GG. Treatment of chronic plaque psoriasis by selective targeting
of memory effector t lymphocytes. N Engl J Med 2001; 345(4):248-255 89

**List of Displays**

**[Page]{.underline}**

Display 1-1 Limitations of major treatments for moderate to severe
psoriasis 15

Display 1-2 Alefacept: a fully human fusion protein 18

Display 1-3 Mechanism of action of alefacept 18

Display 3-1 Alefacept clinical trial program in psoriasis 22

Display 3-2 Exclusion criteria based on prior treatment in the Phase 3
studies 24

Display 3-3 Dosing algorithm used in Phase 3 Studies 25

Display 3-4 Overview of Studies 712 and 717 26

Display 3-5 Overview of Studies 711 and 724 27

Display 4-1 Therapies that disqualified patients as responders 30

Display 4-2 Accounting of patients in Studies 711 and 712 32

Display 4-3 Demographics, baseline disease characteristics, and most
common prior therapies for psoriasis in Phase 3 studies 33

Display 4-4 Placebo substitution rates in alefacept-treated patients in
Phase 3 studies 34

Display 4-5 Proportions of patients responding in the first course of
treatment in Phase 3

Studies 711 and 712 36

Display 4-6 Proportion of patients achieving PASI 75 in the first course
of treatment 37

Display 4-7 Odds ratios of responding 2 weeks post-treatment in Study
711 Course 1 and

Study 712 39

Display 4-8 PASI 75 2 weeks post-treatment − percentage responding by
age, gender,

and baseline disease characteristics 40

Display 4-9 PASI 75 2 weeks post-treatment − percentage responding by
response to prior phototherapy, prior systemic therapy, or no therapy 40

Display 4-10 Overall DLQI score in Studies 711 and 712 41

Display 4-11 Mean change in DLQI Overall Score by responder status at 2
weeks after the last dose 42

Display 4-12 Duration of a 50% reduction from baseline PASI in those who
achieved PASI 75 in Cohort 2 of Study 711 43

Display 4-13 Duration of a 50% reduction from baseline PASI in those who
achieved PGA AC/C in Cohort 2 of Study 711 44

Display 4-14 Proportions of patients responding in Courses 1 and 2 of
Study 711 45

Display 4-15 Study 711: proportion of patients achieving PASI 75 by
course 46

Display 4-16 Endpoints based on proportions of patients responding over
the entire span of Study 711 47

Display 4-17 Endpoints based on proportions of patients responding over
the entire span of Studies 712 and 717 47

**[Page]{.underline}**

Display 4-18 Overall DLQI score in the second course of Study 711 48

Display 4-19 Swollen joint count and tender joint count 49

Display 4-20 Mean C-reactive protein by time 49

Display 5-1 Study 712: mean lymphocyte count by treatment and time 52

Display 5-2 Study 712: mean percentage change from baseline in total
lymphocyte count and lymphocyte subsets at 2 weeks post-dosing 53

Display 5-3 Numbers of patients with counts \<LLN: 15 mg IM and 7.5 mg
IV 53

Display 5-4 Study 711 Cohort 2 (alefacept/placebo): percentage of
patients above 75% of baseline for total lymphocytes 54

Display 5-5 Study 711 Cohort 2 (alefacept/placebo): percentage of
patients with CD4+ T cell count \>LLN 55

Display 5-6 Study 711: mean percentage change from baseline in total
lymphocyte count and lymphocyte subsets at 2 weeks post-dosing in each
course 56

Display 5-7 Study 711: numbers of patients with counts \<LLN in one and
two courses of 7.5 mg alefacept IV 56

Display 5-8 PASI 75 response rates at 2 weeks post-dosing by E~AUC~
quartiles of memory T cells in Course 1 of Study 711 and Study 712 58

Display 5-9 Design of Study 718 60

Display 5-10 Total anti-ϕX174 antibody titers 61

Display 6-1 Number of patients in analyses of safety 63

Display 6-2 Incidence of adverse events in the first course of
placebo-controlled studies experienced by at least 5% of patients who
received alefacept 65

Display 6-3 Incidence of adverse events experienced by at least 5% of
patients by course of alefacept 65

Display 6-4 Adverse events with an incidence of 5% or more in the first
course of phase 3 studies (by route of administration) 66

Display 6-5 Incidence of serious adverse events in the first course of
placebo-controlled studies 68

Display 6-6 Incidence of serious adverse events by course of alefacept
69

Display 6-7 Incidence of adverse events leading to discontinuation of
study drug in the first course of placebo- controlled studies 71

Display 6-8 Incidence of adverse events leading to discontinuation of
study drug by course of alefacept 72

Display 6-9 Incidence of infections in the first course of
placebo-controlled studies experienced by at least 5% of patients who
received alefacept 73

Display 6-10 Incidence of infections experienced by at least 5% of
patients by course of alefacept 73

**[Page]{.underline}**

Display 6-11 Incidence of serious infections in the first course of
placebo-controlled studies 74

Display 6-12 Incidence of serious infections by course of alefacept 75

Display 6-13 Incidence of malignancies experienced in the first course
of placebo-controlled studies 76

Display 6-14 Incidence of malignancies by course of alefacept 76

Display 6-15 Observed and expected rates of non-melanoma skin cancer 77

Display 6-16 Incidence of malignancies in psoriasis and control
populations 78

Display 6-17 Incidence of antibodies to alefacept by course of alefacept
78

Display A2-1 Calculation of E~AUC~ 88

Display A2-2 Calculation of E~AUC~ when counts are greater than baseline
88

**LIST OF ABBREVIATIONS**

ACR American College of Rheumatology

ALT Alanine transaminase

APC Antigen-presenting cells

AST Aspartate transaminase

CD Clusters of differentiation

CI Confidence interval

CLA Cutaneous lymphocyte antigen

CRP C-reactive protein

DAS Disease activity score

DLQI Dermatology Life Quality Index

DTH Delayed-type hypersensitivity

IM Intramuscular

IV Intravenous

LCV Lymphocryptovirus

LFA Lymphocyte functional antigen

LLN Lower limit of normal

MHC Major histocompatibility complex

NK Natural killer

PASI Psoriasis Area and Severity Index

PASI 75 75% or greater reduction from baseline PASI

PASI 50 50% or greater reduction from baseline PASI

PGA Physician's Global Assessment

PGA AC/C Physician's Global Assessment of "almost clear" or "clear"

PUVA Psoralen plus ultraviolet A light

ST Synovial tissue

TCR T cell receptor

UVB Ultraviolet B light

# INTRODUCTION

## Clinical Background

Plaque psoriasis, henceforth referred to as psoriasis, is a chronic,
persistent inflammatory skin disease that affects 1 to 2% of the US and
European populations and accounts for 85 to 95% of all forms of
psoriasis (Nall and Farber, 1977; Griffiths and Voorhees, 1996). Women
and men are affected equally. Although the disease may present at any
age, the median age of diagnosis is 28 years. Approximately one-third of
patients have a family history of psoriasis suggesting a role for
genetic factors.

Clinically, patients present with well-demarcated, raised, scaly,
thickened erythematous plaques. The most common sites involved are the
extensor aspects of the elbows and knees, the scalp, and the lumbosacral
area. Plaques can vary in size from "guttate" lesions (about 2 to 3 mm
in diameter) to those covering the entire trunk (\>20 cm). Eighty to
ninety percent of patients have very itchy lesions, impacting quality of
life (Yosipovitch *et al*, 2000; Rapp *et al*, 1997; Krueger *et al*,
2001). The clinical course of psoriasis is variable. Although some
patients may experience spontaneous remission of variable duration, most
patients require chronic treatment.

Approximately 50% of psoriasis patients have nail involvement and about
10% have associated arthritis. Patients with psoriasis are more likely
to have hypertension, diabetes mellitus, inflammatory bowel disease, or
obesity as co-morbidities (Henseler and Christophers, 1995). Although
psoriasis is rarely a direct cause of death, its chronic, persistent
clinical course starting in young adults has associated morbidity.
Psoriasis is associated with an increased risk of substance abuse,
psychological illness, suicidal ideation, and suicide (Gupta and Gupta,
1998; Devrimci-Ozguven *et al*, 2000). Because of the sensitivity
associated with any cutaneous disease, the patient's quality of life is
compromised, and many patients will avoid social situations with
potential for comment or judgment due to their disease. The impact of
psoriasis on quality of life has been studied in both the United States
and Europe and is comparable to other serious medical conditions such as
diabetes, myocardial infarction, and depression (Rapp *et al*, 1999;
O'Neill and Kelly, 1996; Lundberg *et al*, 2000). It is important for
clinicians to be aware that there is little correlation between the
extent of skin involvement and the patient's sense of disability (Kirby
*et al*, 2001).

The first-line therapies for treatment of mild plaque psoriasis are
topical agents such as corticosteroids, coal tar, or vitamin D analogs
(Lebwohl and Ali, 2001a). Patients who use topical agents are
inconvenienced by the daily time commitment (typically 30 minutes or
more) which leads to poor compliance (van de Kerkhof *et al*, 1998). In
clinical practice, there are no strict cutoffs for defining moderate to
severe disease, but it generally involves psoriasis lesions that either
cover more than 10% of the body surface area or that are otherwise
disabling (Krueger *et al*, 2000). Patients with moderate to severe
psoriasis generally require treatment with phototherapy or systemic
therapy (Feldman, 1998; Lebwohl and Ali, 2001b). The most commonly used
agents are psoralen plus ultraviolet A light (PUVA), ultraviolet B light
(UVB), methotrexate, retinoids, and cyclosporine (Lebwohl and Ali,
2001b). Retinoids, such as acitretin, are rarely adequate as monotherapy
but have benefit in conjunction with PUVA and UVB (Lebwohl and Ali,
2001b). UVB alone is less effective than PUVA, though a new form of UVB,
narrow-band UVB, appears to be nearly as effective as PUVA (Coven *et
al*, 1997; Gordon *et al*, 1999).

Display 1-1 compares the limitations of PUVA, UVB, and the systemic
immunomodulatory therapies, methotrexate and cyclosporine. These agents
vary in efficacy, onset of activity, durability of remission, and the
potential for rebound of disease activity with discontinuation. As
different efficacy outcome measures were used to assess clinical
benefit, an accurate comparison of the effectiveness of these treatments
is difficult. PUVA has good clinical effect but its use, in terms of the
number of treatments, is limited because of the risk for cutaneous
malignancies with increasing exposure (Stern *et al*, 1997; Morison *et
al*, 1998; Stern and Lunder, 1998). Patients also find phototherapy
extremely inconvenient with its requirement for visits to the
physician's office 3 to 5 times per week. Methotrexate has associated
liver, bone marrow, and pulmonary toxicities and a potential increased
risk of lymphoproliferative disease (Kanik and Cash, 1997). Since
monitoring of liver function tests is not indicative of the development
of liver fibrosis, in addition to blood test monitoring, liver biopsies
are recommended after each 1.5 g of methotrexate (Roenigk *et al*,
1998). PUVA, acitretin, and methotrexate are known teratogens. The
clinical effectiveness of low dose cyclosporine is limited by its side
effects, predominantly hypertension and cumulative renal toxicity
(Lebwohl *et al*, 1998; Lowe *et al*, 1996; Zachariae *et al*, 1997).
The latter limits the amount of time that patients can be treated with
cyclosporine. In order to help reduce the known side effects associated
with any one of these agents, rotation between these agents has been
recommended although the long-term risk and benefit of such an approach
has not been studied (Menter *et al*, 1996). For patients who do not
respond to these standard agents alone, combinations of these therapies
may be used (Menter *et al*, 1996).

Other agents that have been used to treat severe psoriasis in patients
who did not respond to, or are not candidates for traditional therapies
include hydroxyurea, 6-thioguanine, mycophenolate mofetil, and systemic
tacrolimus, each of which is associated with potentially severe side
effects (Zackheim *et al*, 1994; Mason and Krueger, 2001; Boyd and
Neldner, 1991; Jegasothy *et al*, 1992; Lebwohl and Ali, 2001b). The
decision to use potentially toxic systemic therapy for psoriasis
requires physician judgement. Despite the use of these potent agents in
the treatment of psoriasis, few patients actually achieve long-term
clearing of their disease (Al Suwaidan and Feldman, 2000). Moreover, 30
to 40% of patients feel that current therapies are neither sufficiently
aggressive nor effective for their disease (Krueger *et al*, 2001).
There is clearly a need for new treatments that target psoriasis
effectively that are not associated with collateral organ damage. Agents
that offer significant relief from disease even after cessation of
treatment, i.e., are disease-remittive, are also highly desirable.

Display 1-1 Limitations of major treatments for moderate to severe
psoriasis

+---------+----------+----------+-------------+-----------+---------+
|         | PUVA     | #######  | #####       | Cyc       | Ac      |
|         |          | # UVB {# | ### Methotr | losporine | itretin |
|         |          | uvb .unn | exate {#met |           |         |
|         |          | umbered} | hotrexate . |           |         |
|         |          |          | unnumbered} |           |         |
+---------+----------+----------+-------------+-----------+---------+
| D       | 6 months | 5 months | 1-5 months. | R         | Rec     |
| uration |          |          | Risk of     | ecurrence | urrence |
| of      |          |          | disease     | in 2-12   | after   |
| effect  |          |          | rebound     | weeks.    | 12      |
|         |          |          | after       | Risk of   | weeks   |
|         |          |          | abrupt      | disease   |         |
|         |          |          | withdrawal  | rebound   |         |
|         |          |          |             | after     |         |
|         |          |          |             | abrupt    |         |
|         |          |          |             | w         |         |
|         |          |          |             | ithdrawal |         |
+---------+----------+----------+-------------+-----------+---------+
| Major   | Nausea   | Burns,   | Abnormal    | \>80%     | E       |
| tox     | 10-25%   | p        | liver tests | with      | levated |
| icities |          | ruritus, | 33%         | adverse   | trigly  |
|         | Burns    | and/or   |             | event,    | cerides |
|         | 5-10%    | erythema | Nausea 32%  | 10%       | 40%     |
|         |          |          |             | severe    |         |
|         | I        | Pho      | Fatigue 13% |           | E       |
|         | ncreased | toaging, |             | Hyp       | levated |
|         | risk of  | small    | Gastr       | ertension | chol    |
|         | non-     | i        | ointestinal | 9%        | esterol |
|         | melanoma | ncreased | 18%         |           | 10%     |
|         | skin     | risk of  |             | Increased |         |
|         | cancer   | non-     | Leucopenia  | c         | E       |
|         | (8-10    | melanoma | 9%          | reatinine | levated |
|         | fold for | skin     |             |           | AST 20% |
|         | squamous | cancer   | Headache 6% | > ≥30%    |         |
|         | cell     |          |             | > 40-50%  | C       |
|         | ca       |          | Thom        | >         | helitis |
|         | rcinoma) |          | bocytopenia | > ≥50%    | 100%    |
|         |          |          | 5%          | > 18-20%  |         |
|         | I        |          |             |           | A       |
|         | ncreased |          | Hepatic     | Hyper     | lopecia |
|         | risk of  |          | fibrosis in | trichosis | 25%     |
|         | melanoma |          | 13% and     | 10-27%    |         |
|         | r        |          | cirrhosis   |           | Dry     |
|         | eported. |          | in 4%       | Headache  | eyes    |
|         |          |          |             | 15%       | 50-100% |
|         | Acc      |          | Pneumonisis |           |         |
|         | elerated |          |             | Pa        | Peeling |
|         | pho      |          | Risk of     | rasthesia | palms & |
|         | toaging, |          | lymphoma    | 14-40%    | soles   |
|         | PUVA     |          |             |           | 50%     |
|         | l        |          | Acute       | Gum       |         |
|         | entignes |          | hematologic | hy        | Chills  |
|         |          |          | toxicity,   | pertrophy | 25%     |
|         |          |          | can be      | 5%        |         |
|         |          |          | fatal       |           | P       |
|         |          |          |             | Enhances  | ruritus |
|         |          |          |             | risk of   | 50%     |
|         |          |          |             | skin      |         |
|         |          |          |             | cancer in | Muscle  |
|         |          |          |             | PUV       | pain    |
|         |          |          |             | A-exposed | 25%     |
|         |          |          |             | patients  |         |
|         |          |          |             |           | Xerosis |
|         |          |          |             |           | 25%     |
|         |          |          |             |           |         |
|         |          |          |             |           | ##      |
|         |          |          |             |           | ####### |
|         |          |          |             |           |  Skelet |
|         |          |          |             |           | al chan |
|         |          |          |             |           | ges {#s |
|         |          |          |             |           | keletal |
|         |          |          |             |           | -change |
|         |          |          |             |           | s .unnu |
|         |          |          |             |           | mbered} |
+---------+----------+----------+-------------+-----------+---------+
| Limit   | 150-250  | No limit | Liver       | Typically | Calcif  |
| on      | tr       |          | biopsy      | \<1 year  | ication |
| tr      | eatments |          | every 1.5 g | due to    | of      |
| eatment |          |          | cumulative  | c         | li      |
| d       |          |          | dose,       | umulative | gaments |
| uration |          |          | typically   | renal     | and     |
|         |          |          | every 2 to  | toxicity  | tendons |
|         |          |          | 3 years     |           |         |
+---------+----------+----------+-------------+-----------+---------+
| Mon     | Annual   | Annual   | Blood       | Blood     | Liver   |
| itoring | skin     | skin     | counts and  | pressure  | f       |
| requi   | exam     | exam     | liver       |           | unction |
| rements | inations | inations | function    | C         | tests   |
|         | for life |          | tests every | reatinine | and     |
|         |          | ###      | 1-2 months  |           | serum   |
|         |          | ######   |             | Magnesium | trigly  |
|         |          | {#sectio |             |           | cerides |
|         |          | n-3 .unn |             |           | every   |
|         |          | umbered} |             |           | 3-4     |
|         |          |          |             |           | months  |
+---------+----------+----------+-------------+-----------+---------+
| C       | Requires | Requires | Bone marrow | Multiple  | Potent  |
| omments | t        | t        | toxicity    | drug      | te      |
|         | reatment | reatment | most common | int       | ratogen |
|         | 3-5      | 3-5      | cause of    | eractions |         |
|         | times    | times    | death. Many |           | #       |
|         | per      | per week | drug        |           | #### Us |
|         | week.    |          | in          |           | ually i |
|         |          |          | teractions. |           | nsuffic |
|         | T        |          |             |           | ient as |
|         | eratogen |          | Potent      |           |  monoth |
|         |          |          | teratogen   |           | erapy { |
|         |          |          |             |           | #usuall |
|         |          |          |             |           | y-insuf |
|         |          |          |             |           | ficient |
|         |          |          |             |           | -as-mon |
|         |          |          |             |           | otherap |
|         |          |          |             |           | y .unnu |
|         |          |          |             |           | mbered} |
|         |          |          |             |           |         |
|         |          |          |             |           | M       |
|         |          |          |             |           | ultiple |
|         |          |          |             |           | drug    |
|         |          |          |             |           | inter   |
|         |          |          |             |           | actions |
+---------+----------+----------+-------------+-----------+---------+

The Medical Advisory Board of the National Psoriasis Foundation has
published a consensus describing the minimal characteristics that new
agents should meet (Krueger *et al*, 2000). These include:

-   consistently clears disease activity, even if it occurs in only 5%
    of subjects,

-   provides consistent, predictable, and statistically significant
    responses, short of complete clearing with minimal or no side
    effects, and

-   predictably enhances quality of life in a statistically significant
    fashion.

These guidelines stress the importance of developing new treatments that
do not have the organ toxicity associated with current therapies, even
if the therapy does not consistently result in complete clearance of the
disease. As advances are made in understanding the pathogenesis of
psoriasis development of therapies with more specific targeting of the
disease becomes possible.

## Pathophysiology of Psoriasis: The Role of T cells

A growing body of research has characterized the central role of T cells
in the pathogenesis of psoriasis. Inflammation in psoriasis is initiated
by the interaction between dermal antigen-presenting cells (APC)
carrying a putative autoantigen and T cells in regional lymph nodes
(Robert and Kupper, 1999). APC-T cell interactions involve binding
between many different cell surface receptors and their ligands. In this
context, the binding of lymphocyte functional antigen 3 (LFA-3) on the
APC to CD2 on the T cell has been shown to be important. It results in T
cell activation, upregulation of CD2, and *de novo* expression of two
cell surface molecules: CD45RO and cutaneous lymphocyte antigen (CLA)
(Fuhlbrigge *et al*, 1997; Robert and Kupper, 1999). These lymphocytes
are now termed CD4+ and CD8+ memory T cells (CD45RO is a "memory"
marker). The memory T cells infiltrate skin because CLA expression
confers skin-homing capability. Immunohistochemical staining of the
psoriatic plaque demonstrates that more than 75% of the infiltrating
lymphocytes are CD4+ and CD8+ memory T cells (Friedrich *et al*, 2000).
The T cell infiltrate expresses high levels of CD2, which facilitates
further interaction with LFA-3 on APC in the skin. Thus LFA-3/CD2
interactions are important in T cell activation both in the lymphoid
tissues and after infiltration into the skin. The exact mechanism(s) by
which infiltrating T cells accelerate keratinocyte proliferation is
unknown. However, *in situ* APC-T cell interactions result in the
production of a cytokine, IFNγ, which may be an important factor in
inducing plaque formation. IFNγ has been shown to induce psoriatic
keratinocyte stem cells to enter the cell cycle and proliferate
(Bata-Csorgo *et al*, 1995; Szabo *et al*, 1998).

## Alefacept -- Mechanism of Action

AMEVIVE^®^ (Alefacept, human LFA-3/IgG~1~ fusion protein, LFA3TIP) is a
fully-human, disulfide-linked, glycosylated, dimeric protein consisting
of the first extra-cellular domain of human LFA-3, fused to the hinge
and constant regions of the human immunoglobulin IgG~1~ heavy chain
(Display 1-2). Alefacept can inhibit T cell activation by blocking APC-T
cell LFA-3/CD2 interactions. In addition, alefacept has been shown to
bind to an immunoglobulin receptor (FcγRIII or CD16) via its IgG~1~
domain. The FcγRIII immunoglobulin receptor is expressed by cytotoxic
cells such as natural killer (NK) cells and macrophages. Binding of the
alefacept IgG~1~ domain to FcγRIII leads to the release of pro-apoptotic
mediators such as granzyme. In turn, granzyme release leads to
programmed cell death or apoptosis of the target bound via the alefacept
LFA-3 domain (Display 1-3) (Majeau *et al*, 1994; daSilva *et al*;
2002). Comparing the various T cell subsets, memory T cells have higher
levels of CD2 expression so that they are preferentially targeted by the
alefacept pro-apoptotic mechanism. In summary, alefacept inhibits both T
cell activation and can cause apoptosis of the CD4+ and CD8+ memory T
cells. Because a significant proportion of the T cell infiltrate is
comprised of CD4+ and CD8+ memory T cells, alefacept has a robust
therapeutic rationale in psoriasis.

In the clinical setting, a number of changes in lymphocyte counts are
predicted by the mechanism of action. The apoptotic effects on CD4+ and
CD8+ memory T cells are detectable as a change in the total CD4+ and
CD8+ T cell counts. Since CD4+ and CD8+ T cells themselves contribute to
the total lymphocyte count, a reduction in this quantity is also
predicted.

## Intended Use of Alefacept

The proposed indication for alefacept is for the treatment of patients
with chronic plaque psoriasis who are candidates for phototherapy or
systemic therapy.

The intended doses and dose regimens are as a once-weekly IM injection
of 15 mg or as a once-weekly IV bolus dose of 7.5 mg for 12 weeks.
Re-treatment with alefacept may be initiated as needed provided that
total lymphocyte and CD4+ T cell counts are within the normal range and
a minimum of 12 weeks has passed between courses of treatment.

Display 1-2 Alefacept: a fully human fusion protein

![](media/image6.wmf)

Display 1-3 Mechanism of action of alefacept

![](media/image7.wmf){width="5.95in" height="3.13125in"}

# NONCLINICAL PHARMACOLOGY AND TOXICOLOGY

Nonclinical safety studies with alefacept were conducted in nonhuman
primates. All pivotal studies were conducted with representative
clinical grade material in compliance with FDA and international
regulatory guidelines. To achieve maximal exposure, alefacept was
administered IV in the majority of the nonclinical studies.

## Nonclinical Pharmacokinetics

The pharmacokinetic profile of alefacept was evaluated in baboons and
cynomolgus monkeys. Administration of alefacept demonstrated predictable
and consistent serum concentrations following single- and repeat-dose
administration. Alefacept serum concentrations were proportional to the
dose administered, and clearance and elimination half-life were
approximately 0.41 mL/h/kg and 150 hours, respectively. No apparent
gender differences in the pharmacokinetics of alefacept were observed.
Following IM administration, the elimination half-life was similar to
that observed following IV administration. The bioavailability of
alefacept following IM administration was approximately 58%.

## Toxicology

A comprehensive toxicologic assessment of alefacept was performed in
baboons and cynomolgus monkeys following single- and repeat-dose
administration at doses in excess of 100 times the clinical dose.

The following is a brief summary of the findings from those studies:

-   Single-dose administration through 10 mg/kg and weekly repeat-dose
    administration through 40 mg/kg was well-tolerated and no clinical
    signs of toxicity were observed during dosing or post-dose recovery
    periods.

-   No occurrence of opportunistic infections was observed.

-   Treatment-related changes included a reversible, dose-dependent
    reduction in absolute lymphocyte counts and T lymphocyte subsets
    including CD2+ T cells, CD3+ T cells, CD4+ T cells, and CD8+ T
    cells.

-   Histologic evaluations revealed a consistent, reversible,
    mild/moderate decrease in the number of small lymphocytes in the
    spleen and lymph nodes. No changes were observed in the thymus.

-   Immunohistochemical analysis revealed that the histologic findings
    were consistent with a reduction in CD2+, CD4+, and CD8+ T cells in
    the peri-arteriolar lymphoid sheath of the spleen and in the
    paracortex of the lymph nodes.

-   The observed changes in T cell populations were accompanied by
    mild/moderate hyperplasia of CD20+ centroblasts within germinal
    centers (follicular hyperplasia). The morphology of CD20+
    centroblast hyperplasia was consistent with modestly exaggerated
    clonal responses to normal antigenic stimulation. Normal follicular
    architecture was preserved.

```{=html}
<!-- -->
```
-   In a 52-week toxicology study, a single case of an acute B cell
    lymphoma was observed during week 28 in one of twelve non-human
    primates administered 20 mg/kg alefacept once weekly. At the time of
    diagnosis, this animal was receiving approximately 260 times a
    single IV dose for humans on a weight adjusted basis, and was
    exposed to a cumulative dose equivalent to 622 12-week courses of
    therapy. All animals in the study were positive for an endemic
    primate gamma herpesvirus known as lymphocryptovirus which has been
    associated with B cell lymphomas under certain circumstances.

```{=html}
<!-- -->
```
-   No adverse effects of alefacept administration were noted in
    reproductive toxicity studies in primates at weekly doses up to 20
    mg/kg.

```{=html}
<!-- -->
```
-   No teratogenicity has been observed.

```{=html}
<!-- -->
```
-   No evidence of genotoxicity was observed in mutagenicity studies.

# OVERVIEW OF CLINICAL EXPERIENCE and design of phase 3 studies

Alefacept has been administered to 240 healthy volunteers and 1357
patients with psoriasis for a total of 18 clinical studies that comprise
the clinical program. Six studies were conducted in healthy volunteers
and 12 in patients with psoriasis, as shown in Display 3-1.

In this section, the following are discussed:

-   results from the placebo-controlled, dose-response study (Study 708)
    that provided data on the choice of doses, and a rationale for fixed
    dosing to be used for the Phase 3 studies (see Section 3.1),

-   the designs of the two pivotal, placebo-controlled, Phase 3 studies
    (Studies 711 and 712), from which most of the discussion on efficacy
    in Section 4 and clinical pharmacology in Section 5 is derived (see
    Section 3.2), and

-   the designs of the extension studies (Studies 717 and 724) conducted
    to obtain more data on the experience with multiple courses of
    alefacept (see Section 3.2).

In addition to the psoriasis program, Biogen is studying alefacept in
three other indications: rheumatoid arthritis, scleroderma, and
psoriatic arthritis. Studies in the former two indications are ongoing,
and the study in psoriatic arthritis has recently completed (preliminary
findings are given in Section 4.9).

![](media/image8.wmf)Display 3-1 Alefacept clinical trial program in
psoriasis

## Phase 2, Dose-response Study and the Rationale for Fixed Dosing

Study 708 was a randomized, double-blind, placebo-controlled,
parallel-group, dose-response study comparing the efficacy and safety of
0.025, 0.075, and 0.15 mg/kg alefacept in 229 patients with moderate to
severe psoriasis. Each patient was to receive an IV bolus every week for
a total of 12 weeks and be followed for efficacy and safety for 12 weeks
after the last dose of study drug. This study was the first
placebo-controlled study to examine the relationship between response
and dose.

The degree of reduction in total lymphocytes, peripheral CD4+ and CD8+ T
cells was dose-dependent and occurred during the treatment period.
Selectivity in reduction of the CD4+ and CD8+ memory T cell populations
over the CD4+ and CD8+ naïve T cell populations was observed in
alefacept-treated patients.

The proportion of patients achieving a reduction of 75% or more from
their baseline Psoriasis Area and Severity Index (PASI) at 2 weeks
following the last dose was 10% in the placebo group compared with 21,
33, and 31% in the 0.025, 0.075, and 0.15 mg/kg groups, respectively (p
= 0.021 for the test of treatment differences and p = 0.018 for the test
of linear dose-response). This study provided strong evidence of
efficacy with a long duration of response, e.g., the median time to
further treatment in an extension study was 306 days (Ellis and Krueger,
2001, a copy of this publication is provided in Appendix 3).
Importantly, efficacy outcomes correlated with changes in memory T cell
subsets.

In this study and in earlier Phase 1 and Phase 2 studies, alefacept
dosing was based on body weight. Analysis of the pharmacokinetic data
from these studies showed no correlation between absolute dose and
either central or peripheral distribution volumes. Study 707 showed that
the disposition of alefacept was similar in lean and obese volunteers,
i.e., disposition was unaffected by total body weight. These results
provided the support for the evaluation of fixed dosing in the pivotal
Phase 3 clinical studies, 711 and 712.

Based upon the analysis of data from Study 708, 0.075 mg/kg was selected
as the optimal dose for further evaluation in Phase 3. Since the median
body weight of patients in Study 708 was 98 kg, a total fixed dose of
7.5 mg IV was used in the Phase 3 IV study, 711. The fixed IM doses
evaluated in Study 712 were based on the 7.5 mg IV dose. Based on the
expected bioavailability of approximately 60% when administered IM,
doses of 10 and 15 mg were chosen to bracket the corresponding
equivalent IV dose.

## Designs of the Phase 3 Studies and Their Extensions

Two placebo-controlled, Phase 3 studies were conducted: Study 712, in
which alefacept was administered IM for one course, and Study 711, in
which alefacept was administered IV for a maximum of two courses.

Both Phase 3 studies had a number of common design features that are
described below.

*Inclusion/exclusion Criteria*

Men and women with chronic plaque psoriasis for at least 12 months, with
a body surface area involvement of at least 10%, were eligible for entry
into the phase 3 studies. Patients also had to have CD4+ T cell counts
above the lower limit of normal (LLN).

Patients were to be excluded if any of the following criteria existed:

-   erythrodermic, guttate, palmar, or generalized pustular forms of
    psoriasis;

-   a serious local or systemic infection;

-   a history of malignancy (patients with a history of basal cell
    carcinoma or \<3 squamous cell carcinomas were eligible)

-   HIV, or hepatitis B or hepatitis C with ALT or AST greater than
    three times the upper limit of normal.

In addition, patients had to have discontinued certain prior therapies
as shown in Display 3-2.

Display 3-2 Exclusion criteria based on prior treatment in the Phase 3
studies

  --------------------------- -------------------------------------------
  Required washout period     Therapy

  Within 4 weeks of the first Any investigational drug or approved
  dose of study drug          therapy for investigational use

                              Systemic retinoids

                              Systemic immunosuppressant agents, e.g.,
                              methotrexate, cyclosporine, azathioprine,
                              thioguanine, prednisone

                              Phototherapy

                              High potency topical corticosteroids

  Within 2 weeks of the first Moderate potency topical corticosteroids
  dose of study drug          (other than on the scalp, palms, groin,
                              and/or soles)

                              Vitamin D analogues and topical retinoids
                              (other than on the scalp, palms, groin,
                              and/or soles)

                              Keratolytics and coal tar (other than on
                              the scalp, palms, groin, and/or soles)
  --------------------------- -------------------------------------------

*Randomization*

In both Phase 3 studies, randomization to treatment group (Study 712) or
cohort (Study 711) was stratified by screening PASI and prior systemic
therapy as follows:

-   PASI \>20 and never received phototherapy or systemic therapy,

-   PASI \>20 and previously received phototherapy or systemic therapy,

-   PASI ≤20 and never received phototherapy or systemic therapy, and

-   PASI ≤20 and previously received phototherapy or systemic therapy.

*Dosing*

A course of therapy comprised 12 weekly doses of study drug with at
least 12 weeks of follow-up. Study drug was administered by the
investigator or his/her designee at each site. Following the first dose,
patients had blood drawn for determination of complete blood and
lymphocyte counts. Further dosing was based upon an algorithm specifying
the need for patients to be within specific limits for lymphocyte
counts; otherwise placebo (saline) was substituted if counts fell
outside those limits. The algorithm is presented in Display 3-3.

Display 3-3 Dosing algorithm used in Phase 3 Studies

+-----------------------------------------------------------------------+
| -   Each dose of study drug was to be separated by an interval of 5   |
|     to 9 days.                                                        |
|                                                                       |
| -   Study drug was to be given if no clinical evidence of significant |
|     viral, bacterial, or fungal infection.                            |
|                                                                       |
| -   Study drug was to be withheld for 2 weeks if the patient had a    |
|     fever (body temperature \>38°C) or if there was evidence of a     |
|     clinically significant infection (including upper respiratory     |
|     infection).                                                       |
|                                                                       |
| ```{=html}                                                            |
| <!-- -->                                                              |
| ```                                                                   |
| -   Study drug was to be substituted with placebo if the CD4+ count   |
|     from the previous week was \<250 cells/μL. If CD4+ counts were    |
|     \<250 cells/μL for ≥4 consecutive visits, study drug was to be    |
|     permanently substituted with placebo.                             |
+-----------------------------------------------------------------------+

*Blinding*

All conventional precautions to maintain study blind were used in
Studies 711 and 712. In addition, to prevent potential unblinding based
on laboratory results (lymphocyte counts), the studies were conducted
with an examining dermatologist *and* a laboratory physician at each
site. The examining dermatologists remained blinded to laboratory
results as they documented patients' clinical response to study drug.
The laboratory physician received all laboratory data and monitored
lymphocyte results, and communicated changes in the dosing regimen to
the study pharmacist. When necessary, the study pharmacist substituted
an injection of placebo (saline) with similar appearance to, and same
volume as study drug. All other safety issues relating to lymphocytes
and lymphocyte subsets were handled by unblinded physicians at the
Sponsor's Contract Research Organization. Using these safeguards, all
patients were assessed for clinical response in a blinded fashion.

### Placebo-controlled Study of IM Administration of Alefacept (Study 712) and Extension Study (Study 717)

Study 712 was a randomized, double-blind, placebo-controlled, safety,
and efficacy study involving 507 patients with moderate to severe
psoriasis. Patients were randomized to receive 12 once-weekly IM
injections of placebo, or 10 or 15 mg alefacept, with 12 weeks of
follow-up (Display 3-4). Patients were seen weekly during the dosing
period, and at 2, 4, 6, 8, and 12 weeks after the last dose.

The study was conducted at 64 centers in the United States, Canada, and
Europe.

After completion of Study 712, patients were allowed to enter a
double-blind extension study, Study 717, that has recently completed.
The goal of Study 717 was to evaluate the safety and efficacy of a
second 12-week course of alefacept when given IM to patients who
received alefacept in Study 712. It also offered a course of alefacept
to those who received placebo in Study 712. Patients who received
placebo or 10 mg alefacept in Study 712 received a course of 10 mg in
Study 717, and those who received 15 mg alefacept in Study 712 received
a further course of 15 mg in Study 717.

To be eligible, patients had to have received at least eight injections
in Study 712, and had to have completed all post-dosing visits in Study
712. Patients were required to enroll into Study 717 within 14 days of
completing the last visit in Study 712. Patients who initiated
alternative systemic therapy, phototherapy, or disallowed therapy prior
to Week 8 in Study 712 were excluded from entry.

In order to receive a course of alefacept in Study 717, a patient's
disease severity had to be "mild" or worse by Physician's Global
Assessment (Appendix 1), and CD4+ T cell counts had to be at or above
the LLN. Patients not satisfying these two criteria were followed at
"interim visits" until they were eligible to be dosed.

Display 3-4 Overview of Studies 712 and 717

![](media/image1.wmf)

### Placebo-controlled Study of Two Courses of IV Administration of Alefacept (Study 711) and Extension Study (Study 724)

Study 711 was a randomized, double-blind, placebo-controlled study
involving 553 patients with moderate to severe psoriasis conducted at 51
sites in the United States and Canada. This study evaluated the safety
and efficacy of two courses of alefacept. Each course consisted of 12
once-weekly IV injections followed by at least 12 weeks of follow-up
(Display 3-5). Patients were randomized to one of three cohorts:

-   Cohort 1: two courses of 7.5 mg alefacept,

-   Cohort 2: a course of 7.5 mg alefacept followed by a course of
    placebo, or

-   Cohort 3: a course of placebo followed by a course of 7.5 mg
    alefacept.

![](media/image1.wmf)Display 3-5 Overview of Studies 711 and 724

In Course 1, patients were seen weekly during the dosing period, and at
2, 4, 6, 8, and 12 weeks after the last dose. To be eligible for a
second course, patients had to have

-   a disease severity worse than "clear" by Physician's Global
    Assessment,

-   a CD4+ T cell count greater than or equal to the LLN, and

-   not received disallowed medications, principally phototherapy or
    systemic therapies, in the time frames specified for the first
    course (Display 3-2).

Patients who did not satisfy these criteria were followed at "interim
visits" until they met the conditions for a second course. As in the
first course, patients were seen weekly during the dosing period of
Course 2, and at 2, 4, 6, 8, and 12 weeks after the last dose.

In addition to demonstrating the effectiveness and safety of a second
course of alefacept, the extensive 36-week period of follow-up for
Cohort 2 (a course of alefacept followed by a course of placebo) allowed
a more precise determination of safety, pharmacodynamic, and efficacy
outcomes after one 12-week dosing period of 7.5 mg alefacept IV.

After completion of Study 711, eligible patients were allowed to enter
Study 724, an open-label extension study to determine the safety and
efficacy of further courses of alefacept (Display 3-5). Study 724 is
ongoing. All patients receive 12 once-weekly injections of 7.5 mg
alefacept IV when their disease has progressed to warrant systemic
therapy or phototherapy. Patients are required to have a CD4+ T cell
count at or above the LLN prior to their first dose.

# CLINICAL EFFICACY

The following review of the efficacy of alefacept focuses on the two
Phase 3 studies, 711 and 712, the designs of which are described in
Section 3.2. Studies 711 and 712 support the efficacy of alefacept
administered either IV or IM, respectively. In addition, data from
Studies 711 and 717 (the extension to Study 712) support the efficacy of
repeat courses of alefacept.

## Measurement of Disease Activity in Chronic Plaque Psoriasis 

Three measures of efficacy were used in the Phase 3 studies, the
Psoriasis Area and Severity Index (PASI), a Physician's Global
Assessment (PGA), and the Dermatology Life Quality Index (DLQI).

The primary endpoint in both Phase 3 studies was based on PASI. This
index was developed by Fredriksson and Pettersson (1978) in an effort to
establish a standardized and reproducible clinical rating system that
assesses the body area affected by psoriasis and the intensity of main
symptoms on a scale ranging from 0 to 72. The PASI quantifies the
severity and extent of disease by measuring the sum of the redness,
thickness, and scale of the lesions, and weights these by the extent of
body surface area involved (Appendix 1). A 75% or greater improvement in
PASI (PASI 75) is accepted as the most stringent outcome measure
demonstrating clinical benefit. Supportive evidence of clinical benefit
is provided by the assessment of a 50% or greater reduction in PASI
(PASI 50) and by the PGA. PGA is relevant to clinical practice because
many physicians rate disease activity on a scale ranging from "severe"
to "clear" (Appendix 1).

All physicians received instructions on the application of PASI and PGA
prior to study initiation. In addition, the protocol specified that
patients were to be examined by the same physician throughout the study.
Sites were monitored for their consistency.

One of the critical assessments of clinical benefit in trials evaluating
new therapies for patients with psoriasis is the demonstration of
improvement in quality of life. In the Phase 3 studies, the DLQI was
used to measure the effect of alefacept treatment on a patient's quality
of life. DLQI is a validated assessment of the impact of skin disease on
patients' lives (Finlay and Khan, 1994). Patients were asked to consider
the previous 7 days and answer questions on an ordinal scale (Appendix
1). DLQI includes assessment of skin disease symptoms (such as itching
and pain), patient feelings, daily activities, leisure activities,
work/school function, personal relationships, and the negative aspects
of treatment (for example, odor and mess). A reduction in DLQI score
with treatment demonstrates improvement in a patient's quality of life.

## Endpoints in Phase 3 Studies

For both pivotal Phase 3 studies, the primary endpoint was the
proportion of patients who achieved PASI 75 2 weeks after administration
of the final dose.

Other pre-specified endpoints for both studies included the proportion
of patients achieving, at 2 weeks after the last dose,

-   a PGA of "almost clear" or "clear" (PGA AC/C), and

-   PASI 50;

the proportion of patients achieving, at any time after the first dose
(equivalent to an overall response rate),

-   PASI 75,

-   a PGA AC/C, and

-   PASI 50;

and the mean DLQI score, 2 and 12 weeks after the last dose.

The clinical endpoints specified stringent criteria to ensure that
clinical benefit was attributable to treatment with alefacept. Patients
were considered treatment failures if they received phototherapy or any
of the medications shown in Display 4-1 prior to reaching the specified
efficacy endpoint. Use of moderately potent topical corticosteroids,
keratolytics, coal tar, or vitamin D analogs was permitted on the groin,
anal fold region, scalp, palms, and soles of the feet. However,
application of these therapies to other regions of the body was
considered a protocol violation and the patient was considered a
treatment failure from the time of the violation onward.

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                                               |
|                                                                       |
| ```{=html}                                                            |
| <!-- -->                                                              |
| ```                                                                   |
| -   Inappropriate use of moderate potency topical corticosteroids,    |
|     keratolytics, coal tar, or vitamin D analogs                      |
+-----------------------------------------------------------------------+

Furthermore, patients who discontinued the study prior to the assessment
at 2 weeks post-dosing, or failed to present for that visit, or did not
have an efficacy assessment at that visit were also categorized as
treatment failures.

Given these stringent criteria, the analyses underestimate the true
proportion of patients responding to alefacept treatment. Analyses of
the endpoints are based, therefore, on an intent-to-treat approach.

## Statistical Methods

In the Phase 3 studies, sites were grouped into regions based on
latitude to account for the varying amount of ultraviolet exposure from
the sun. The choice of regions was pre-determined and specified in
either the study protocol or study Statistical Analysis Plan. At
randomization, patients were stratified by disease severity and by prior
use of systemic therapy for psoriasis (Section 3.2).

For PASI 75, PASI 50, and PGA AC/C, the probability of responding was
analyzed by fitting logistic regression models that included terms for
geographic region, stratum, and treatment. For the overall DLQI score,
analysis of variance was used with geographic region, stratum, baseline
DLQI, the usage of phototherapy or other systemic therapies, and
treatment terms in the model.

In Study 712, two comparisons were to be made, 10 mg alefacept IM *vs*
placebo IM and 15 mg alefacept IM *vs* placebo IM. To preserve an
overall Type I error of 0.050, each comparison with placebo used a Type
I error of 0.025.

## Study Populations in Phase 3

### Accounting of Patients

A total of 1060 patients were dosed in the two Phase 3 studies, 553 in
Study 711, and 507 in Study 712. Display 4-2 shows the numbers of
patients dosed by treatment cohort (Study 711) and treatment group
(Study 712). Withdrawal rates in each study were low but slightly higher
during a course of placebo than during a course of alefacept.

Display 4-2 Accounting of patients in Studies 711 and 712

+------------+--------+--------+--------+---+--------+--------+--------+
|            | Study  |        |        |   | Study  |        |        |
|            | 711    |        |        |   | 712    |        |        |
+------------+--------+--------+--------+---+--------+--------+--------+
|            | Cohort | Cohort | Cohort |   |        |        |        |
|            | 1      | 2      | 3      |   |        |        |        |
+------------+--------+--------+--------+---+--------+--------+--------+
| ####### Co | 7.5 mg | 7.5 mg | P      |   | P      | 10 mg  | 15 mg  |
| urse 1 {#c |        |        | lacebo |   | lacebo |        |        |
| ourse-1 .u | ale    | ale    | IV     |   | IM     | ale    | ale    |
| nnumbered} | facept | facept |        |   |        | facept | facept |
|            | IV     | IV     |        |   |        | IM     | IM     |
+------------+--------+--------+--------+---+--------+--------+--------+
| Number     | 183    | 184    | 186    |   | 168    | 173    | 166    |
| dosed      | (100)  | (100)  | (100)  |   | (100)  | (100)  | (100)  |
|            |        |        |        |   |        |        |        |
| in Course  |        |        |        |   |        |        |        |
| 1          |        |        |        |   |        |        |        |
+------------+--------+--------+--------+---+--------+--------+--------+
| Number     | 16 (   | 26 (   | 29 (   |   | 16 (   | 6 ( 3) | 14 (   |
| withdrawn  | 9)     | 14)    | 16)    |   | 10)    |        | 8)     |
+------------+--------+--------+--------+---+--------+--------+--------+
| Adverse    | 1 (    | 5 ( 3) | 1 (    |   | 3 ( 2) | 0      | 0      |
| event      | \<1)   |        | \<1)   |   |        |        |        |
+------------+--------+--------+--------+---+--------+--------+--------+
| Worsening  | 3 ( 2) | 6 ( 3) | 2 ( 1) |   | 0      | 0      | 3 ( 2) |
| of         |        |        |        |   |        |        |        |
|            |        |        |        |   |        |        |        |
| disease    |        |        |        |   |        |        |        |
+------------+--------+--------+--------+---+--------+--------+--------+
| Other      | 12 (   | 15 (   | 26 (   |   | 13 (   | 6 ( 3) | 11 (   |
|            | 7)     | 8)     | 14)    |   | 8)     |        | 7)     |
+------------+--------+--------+--------+---+--------+--------+--------+
|            |        |        |        |   |        |        |        |
+------------+--------+--------+--------+---+--------+--------+--------+
| ####### Co | 7.5 mg | P      | 7.5 mg |   | Only 1 |        |        |
| urse 2 {#c |        | lacebo |        |   | course |        |        |
| ourse-2 .u | ale    | IV     | ale    |   | admini |        |        |
| nnumbered} | facept |        | facept |   | stered |        |        |
|            | IV     |        | IV     |   | in     |        |        |
|            |        |        |        |   | Study  |        |        |
|            |        |        |        |   | 712    |        |        |
+------------+--------+--------+--------+---+--------+--------+--------+
| Number     | 154    | 142    | 153    |   |        |        |        |
| dosed      | (100)  | (100)  | (100)  |   |        |        |        |
|            |        |        |        |   |        |        |        |
| in Course  |        |        |        |   |        |        |        |
| 2          |        |        |        |   |        |        |        |
+------------+--------+--------+--------+---+--------+--------+--------+
| Number     | 11 (   | 24 (   | 13 (   |   |        |        |        |
| withdrawn  | 7)     | 17)    | 8)     |   |        |        |        |
+------------+--------+--------+--------+---+--------+--------+--------+
| Adverse    | 0      | 0      | 0      |   |        |        |        |
| event      |        |        |        |   |        |        |        |
+------------+--------+--------+--------+---+--------+--------+--------+
| Worsening  | 2 ( 1) | 3 ( 2) | 1 (    |   |        |        |        |
| of         |        |        | \<1)   |   |        |        |        |
|            |        |        |        |   |        |        |        |
| disease    |        |        |        |   |        |        |        |
+------------+--------+--------+--------+---+--------+--------+--------+
| Other      | 9 ( 6) | 21 (   | 12 (   |   |        |        |        |
|            |        | 15)    | 8)     |   |        |        |        |
+------------+--------+--------+--------+---+--------+--------+--------+

NOTE: Numbers in parentheses are percentages.

### Demographic and Baseline Disease Characteristics

In Phase 3, demographic characteristics were similar across treatment
groups across studies (Display 4-3). Median age ranged from 44 to 46
years with the youngest patient aged 16 and the oldest 84. Approximately
75% of patients were aged between 30 and 59 years. The male to female
ratio was approximately 2:1. Approximately 90% of the patients were
Caucasian.

The median duration of disease across treatment groups ranged from 17 to
20 years. Median body surface area involvement ranged from 20 to 24%
across all treatment groups. Approximately 90% of patients were
considered to have "moderate" to "severe" disease as measured by PGA.
Baseline PASI ranged from 3.4 to 58.8, with the median ranging from 13.2
to 15.2 across treatment groups. Approximately 17% of patients had a
PASI in the range 5.0 to 9.9, 51% were in the 10.0 to 19.9 range, and
19% were in the 20.0 to 29.9 range.

Consistent with baseline disease characteristics, data regarding prior
treatment suggest a disease severity suitable for management with
systemic- and/or phototherapy-based approaches. The most common prior
treatments were UVB therapy (43 to 54%), PUVA (30 to 42%), methotrexate
(28 to 36%), retinoids (15 to 31%, with greater usage in Study 712), and
cyclosporine (8 to 17%). The percentage of patients who reported no
improvement or a worsening of disease with prior agents ranged from 30
to 47% for UVB, 23 to 36% for PUVA, 17 to 36% for methotrexate, 41 to
50% for retinoids, and 22 to 29% for cyclosporine. Thus, many patients
enrolled in the Phase 3 studies had experienced an incomplete response
or failed to respond to commonly used therapies.

Review of Display 4-3 leads to the conclusion that patients with
moderate to severe psoriasis undergo treatment with many different
modalities, i.e., no single agent predominates because of its
risk-benefit profile, and that many patients are refractory to existing
approaches.

Treatment groups were well balanced with respect to demographic and
baseline disease characteristics.

Display 4-3 Demographics, baseline disease characteristics, and most
common prior therapies for psoriasis in Phase 3 studies

+-------------------+--------+--------+---+--------+--------+--------+
|                   | Study  |        |   | Study  |        |        |
|                   | 711    |        |   | 712    |        |        |
|                   | Course |        |   |        |        |        |
|                   | 1      |        |   |        |        |        |
+-------------------+--------+--------+---+--------+--------+--------+
|                   | P      | 7.5 mg |   | P      | 10 mg  | 15 mg  |
|                   | lacebo |        |   | lacebo |        |        |
|                   | IV     | ale    |   | IM     | ale    | ale    |
|                   |        | facept |   |        | facept | facept |
|                   | (      | IV     |   | (      | IM     | IM     |
|                   | N=186) |        |   | N=168) |        |        |
|                   |        | (      |   |        | (      | (      |
|                   |        | N=367) |   |        | N=173) | N=166) |
+-------------------+--------+--------+---+--------+--------+--------+
| ###### Demogr     | 44     | 45     |   | 46     | 45     | 45     |
| aphics {#demograp | (18,   | (16,   |   | (20,   | (18,   | (19,   |
| hics .unnumbered} | 76)    | 84)    |   | 80)    | 72)    | 78)    |
|                   |        |        |   |        |        |        |
| Median (min, max) | 68:32  | 71:29  |   | 65:35  | 69:31  | 62:38  |
| age (years)       |        |        |   |        |        |        |
|                   | 87:13  | 90:10  |   | 88:12  | 92: 8  | 90:10  |
| Gender (%M: %F)   |        |        |   |        |        |        |
|                   | 91     | 90     |   | 86     | 84     | 83     |
| Race (%           | (54,   | (46,   |   | (45,   | (40,   | (43,   |
| Caucasian: %      | 170)   | 206)   |   | 144)   | 170)   | 142)   |
| Other)            |        |        |   |        |        |        |
|                   |        |        |   |        |        |        |
| Median (min, max) |        |        |   |        |        |        |
| weight (kg)       |        |        |   |        |        |        |
+-------------------+--------+--------+---+--------+--------+--------+
| ##                | 17 (2, | 19 (2, |   | 20 (3, | 19 (4, | 19 (2, |
| #### Baseline dis | 55)    | 60)    |   | 77)    | 50)    | 70)    |
| ease characterist |        |        |   |        |        |        |
| ics {#baseline-di | 22     | 22     |   | 24 (7, | 22 (9, | 20 (6, |
| sease-characteris | (10,   | (10,   |   | 90)    | 95)    | 85)    |
| tics .unnumbered} | 85)    | 98)    |   |        |        |        |
|                   |        |        |   | 10     | 10     | 12     |
| Median (min, max) | 17     | 18     |   |        |        |        |
| duration of       |        |        |   | 39     | 37     | 32     |
|                   | 35     | 42     |   |        |        |        |
| disease (years)   |        |        |   | 37     | 40     | 39     |
|                   | 41     | 33     |   |        |        |        |
| Median (min, max) |        |        |   | 13     | 10     | 15     |
| body surface      | 4      | 7      |   |        |        |        |
|                   |        |        |   | 1      | 2      | 2      |
| area involvement  | 2      | 0      |   |        |        |        |
| (%)               |        |        |   | 0      | 0      | 0      |
|                   | 0      | 0      |   |        |        |        |
| PGA: % who were   |        |        |   | 0      | 0      | 0      |
|                   | 0      | 0      |   |        |        |        |
| Severe            |        |        |   |        |        |        |
|                   |        |        |   |        |        |        |
| Moderate to       |        |        |   |        |        |        |
| severe            |        |        |   |        |        |        |
|                   |        |        |   |        |        |        |
| Moderate          |        |        |   |        |        |        |
|                   |        |        |   |        |        |        |
| Mild to moderate  |        |        |   |        |        |        |
|                   |        |        |   |        |        |        |
| Mild              |        |        |   |        |        |        |
|                   |        |        |   |        |        |        |
| Almost clear      |        |        |   |        |        |        |
|                   |        |        |   |        |        |        |
| Clear             |        |        |   |        |        |        |
+-------------------+--------+--------+---+--------+--------+--------+
| Median (min, max) | 15.1   | 15.2   |   | 14.3   | 15.1   | 13.2   |
| PASI              | (4.2,  | (4.3,  |   | (5.3,  | (3.4,  | (3.7,  |
|                   | 51.5)  | 56.4)  |   | 44.8)  | 58.8)  | 52.8)  |
+-------------------+--------+--------+---+--------+--------+--------+
| ####### *Most     | 54     | 49     |   | 49     | 45     | 43     |
| common prior trea |        |        |   |        |        |        |
| tments* {#most-co | 30     | 36     |   | 40     | 40     | 42     |
| mmon-prior-treatm |        |        |   |        |        |        |
| ents .unnumbered} | 30     | 36     |   | 28     | 31     | 30     |
|                   |        |        |   |        |        |        |
| \% who had prior  | 15     | 17     |   | 27     | 31     | 30     |
| treatment with    |        |        |   |        |        |        |
|                   | 8      | 12     |   | 14     | 17     | 17     |
| UVB               |        |        |   |        |        |        |
|                   |        |        |   |        |        |        |
| PUVA              |        |        |   |        |        |        |
|                   |        |        |   |        |        |        |
| Methotrexate      |        |        |   |        |        |        |
|                   |        |        |   |        |        |        |
| Retinoids         |        |        |   |        |        |        |
|                   |        |        |   |        |        |        |
| Cyclosporine      |        |        |   |        |        |        |
+-------------------+--------+--------+---+--------+--------+--------+

## Modification of Exposure to Alefacept

As described earlier, in the clinical trials evaluating alefacept, CD4+
T cell counts were monitored and the exposure to alefacept adjusted
according to a protocol-defined algorithm (Display 3-3). Placebo was
substituted for alefacept when a patient's CD4+ T cell counts were ≤250
cells/μL the week prior to dosing. Alefacept was permanently
discontinued if the CD4+ T cell count was \<250 cells/μL for four or
more consecutive visits.

As shown in Display 4-4, the number of patients with one or more placebo
substitutions was greater with IV alefacept compared to either dose of
IM alefacept. However, the proportion did not increase with the second
course of alefacept in Study 711. None of the patients treated with
either the 10 or 15 mg dose of alefacept IM had permanent substitution
of study drug with placebo. Seven patients, all of whom had received 7.5
mg alefacept IV, received placebo through the remainder of Study 711.
Following withdrawal of alefacept, the CD4+ T cell counts for these 7
patients began to recover.

Display 4-4 Placebo substitution rates in alefacept-treated patients in
Phase 3 studies

+--------------------------+---------+---------+---+--------+---------+
|                          | Study   |         |   | Study  |         |
|                          | 711     |         |   | 712    |         |
|                          | (7.5 mg |         |   |        |         |
|                          | IV)     |         |   |        |         |
+--------------------------+---------+---------+---+--------+---------+
|                          | Course  | Course  |   | 10 mg  | 15 mg   |
|                          | 1 (a)   | 2 (b)   |   | IM     | IM      |
+--------------------------+---------+---------+---+--------+---------+
| Number of patients dosed | 367     | 154     |   | 173    | 166     |
|                          | (100)   | (100)   |   | (100)  | (100)   |
| Number of patients with  |         |         |   |        |         |
| ≥1 placebo substitution  | 38 (    | 14 ( 9) |   | 5 ( 3) | 9 ( 5)  |
|                          | 10)     |         |   |        |         |
| Number of patients with  |         | 0       |   | 0      | 0       |
| permanent placebo        | 7 ( 2)  |         |   |        |         |
| substitutions            |         |         |   |        |         |
+--------------------------+---------+---------+---+--------+---------+

NOTE: Numbers in parentheses are percentages.

\(a\) Number of patients who received alefacept in Course 1 (Cohorts 1
and 2 combined).

\(b\) Number of patients who received two courses of alefacept (Cohort
1).

## Clinical Response following One Course of Alefacept

Analysis of the proportions of patients achieving clinical response
following one course of therapy is based on 507 patients in Study 712
for IM administration and 553 patients in the first course of Study 711.
For Study 711, the comparison between alefacept and placebo for the
first course of therapy is between Cohort 3 (placebo treatment during
Course 1) and Cohorts 1 and 2 combined since both received alefacept
during the first course.

### Analyses of Response by PASI 75, PASI 50, and PGA AC/C

As shown in Display 4-5, a greater proportion of patients treated with
either IV or IM alefacept than placebo achieved PASI 75 two weeks after
the last dose, the primary endpoint of each study. In Study 711, 14% of
patients treated with alefacept, compared to 4% who received placebo,
responded 2 weeks after the last dose of Course 1 (p \< 0.001). In Study
712, the proportions responding in the placebo, 10 and 15 mg alefacept
IM groups were 5%, 12% (p = 0.041), and 21% (p \< 0.001), respectively.
Thus, the 7.5 mg IV and 15 mg IM groups were statistically significantly
superior to placebo. Although the proportion of patients treated with 10
mg alefacept IM was higher than placebo, it was not statistically
significant.

It is also worth noting that the effects of alefacept on the components
of the PASI score, i.e., erythema, induration, and desquamation, were of
similar magnitude.

Analysis of the secondary endpoint, PGA AC/C 2 weeks after the last
dose, supports the primary outcome measure. In Study 711, 4% of those
who received placebo compared to 11% of alefacept-treated patients
improved by PGA AC/C assessment (p = 0.004). In Study 712, the response
rates were 5, 10, and 14% in the placebo, 10 and 15 mg treatment groups,
respectively, with a statistically significantly greater proportion in
the 15 mg group compared to placebo (p = 0.006).

Analysis of the other efficacy endpoints of PASI 75 and PGA AC/C at any
time, PASI 50 at 2 weeks after the last dose and at any time are
consistent in demonstrating the efficacy of alefacept compared to
placebo.

While statistically and clinically significant treatment benefit with
alefacept has been shown in both pivotal studies at the time of the
primary endpoint, the true magnitude of clinical benefit is
underestimated at that time point. Results of the efficacy analyses
suggest that the assessment of clinical response "at any time" during
the course of treatment is a more relevant measure of clinical benefit.
For all three alefacept treatment groups, the greatest response rate
occurred after completion of dosing (Display 4-6). In Study 711, 21% of
patients achieved PASI 75 6 weeks after alefacept treatment compared to
14% at 2 weeks after dosing. Similarly, in Study 712, 17% of patients
treated with 10 mg IM alefacept had a PASI 75 at 4 weeks after treatment
and 21% of the 15 mg treatment group achieved PASI 75 2 weeks after
treatment. The occurrence of clinical benefit later in the dosing
interval for some patients is consistent with the pharmacodynamic effect
of alefacept. Maximum T cell reductions occurred later in the alefacept
dosing interval in some patients. Consequently, maximum clinical benefit
would be predicted to occur after completion of treatment.

Display 4-5 Proportions of patients responding in the first course of
treatment in Phase 3 Studies 711 and 712

+-------------------+--------+--------+---+--------+--------+--------+
|                   | Study  |        |   | Study  |        |        |
|                   | 711    |        |   | 712    |        |        |
|                   | Course |        |   |        |        |        |
|                   | 1      |        |   |        |        |        |
+-------------------+--------+--------+---+--------+--------+--------+
|                   | P      | 7.5 mg |   | P      | 10 mg  | 15 mg  |
|                   | lacebo |        |   | lacebo |        |        |
|                   | IV     | ale    |   | IM     | ale    | ale    |
|                   |        | facept |   |        | facept | facept |
|                   |        | IV     |   |        | IM     | IM     |
+-------------------+--------+--------+---+--------+--------+--------+
| Number of         | 186    | 367    |   | 168    | 173    | 166    |
| patients dosed    | (100)  | (100)  |   | (100)  | (100)  | (100)  |
+-------------------+--------+--------+---+--------+--------+--------+
| *PASI 75*         | 7 ( 4) | 53 (   |   | 9 ( 5) | 21 (   | 35 (   |
|                   |        | 14)    |   |        | 12)    | 21)    |
| \- 2 weeks        | 15 (   |        |   | 21 (   |        |        |
| post-treatment    | 8)     | p \<   |   | 13)    | p =    | p \<   |
| (a)               |        | 0.001  |   |        | 0.041  | 0.001  |
|                   |        |        |   |        |        |        |
| \- at any time    |        | 102 (  |   |        | 48 (   | 54 (   |
| (overall          |        | 28)    |   |        | 28)    | 33)    |
| response)         |        |        |   |        |        |        |
|                   |        | p \<   |   |        | p \<   | p \<   |
|                   |        | 0.001  |   |        | 0.001  | 0.001  |
+-------------------+--------+--------+---+--------+--------+--------+
| *PGA AC/C*        | 7 ( 4) | 42 (   |   | 8 ( 5) | 18 (   | 23 (   |
|                   |        | 11)    |   |        | 10)    | 14)    |
| \- 2 weeks        | 11 (   |        |   | 14 (   |        |        |
| post-treatment    | 6)     | p =    |   | 8)     | p =    | p =    |
|                   |        | 0.004  |   |        | 0.065  | 0.006  |
| \- at any time    |        |        |   |        |        |        |
| (overall          |        | 83 (   |   |        | 38 (   | 40 (   |
| response)         |        | 23)    |   |        | 22)    | 24)    |
|                   |        |        |   |        |        |        |
|                   |        | p \<   |   |        | p \<   | p \<   |
|                   |        | 0.001  |   |        | 0.001  | 0.001  |
+-------------------+--------+--------+---+--------+--------+--------+
| *PASI 50*         | 18 (   | 139 (  |   | 30 (   | 62 (   | 69 (   |
|                   | 10)    | 38)    |   | 18)    | 36)    | 42)    |
| \- 2 weeks        |        |        |   |        |        |        |
| post-treatment    | 44 (   | p \<   |   | 59 (   | p \<   | p \<   |
|                   | 24)    | 0.001  |   | 35)    | 0.001  | 0.001  |
| \- at any time    |        |        |   |        |        |        |
| (overall          |        | 204 (  |   |        | 91 (   | 94 (   |
| response)         |        | 56)    |   |        | 53)    | 57)    |
|                   |        |        |   |        |        |        |
|                   |        | p \<   |   |        | p =    | p \<   |
|                   |        | 0.001  |   |        | 0.002  | 0.001  |
+-------------------+--------+--------+---+--------+--------+--------+

NOTE: Numbers in parentheses are percentages.

PASI 75 and PASI 50 represent 75% or greater and 50% or greater
reductions from baseline PASI, respectively;

PGA AC/C is a PGA of "almost clear" or "clear", each without the
concomitant use of phototherapy or other systemic

therapies.

\(a\) Primary endpoint.

P-values for comparisons with placebo are considered statistically
significant if \<0.050 for Study 711 Course 1,

if \<0.025 for each dose group in Study 712.

Display 4-6 Proportion of patients achieving PASI 75 in the first course
of treatment

***IV administration (Study 711 Course 1)***

![](media/image1.wmf)

***IM administration (Study 712)***

![](media/image1.wmf)

The efficacy results described above characterize three unique features
of alefacept therapy:

1.  The clinical response with alefacept treatment is seen within 6 to 8
    weeks of the initiation of dosing and corresponds to the reductions
    in memory T cells (Section 5.2).

2.  Continued improvement is observed following cessation of dosing in
    the face of increasing T cell counts.

3.  Treatment with alefacept provides a durable response. During the
    follow-up period, clinical response was maintained.

All efficacy evaluations consistently demonstrate these three
characteristics of alefacept activity.

While minor differences in the response rates of the primary endpoint
were observed in the two pivotal studies, a comparison of the two
studies can be done by calculating the odds ratio of responding. If the
odds of responding in each treatment group are the same, then the odds
ratio will be 1. If alefacept is better than placebo, the odds ratio
will be greater than 1, and if placebo is better than alefacept then the
odds ratio will be less than 1. To compare the alefacept response to the
placebo response *across* studies, the odds ratios of responding at 2
weeks after the last dose have been calculated for:

-   the 7.5 mg IV group relative to the placebo IV group in the first
    course of Study 711,

-   the 10 mg IM group relative to the placebo IM group in Study 712,
    and

-   the 15 mg IM group relative to the placebo IM group in Study 712.

The odds ratios are based on the models fitted to the data that
generated the p-values in Display 4-5 for treatment comparisons, and are
thus adjusted for geographic region and stratum.

Display 4-7 presents the estimated odds ratios, and confidence intervals
(CIs) for these estimates (95% intervals for Study 711 and 97.5%
intervals for Study 712). CIs are determined according to the p-value
used to determine statistical significance in the study protocol.
Confidence intervals that do not contain 1 are statistically
significant.

As can be seen from Display 4-7, the magnitude of benefit of alefacept
administration was consistent across the 7.5 mg IV and 15 mg IM
treatments. The odds ratio of responding to 10 mg alefacept IM is lower
than that of 15 mg alefacept IM and 7.5 mg alefacept IV.

Display 4-7 Odds ratios of responding 2 weeks post-treatment in Study
711 Course 1 and Study 712

### Analysis of Clinical Effect by Subgroups

Display 4-8 shows PASI 75 response rates 2 weeks following treatment by
age, gender, and baseline disease characteristics. Display 4-9 shows
PASI 75 response rates 2 weeks following treatment according to whether
or not a patient had an improvement in disease with prior phototherapy
or systemic therapy. For example, in Study 712, 127 patients in the 15
mg alefacept IM group had received prior therapy, of whom 99 reported
improvement with that prior therapy. Of these 99, 17% achieved PASI 75 2
weeks post-dosing *vs* 3% in the comparable group who received placebo.

Despite the low numbers of patients in some categories,

-   treatment with 7.5 mg alefacept IV and 15 mg alefacept IM results in
    greater response rates than placebo regardless of age, gender, and
    baseline disease characteristics,

-   treatment with 7.5 mg alefacept IV and 15 mg alefacept IM results in
    greater response rates than placebo regardless of exposure to or
    improvement with prior therapy, and

-   patients who had never been exposed to prior therapy tended to have
    a greater response rate than those who improved with a prior
    therapy.

Display 4-8 PASI 75 2 weeks post-treatment − percentage responding by
age, gender, and baseline disease characteristics

+-----------+--------------+-------+-------+---+-------+-------+-------+
|           |              | Study |       |   | Study |       |       |
|           |              | 711   |       |   | 712   |       |       |
|           |              | C     |       |   |       |       |       |
|           |              | ourse |       |   |       |       |       |
|           |              | 1     |       |   |       |       |       |
+-----------+--------------+-------+-------+---+-------+-------+-------+
|           |              | Pl    | 7.5   |   | Pl    | 10 mg | 15 mg |
|           |              | acebo | mg    |   | acebo | alef  | alef  |
|           |              | IV    | alef  |   | IM    | acept | acept |
|           |              |       | acept |   |       | IM    | IM    |
|           |              |       | IV    |   |       |       |       |
+-----------+--------------+-------+-------+---+-------+-------+-------+
| Age       | \<40         | 3/ 68 | 2     |   | 5/ 57 | 11/   | 17/   |
| (years)   |              | ( 4)  | 0/131 |   | ( 9)  | 61    | 63    |
|           | ≥40 but \<60 |       | (15)  |   |       | (18)  | (27)  |
|           |              | 4/ 89 |       |   | 2/ 82 |       |       |
|           | ≥60          | ( 4)  | 2     |   | ( 2)  | 7/ 95 | 10/   |
|           |              |       | 6/186 |   |       | ( 7)  | 73    |
|           |              | 0/ 29 | (14)  |   | 2/ 29 |       | (14)  |
|           |              |       |       |   | ( 7)  | 3/ 17 |       |
|           |              |       | 7/ 50 |   |       | (18)  | 8/ 30 |
|           |              |       | (14)  |   |       |       | (27)  |
+-----------+--------------+-------+-------+---+-------+-------+-------+
| Gender    | Male         | 3/127 | 3     |   | 6/110 | 1     | 2     |
|           |              | ( 2)  | 3/260 |   | ( 5)  | 4/120 | 0/103 |
|           | Female       |       | (13)  |   |       | (12)  | (19)  |
|           |              | 4/ 59 |       |   | 3/ 58 |       |       |
|           |              | ( 7)  | 2     |   | ( 5)  | 7/ 53 | 15/   |
|           |              |       | 0/107 |   |       | (13)  | 63    |
|           |              |       | (19)  |   |       |       | (24)  |
+-----------+--------------+-------+-------+---+-------+-------+-------+
| BSA       | ≤30          | 5/129 | 3     |   | 5/117 | 1     | 2     |
| in        |              | ( 4)  | 9/250 |   | ( 4)  | 7/112 | 2/119 |
| volvement | \>30         |       | (16)  |   |       | (15)  | (18)  |
| (%)       |              | 2/ 57 |       |   | 4/ 51 |       |       |
|           |              | ( 4)  | 1     |   | ( 8)  | 4/ 61 | 13/   |
|           |              |       | 4/117 |   |       | ( 7)  | 47    |
|           |              |       | (12)  |   |       |       | (28)  |
+-----------+--------------+-------+-------+---+-------+-------+-------+
| PASI      | ≤10          | 1/ 32 | 15/   |   | 0/ 32 | 6/ 33 | 7/ 39 |
|           |              | ( 3)  | 67    |   |       | (18)  | (18)  |
|           | \>10 but ≤20 |       | (22)  |   | 6/ 95 |       |       |
|           |              | 5/ 91 |       |   | ( 6)  | 10/   | 15/   |
|           | \>20         | ( 5)  | 2     |   |       | 86    | 84    |
|           |              |       | 5/190 |   | 3/ 41 | (12)  | (18)  |
|           |              | 1/ 63 | (13)  |   | ( 7)  |       |       |
|           |              | ( 2)  |       |   |       | 5/ 54 | 13/   |
|           |              |       | 1     |   |       | ( 9)  | 43    |
|           |              |       | 3/110 |   |       |       | (30)  |
|           |              |       | (12)  |   |       |       |       |
+-----------+--------------+-------+-------+---+-------+-------+-------+
| PGA       | "Severe" or  | 3/ 98 | 2     |   | 6/ 82 | 11/   | 15/   |
|           | "Moderate to | ( 3)  | 9/220 |   | ( 7)  | 81    | 73    |
|           | severe"      |       | (13)  |   |       | (14)  | (21)  |
|           |              | 4/ 78 |       |   | 2/ 62 |       |       |
|           | "Moderate"   | ( 5)  | 1     |   | ( 3)  | 5/ 70 | 15/   |
|           |              |       | 7/122 |   |       | ( 7)  | 65    |
|           | "Mild to     | 0/ 10 | (14)  |   | 1/ 24 |       | (23)  |
|           | moderate" or |       |       |   | ( 4)  | 5/ 22 |       |
|           | "Mild"       |       | 7/ 25 |   |       | (23)  | 5/ 28 |
|           |              |       | (28)  |   |       |       | (18)  |
+-----------+--------------+-------+-------+---+-------+-------+-------+

NOTE: Entries are number responding/number in category (percentage).

Display 4-9 PASI 75 2 weeks post-treatment − percentage responding by
response to prior phototherapy, prior systemic therapy, or no therapy

+-----------+--------------+-------+-------+---+-------+-------+-------+
|           | Response to  | Study |       |   | Study |       |       |
|           | prior        | 711   |       |   | 712   |       |       |
|           | therapy      | C     |       |   |       |       |       |
|           |              | ourse |       |   |       |       |       |
|           |              | 1     |       |   |       |       |       |
+-----------+--------------+-------+-------+---+-------+-------+-------+
|           |              | Pl    | 7.5   |   | Pl    | 10 mg | 15 mg |
|           |              | acebo | mg    |   | acebo | alef  | alef  |
|           |              | IV    | alef  |   | IM    | acept | acept |
|           |              |       | acept |   |       | IM    | IM    |
|           |              |       | IV    |   |       |       |       |
+-----------+--------------+-------+-------+---+-------+-------+-------+
| Any prior | No change or | 0/ 41 | 12/   |   | 2/ 24 | 3/ 22 | 7/ 28 |
| therapy   | worsened     |       | 59    |   | ( 8)  | (14)  | (25)  |
|           |              | 6/106 | (20)  |   |       |       |       |
|           | Improved     | ( 6)  |       |   | 3/107 | 1     | 17/   |
|           |              |       | 2     |   | ( 3)  | 3/112 | 99    |
|           | Never        | 1/ 39 | 8/223 |   |       | (12)  | (17)  |
|           | exposed      | ( 3)  | (13)  |   | 4/ 37 |       |       |
|           |              |       |       |   | (11)  | 5/ 39 | 11/   |
|           |              |       | 13/   |   |       | (13)  | 39    |
|           |              |       | 85    |   |       |       | (28)  |
|           |              |       | (15)  |   |       |       |       |
+-----------+--------------+-------+-------+---+-------+-------+-------+
| UVB       | No change or | 0/ 47 | 14/   |   | 2/ 25 | 3/ 29 | 8/ 28 |
|           | worsened     |       | 76    |   | ( 8)  | (10)  | (29)  |
|           |              | 3/ 54 | (18)  |   |       |       |       |
|           | Improved     | ( 6)  |       |   | 1/ 56 | 7/ 48 | 7/ 43 |
|           |              |       | 1     |   | ( 2)  | (15)  | (16)  |
|           | Never        | 4/ 85 | 4/101 |   |       |       |       |
|           | exposed      | ( 5)  | (14)  |   | 6/ 87 | 11/   | 20/   |
|           |              |       |       |   | ( 7)  | 96    | 95    |
|           |              |       | 2     |   |       | (11)  | (21)  |
|           |              |       | 5/189 |   |       |       |       |
|           |              |       | (13)  |   |       |       |       |
+-----------+--------------+-------+-------+---+-------+-------+-------+
| PUVA      | No change or | 0/ 20 | 6/ 47 |   | 0/ 18 | 3/ 21 | 2/ 16 |
|           | worsened     |       | (13)  |   |       | (14)  | (13)  |
|           |              | 2/ 36 |       |   | 1/ 48 |       |       |
|           | Improved     | ( 6)  | 8/ 84 |   | ( 2)  | 5/ 46 | 10/   |
|           |              |       | (10)  |   |       | (11)  | 52    |
|           | Never        | 5/130 |       |   | 8/102 |       | (19)  |
|           | exposed      | ( 4)  | 3     |   | ( 8)  | 1     |       |
|           |              |       | 9/236 |   |       | 3/106 | 23/   |
|           |              |       | (17)  |   |       | (12)  | 98    |
|           |              |       |       |   |       |       | (23)  |
+-----------+--------------+-------+-------+---+-------+-------+-------+
| Met       | No change or | 0/ 17 | 6/ 48 |   | 0/ 13 | 4/ 9  | 2/ 17 |
| hotrexate | worsened     |       | (13)  |   |       | (44)  | (12)  |
|           |              | 0/ 38 |       |   | 2/ 34 |       |       |
|           | Improved     |       | 11/   |   | ( 6)  | 2/ 44 | 4/ 32 |
|           |              | 7/131 | 85    |   |       | ( 5)  | (13)  |
|           | Never        | ( 5)  | (13)  |   | 7/121 |       |       |
|           | exposed      |       |       |   | ( 6)  | 1     | 2     |
|           |              |       | 3     |   |       | 5/120 | 9/117 |
|           |              |       | 6/233 |   |       | (13)  | (25)  |
|           |              |       | (15)  |   |       |       |       |
+-----------+--------------+-------+-------+---+-------+-------+-------+
| Retinoids | No change or | 1/ 14 | 2/ 32 |   | 0/ 19 | 3/ 24 | 4/ 23 |
|           | worsened     | ( 7)  | ( 6)  |   |       | (13)  | (17)  |
|           |              |       |       |   | 1/ 27 |       |       |
|           | Improved     | 0/ 14 | 4/ 31 |   | ( 4)  | 0/ 29 | 7/ 27 |
|           |              |       | (13)  |   |       |       | (26)  |
|           | Never        | 6/158 |       |   | 8/122 | 1     |       |
|           | exposed      | ( 4)  | 4     |   | ( 7)  | 8/120 | 2     |
|           |              |       | 7/304 |   |       | (15)  | 4/116 |
|           |              |       | (15)  |   |       |       | (21)  |
+-----------+--------------+-------+-------+---+-------+-------+-------+
| Cyc       | No change or | 0/ 4  | 3/ 12 |   | 0/ 5  | 0/ 6  | 0/ 8  |
| losporine | worsened     |       | (25)  |   |       |       |       |
|           |              | 1/ 10 |       |   | 1/ 17 | 5/ 23 | 2/ 20 |
|           | Improved     | (10)  | 3/ 33 |   | ( 6)  | (22)  | (10)  |
|           |              |       | ( 9)  |   |       |       |       |
|           | Never        | 6/172 |       |   | 8/146 | 1     | 3     |
|           | exposed      | ( 3)  | 4     |   | ( 5)  | 6/144 | 3/138 |
|           |              |       | 7/321 |   |       | (11)  | (24)  |
|           |              |       | (15)  |   |       |       |       |
+-----------+--------------+-------+-------+---+-------+-------+-------+

NOTE: Entries are number responding/number in category (percentage).

### Analysis of Quality of Life

Display 4-10 shows the mean DLQI scores at 2 and 12 weeks after the last
dose of study drug in Studies 711 and 712. A reduction in DLQI score
reflects improvement in quality of life. In Study 711, a statistically
significant difference in mean DLQI between alefacept- and
placebo-treated patients was apparent at 2 weeks (p \< 0.001) and 12
weeks (p = 0.002) following treatment. In Study 712, benefit was seen 2
weeks following treatment with 15 mg alefacept IM (p \< 0.001). Although
the scores in quality of life at 12 weeks after dosing showed
improvement for both the 10 and 15 mg alefacept IM groups, the
differences from placebo were not statistically significant.

Display 4-10 Overall DLQI score in Studies 711 and 712

+-----------------------+--------+--------+--------+--------+-------+
|                       | Study  |        | Study  |        |       |
|                       | 711    |        | 712    |        |       |
|                       |        |        |        |        |       |
|                       | Course |        |        |        |       |
|                       | 1      |        |        |        |       |
+-----------------------+--------+--------+--------+--------+-------+
|                       | P      | 7.5 mg | P      | 10 mg  | 15 mg |
|                       | lacebo |        | lacebo |        |       |
|                       | IV     | ale    | IM     | ale    | alef  |
|                       |        | facept |        | facept | acept |
|                       |        | IV     |        | IM     | IM    |
+-----------------------+--------+--------+--------+--------+-------+
| No. of patients dosed | 186    | 367    | 168    | 173    | 166   |
|                       | (100)  | (100)  | (100)  | (100)  | (100) |
+-----------------------+--------+--------+--------+--------+-------+
| ####### At            |        |        |        |        |       |
| 2 weeks post-treatmen |        |        |        |        |       |
| t {#at-2-weeks-post-t |        |        |        |        |       |
| reatment .unnumbered} |        |        |        |        |       |
+-----------------------+--------+--------+--------+--------+-------+
| No. of evaluable      | 158 (  | 314 (  | 150 (  | 152 (  | 141 ( |
| patients (a)          | 85)    | 86)    | 89)    | 88)    | 85)   |
+-----------------------+--------+--------+--------+--------+-------+
| Mean DLQI at baseline | 11.0   | 11.0   | 10.7   | 11.1   | 12.1  |
+-----------------------+--------+--------+--------+--------+-------+
| Adjusted mean DLQI    | 9.9    | 7.6    | 9.1    | 7.8    | 6.7   |
|                       |        |        |        |        |       |
| 2 weeks               |        |        |        |        |       |
| post-treatment (b)    |        |        |        |        |       |
+-----------------------+--------+--------+--------+--------+-------+
|                       |        | p \<   |        | p =    | p \<  |
|                       |        | 0.001  |        | 0.049  | 0.001 |
+-----------------------+--------+--------+--------+--------+-------+
|                       |        |        |        |        |       |
+-----------------------+--------+--------+--------+--------+-------+
| ####### At 12         |        |        |        |        |       |
|  weeks post-treatment |        |        |        |        |       |
|  {#at-12-weeks-post-t |        |        |        |        |       |
| reatment .unnumbered} |        |        |        |        |       |
+-----------------------+--------+--------+--------+--------+-------+
| No. of evaluable      | 172 (  | 332 (  | 156 (  | 157    | 149 ( |
| patients (a)          | 92)    | 90)    | 93)    | (91)   | 90)   |
+-----------------------+--------+--------+--------+--------+-------+
| Mean DLQI at baseline | 10.8   | 11.0   | 10.8   | 11.1   | 12.2  |
+-----------------------+--------+--------+--------+--------+-------+
| Adjusted mean DLQI    | 9.8    | 8.1    | 8.6    | 7.5    | 7.4   |
|                       |        |        |        |        |       |
| 12 weeks              |        |        |        |        |       |
| post-treatment (b)    |        |        |        |        |       |
+-----------------------+--------+--------+--------+--------+-------+
|                       |        | p =    |        | p =    | p =   |
|                       |        | 0.002  |        | 0.079  | 0.060 |
+-----------------------+--------+--------+--------+--------+-------+

NOTE: Numbers in parentheses are percentages.

A reduction in score reflects improvement in quality of life.

P-values for comparisons with placebo are considered statistically
significant if \<0.050 for Study 711 Course 1, if \<0.025

for each dose group in Study 712.

\(a\) Number who completed questionnaire and respective visit.

\(b\) Mean is adjusted for geographic region, stratum, baseline DLQI
score, and disallowed concomitant therapy.

In order to correlate the changes in quality-of-life scores with
clinical response, treatment groups within each study were combined.
Patients were classified as responders or non-responders according to
their PASI 75, PGA AC/C, and PASI 50 responses irrespective of their
treatment group. As shown in Display 4-11, the decrease in DLQI
correlated significantly with improvement in the clinical assessment
scores.

Display 4-11 Mean change in DLQI Overall Score by responder status at 2
weeks after the last dose

+---------------+-------+-----------+---+-------+----------+---+-------+
|               | Resp  |           |   | Non   |          |   | p-    |
|               | onder |           |   | -resp |          |   | value |
|               |       |           |   | onder |          |   |       |
|               |       |           |   |       |          |   | \(a\) |
+---------------+-------+-----------+---+-------+----------+---+-------+
|               | Bas   | Mean      |   | Bas   | Mean     |   |       |
|               | eline | change    |   | eline | change   |   |       |
|               |       | from      |   |       | from     |   |       |
|               |       | baseline  |   |       | baseline |   |       |
+---------------+-------+-----------+---+-------+----------+---+-------+
| *PASI 75*     | 10.95 | -8.60     |   | 10.83 | -2.83    |   | \<    |
|               |       |           |   |       |          |   | 0.001 |
| Study 711     | 10.51 | -7.18     |   | 11.51 | -2.92    |   |       |
| Course 1      |       |           |   |       |          |   | \<    |
|               |       |           |   |       |          |   | 0.001 |
| Study 712     |       |           |   |       |          |   |       |
+---------------+-------+-----------+---+-------+----------+---+-------+
| *PASI 50*     | 11.57 | -7.36     |   | 10.52 | -1.81    |   | \<    |
|               |       |           |   |       |          |   | 0.001 |
| Study 711     | 10.81 | -5.97     |   | 11.23 | -2.24    |   |       |
| Course 1      |       |           |   |       |          |   | \<    |
|               |       |           |   |       |          |   | 0.001 |
| Study 712     |       |           |   |       |          |   |       |
+---------------+-------+-----------+---+-------+----------+---+-------+
| *PGA AC/C*    | 10.44 | -8.06     |   | 10.89 | -3.02    |   | \<    |
|               |       |           |   |       |          |   | 0.001 |
| Study 711     | 9.63  | -7.12     |   | 11.26 | -3.09    |   |       |
| Course 1      |       |           |   |       |          |   | \<    |
|               |       |           |   |       |          |   | 0.001 |
| Study 712     |       |           |   |       |          |   |       |
+---------------+-------+-----------+---+-------+----------+---+-------+

NOTE: A reduction in score reflects improvement in quality of life.

\(a\) Comparison of responders *vs* non-responders using one-way
analysis of variance.

## Duration of Clinical Response Following One Course of Alefacept

Systemic agents used in the treatment of moderate to severe psoriasis
include cyclosporine the effects of which last for approximately 2 to 12
weeks, etretinate for 8 weeks, methotrexate for 1 to 5 months, and PUVA
for approximately 6 months (Ellis *et al*, 1991; Ellis *et al*, 1995;
Kaplan *et al*, 1983; Dooren-Greebe *et al*, 1994; Dooren-Greebe *et
al*, 1995; Hesse *et al*, 1987). However, these therapies are associated
with toxicity (Display 1-1). The need exists, therefore, for a safe and
effective therapy that will give a durable response greater than that of
existing systemic agents.

Currently, no consensus exists on the quantification of duration of
response. However, in other published studies, duration has been defined
as the time in which a patient has an increase to no more than 50% of
the pre-study baseline PASI score and an increase to no more than 50% of
the pre-study baseline body surface area affected (Ozawa *et al*, 1999;
Shupack *et al*, 1997).

For alefacept, the best estimate of duration of response comes from
patients who received a course of alefacept followed by a course of
placebo, namely Cohort 2, in Study 711. In Study 711, duration of
clinical response was defined in two ways:

-   the maintenance of PASI 50 or better in patients who achieved a best
    observed response of PASI 75 at any time, and

-   the maintenance of PASI 50 or better in patients who achieved a best
    observed response of PGA AC/C at any time.

Duration of response has been estimated using Kaplan-Meier methodology.
This methodology takes into account the fact that the measurement of
duration times may be right-censored due to a patient's participation in
the study being cut short due to, for example, voluntary withdrawal, an
adverse event, termination of the study.

As shown in Displays 4-12 and 4-13, duration of response according to
the two definitions above was long: for those who achieved PASI 75, the
median duration of response at PASI 50 was 216 days (almost 31 weeks),
and for those who achieved a PGA AC/C, 241 days (approximately 34
weeks). Unlike current systemic treatments including cyclosporine and
methotrexate, treatment with alefacept provides a markedly durable
clinical response.

Display 4-12 Duration of a 50% reduction from baseline PASI in those who
achieved PASI 75 in Cohort 2 of Study 711

![](media/image2.wmf){width="5.9in" height="4.1625in"}

Display 4-13 Duration of a 50% reduction from baseline PASI in those who
achieved PGA AC/C in Cohort 2 of Study 711

![](media/image3.wmf){width="6.0in" height="4.186805555555556in"}

## Clinical Response with Two Courses of Alefacept

The efficacy of two courses of alefacept was evaluated in the Study 711.
In Study 711, patients were eligible to receive a second course of study
drug if, at 12 weeks post-treatment in Course 1:

-   their disease severity was worse than "clear" by PGA,

-   their CD4+ T cell count was greater than or equal to the LLN, and

-   they had not received disallowed concomitant medications,
    principally systemic or phototherapy within the same time frame as
    that for the first course (Display 3-2).

Patients who were not eligible to start dosing in Course 2 were followed
at "interim visits" until they were eligible for a second course of
treatment. Twenty-three of the 367 patients who received alefacept
during the first course were never dosed during the second course. Of
these 23 patients, 6 were in remission, i.e., had PGA ratings of
"clear."

Assessment of clinical response with a second course of alefacept is
based upon the comparison between the 154 patients in Cohort 1 and the
142 patients in Cohort 2 of Study 711. Patients in Cohort 1 received
alefacept during both courses of treatment while patients in Cohort 2
received placebo during the second course (this cohort had received
alefacept during the first course).

At 2 weeks after the last dose of the second dosing period, a greater
proportion of patients treated with a second course of 7.5 mg alefacept
IV compared to placebo had a clinical response as measured by PASI 75
and PGA AC/C (Display 4-14). Twenty-three percent of alefacept-treated
patients achieved PASI 75 compared to 7% who received placebo
(p\<0.001); and 20% of alefacept-treated patients achieved PGA AC/C
compared to 6% who received placebo (p\<0.001).

Patients treated with a second course of alefacept also demonstrated a
clinical response compared to placebo as measured by PASI 50 at 2 weeks
after treatment and at any time, PGA AC/C at any time, and PASI 75 at
any time.

Note that the higher response rates for placebo in Course 2 may be due
to the long duration of improvement following the first course of
alefacept, and the higher response rates for alefacept in Course 2
suggest a cumulative benefit in efficacy (Display 4-15). Overall,
patients who responded in Course 1 also responded in Course 2. Also,
some patients who did not respond in Course 1 achieved response in
Course 2.

Display 4-14 Proportions of patients responding in Courses 1 and 2 of
Study 711

+------------------------+-----------+-----------+---+---------+--------+
|                        | Study 711 |           |   | Study   |        |
|                        | Course 1  |           |   | 711     |        |
|                        | (a)       |           |   | Course  |        |
|                        |           |           |   | 2       |        |
+------------------------+-----------+-----------+---+---------+--------+
|                        | Placebo   | 7.5 mg    |   | Placebo | 7.5 mg |
|                        | IV        |           |   | IV      |        |
|                        |           | alefacept |   |         | ale    |
|                        | (Cohort   | IV        |   | (Cohort | facept |
|                        | 3)        |           |   | 2)      | IV     |
|                        |           | (Cohorts  |   |         |        |
|                        |           | 1 and 2)  |   |         | (      |
|                        |           |           |   |         | Cohort |
|                        |           |           |   |         | 1)     |
+------------------------+-----------+-----------+---+---------+--------+
| Number of patients     | 186 (100) | 367 (100) |   | 142     | 154    |
| dosed                  |           |           |   | (100)   | (100)  |
+------------------------+-----------+-----------+---+---------+--------+
| *PASI 75*              | 7 ( 4)    | 53 ( 14)  |   | 10 ( 7) | 36 (   |
|                        |           |           |   |         | 23)    |
| \- 2 weeks             | 15 ( 8)   | p \<      |   | 27 (    |        |
| post-treatment         |           | 0.001     |   | 19)     | p \<   |
|                        |           |           |   |         | 0.001  |
| \- at any time         |           | 102 ( 28) |   |         |        |
| (overall response)     |           |           |   |         | 57 (   |
|                        |           | p \<      |   |         | 37)    |
|                        |           | 0.001     |   |         |        |
|                        |           |           |   |         | p \<   |
|                        |           |           |   |         | 0.001  |
+------------------------+-----------+-----------+---+---------+--------+
| *PGA AC/C*             | 7 ( 4)    | 42 ( 11)  |   | 8 ( 6)  | 31 (   |
|                        |           |           |   |         | 20)    |
| \- 2 weeks             | 11 ( 6)   | p = 0.004 |   | 25 (    |        |
| post-treatment         |           |           |   | 18)     | p \<   |
|                        |           | 83 ( 23)  |   |         | 0.001  |
| \- at any time         |           |           |   |         |        |
| (overall response)     |           | p \<      |   |         | 46 (   |
|                        |           | 0.001     |   |         | 30)    |
|                        |           |           |   |         |        |
|                        |           |           |   |         | p =    |
|                        |           |           |   |         | 0.011  |
+------------------------+-----------+-----------+---+---------+--------+
| *PASI 50*              | 18 ( 10)  | 139 ( 38) |   | 35 (    | 74 (   |
|                        |           |           |   | 25)     | 48)    |
| \- 2 weeks             | 44 ( 24)  | p \<      |   |         |        |
| post-treatment         |           | 0.001     |   | 70 (    | p \<   |
|                        |           |           |   | 49)     | 0.001  |
| \- at any time         |           | 204 ( 56) |   |         |        |
| (overall response)     |           |           |   |         | 99 (   |
|                        |           | p \<      |   |         | 64)    |
|                        |           | 0.001     |   |         |        |
|                        |           |           |   |         | p =    |
|                        |           |           |   |         | 0.002  |
+------------------------+-----------+-----------+---+---------+--------+

NOTE: Numbers in parentheses are percentages.

P-values for comparisons with placebo.

\(a\) From Display 4-5.

Display 4-15 shows the proportion of patients achieving PASI 75 in
Course 1 and those achieving PASI 75 in Course 2. As described earlier,
all patients are included in the analysis of Course 1, but only those
who received alefacept in Course 1, i.e., Cohorts 1 and 2, are included
in the analysis of Course 2.

Patients in Cohort 2 (alefacept/placebo) have a long lasting benefit
from the first course which declines slowly during the second course
when they received placebo. In contrast, the proportion of patients
treated with a second course of alefacept (Cohort 1) who achieved PASI
75 was initially stable but increased to a maximum of 27% at 6 weeks
after treatment. Results were similar for PASI 50 and PGA AC/C. It
should also be borne in mind that the total benefit of receiving
alefacept is underestimated since 23 patients who achieved optimal
levels of clinical response or had CD4+ T cell counts below the LLN were
not dosed during the second course.

Display 4-15 Study 711: proportion of patients achieving PASI 75 by
course

***Course 1 (all patients) Course 2 (patients who***

> ![](media/image1.wmf) ***received alefacept in Course 1)***

In clinical terms, the best approximation of benefit from two courses is
gauged by comparing the response rates over two courses *versus* one.
The greatest proportion of patients achieving clinical response was seen
in Cohort 1, the cohort that received two courses of alefacept (Display
4-16). For Cohorts 1, 2 and 3, the proportions achieving PASI 75 were
40, 31, and 28%, achieving PGA AC/C were 32, 27, and 22%, and achieving
PASI 50 were 71, 63, and 52%, respectively.

Display 4-16 Endpoints based on proportions of patients responding over
the entire span of Study 711

+----------------------------+------------+------------+-------------+
|                            | 7.5 mg     | 7.5 mg     | Placebo IV  |
|                            | alefacept  | alefacept  |             |
|                            | IV then    | IV then    | then        |
|                            |            |            |             |
|                            | 7.5 mg     | placebo IV | 7.5 mg      |
|                            | alefacept  |            | alefacept   |
|                            | IV         | (Cohort 2) | IV          |
|                            |            |            |             |
|                            | (Cohort 1) |            | (Cohort 3)  |
+----------------------------+------------+------------+-------------+
| Number of patients dosed   | 183 (100)  | 184 (100)  | 186 (100)   |
+----------------------------+------------+------------+-------------+
| PASI 75                    | 73 ( 40)   | 57 ( 31)   | 53 ( 28)    |
+----------------------------+------------+------------+-------------+
| PGA AC/C                   | 58 ( 32)   | 50 ( 27)   | 40 ( 22)    |
+----------------------------+------------+------------+-------------+
| PASI 50                    | 130 ( 71)  | 116 ( 63)  | 97 ( 52)    |
+----------------------------+------------+------------+-------------+

NOTE: Numbers in parentheses are percentages.

Display 4-17 presents the preliminary findings for response rates when
the IM administration study, 712, and its extension, 717, are combined.
For the placebo/10 mg cohort, the 10 mg/10 mg cohort, and the 15 mg/15
mg cohort, the proportions achieving PASI 75 were 23, 37, and 43%,
achieving PGA AC/C were 17, 29, and 31%, and achieving PASI 50 were 57,
64, and 69%, respectively.

Display 4-17 Endpoints based on proportions of patients responding over
the entire span of Studies 712 and 717

+-----------------------------+------------+-------------+------------+
|                             | Placebo    | 10 mg       | 15 mg      |
|                             |            | alefacept   | alefacept  |
|                             | then       | IM          | IM         |
|                             |            |             |            |
|                             | 10 mg      | then        | then       |
|                             | alefacept  |             |            |
|                             | IM         | 10 mg       | 15 mg      |
|                             |            | alefacept   | alefacept  |
|                             |            | IM          | IM         |
+-----------------------------+------------+-------------+------------+
| Number of patients dosed    | 168 (100)  | 173 (100)   | 166 (100)  |
+-----------------------------+------------+-------------+------------+
| PASI 75                     | 38 ( 23)   | 64 ( 37)    | 71 ( 43)   |
+-----------------------------+------------+-------------+------------+
| PGA AC/C                    | 29 ( 17)   | 51 ( 29)    | 51 ( 31)   |
+-----------------------------+------------+-------------+------------+
| PASI 50                     | 95 ( 57)   | 111 ( 64)   | 114 ( 69)  |
+-----------------------------+------------+-------------+------------+

NOTE: Numbers in parentheses are percentages.

In Study 711, patients' quality of life was assessed using the DLQI at 2
and 12 weeks following treatment during the second course. Compared to
placebo, alefacept-treated patients had a statistically significant
improvement in their quality of life at both time points (Display 4-18).

Display 4-18 Overall DLQI score in the second course of Study 711

+----------------------------------+-----------+-------------+--------+
|                                  | Study 711 |             |        |
|                                  | Course 2  |             |        |
+----------------------------------+-----------+-------------+--------+
|                                  | Placebo   | 7.5 mg      | p      |
|                                  | IV        |             | -value |
|                                  |           | alefacept   |        |
|                                  |           | IV          |        |
+----------------------------------+-----------+-------------+--------+
| Number of patients dosed         | 142 (100) | 154 (100)   |        |
+----------------------------------+-----------+-------------+--------+
| At 2 weeks post-treatment        |           |             |        |
+----------------------------------+-----------+-------------+--------+
| No. of evaluable patients (a)    | 117 ( 82) | 138 ( 90)   |        |
+----------------------------------+-----------+-------------+--------+
| Mean DLQI at baseline            | 10.0      | 11.1        |        |
+----------------------------------+-----------+-------------+--------+
| Adjusted mean DLQI 2 weeks       | 8.0       | 6.5         | 0.026  |
| post-treatment (b)               |           |             |        |
+----------------------------------+-----------+-------------+--------+
|                                  |           |             |        |
+----------------------------------+-----------+-------------+--------+
| At 12 weeks post-treatment       |           |             |        |
+----------------------------------+-----------+-------------+--------+
| No. of evaluable patients (a)    | 135 ( 95) | 149 ( 97)   |        |
+----------------------------------+-----------+-------------+--------+
| Mean DLQI at baseline            | 10.0      | 11.4        |        |
+----------------------------------+-----------+-------------+--------+
| Adjusted mean DLQI 12 weeks      | 8.8       | 6.9         | 0.007  |
| post-treatment (b)               |           |             |        |
+----------------------------------+-----------+-------------+--------+

NOTE: Numbers in parentheses are percentages.

A reduction in score reflects improvement in quality of life.

\(a\) Number who completed questionnaire and respective visit.

\(b\) Mean is adjusted for geographic region, stratum, baseline DLQI
score, and disallowed concomitant therapy.

## Preliminary Findings in Psoriatic Arthritis

Like psoriasis, psoriatic arthritis is a T-cell-mediated disorder. The
LFA-3/CD2 interaction plays a significant role in the T-cell activation
involved in both conditions.

Eleven patients with active psoriatic arthritis were treated with
alefacept 7.5 mg IV for 12 weeks in an open-label study. Clinical joint
assessment and laboratory assessments were performed at baseline, and
after 4, 9, 12, and 16 weeks of treatment. Serial synovial tissue (ST)
biopsies of an inflamed index joint (knee, ankle, wrist, or
metacarpophalangeal joint) were obtained by arthroscopy at baseline, and
after 4 and 12 weeks of treatment. At baseline, the mean swollen and
tender joint count were both 7.

At completion of treatment, 6 of 11 patients (56%) fulfilled the disease
activity score (DAS) response criteria (Display 4-19). Nine patients
(82%) fulfilled the DAS response criteria at any point during the study.
Using the American College of Rheumatology (ACR) scoring criteria, 7 of
the 11 patients (64%) fulfilled the ACR 20 response of whom 3 (27%) also
fulfilled ACR 50. Improvement in disease activity was associated with
statistically significant reduction in C-reactive protein (CRP) (Display
4-20). There was also a statistically significant reduction in CD4+ T
cells (p \< 0.05), CD8+ T cells (p = 0.05), and CD68+ macrophages (p \<
0.02) in the ST after 12 weeks of treatment compared to baseline. The ST
and peripheral blood of those patients fulfilling the DAS response
criteria contained more memory T cells at baseline and displayed a
significant reduction in these cells compared to non-responding
patients. It was concluded that the changes in ST, together with the
improvement in clinical joint scores and CRP, after treatment with
alefacept support the hypothesis that T-cell activation plays an
important role in this chronic inflammatory disease. Further
investigation of alefacept in psoriatic arthritis is warranted.

![](media/image1.wmf)

Display 4-19 Swollen joint count and tender joint count

Display 4-20 Mean C-reactive protein by time

![](media/image1.wmf)

## Summary of Clinical Efficacy

The clinical efficacy data from the two pivotal Phase 3 studies
evaluating alefacept in patients with chronic plaque psoriasis
demonstrate:

-   Compared to placebo treated patients, a greater proportion of
    patients treated with either 7.5 mg IV, 10 mg IM, or 15 mg IM
    alefacept experienced a clinical response as measured by PASI 75 two
    weeks after completion of treatment. The differences between 7.5 mg
    IV and placebo, and between 15 mg IM and placebo were statistically
    significant.

-   Support for clinical benefit is provided by all other pre-specified
    assessments of clinical response. These assessments include PGA AC/C
    at 2 weeks after treatment and at any time, PASI 50 at 2 weeks after
    treatment and at any time, and PASI 75 at any time. All of these
    analyses demonstrated significant benefit with either 7.5 mg IV or
    15 mg IM alefacept treatment compared to placebo.

-   In addition to these measurements of cutaneous responses, assessment
    of the patient's quality of life using DLQI demonstrates significant
    improvement in the patients' quality of life after treatment with
    alefacept. The improvement in quality of life as measured by DLQI
    correlates with clinical response as measured by PASI 75, PASI 50,
    and PGA AC/C.

-   The onset of clinical response is seen at 6 weeks after initiation
    of alefacept in most patients. This timing of onset of activity
    corresponds with the maximal reduction in the memory T cells
    associated with alefacept treatment.

-   In the clinical studies, the greatest response rate as measured by
    PASI 75 occurred between 2 to 6 weeks after completion of dosing for
    the three alefacept treatment groups.

-   Clinical response to treatment with alefacept is durable and
    duration of response increases following a second course of
    treatment. These results contrast markedly with the clinical
    experience with cyclosporine or methotrexate where cessation of
    treatment is associated with disease activation.

-   Treatment with two courses of alefacept provides cumulative
    efficacy, i.e., some patients who failed to respond to one course
    experienced a clinical response with a second course.

-   Preliminary results from a study in psoriatic arthritis show
    alefacept to be a promising agent for this indication.

# CLINICAL PHARMACOLOGY

## Pharmacokinetics

The pharmacokinetics of alefacept were characterized in healthy
volunteers and in patients with chronic plaque psoriasis.

In healthy-volunteer studies, single-dose IV administration of alefacept
at doses ranging from 0.005 to 0.225 mg/kg showed that serum alefacept
concentrations were proportional to the dose administered. Clearance,
half-life, and volume of distribution were independent of absolute dose.
In studies of patients with chronic plaque psoriasis, repeat-dose IV
administration at doses ranging from 0.005 to 0.15 mg/kg showed that
steady-state serum alefacept concentrations were proportional to dose.

When administered as a fixed dose of 7.5 mg IV, the half-life of
alefacept was estimated as 267 hours (approximately 11 days), the
clearance as 0.25 mL/h/kg, and the volume of distribution as 94 mL/kg.

## Pharmacodynamic Effects on Peripheral T Cell Counts

Based on the mechanism of action described in Section 1.3, the
pharmacodynamic effects of alefacept on

-   total lymphocyte counts,

-   total CD4+ and CD8+ T cells,

-   memory T cells (CD4+CD45RO+ and CD8+CD45RO+),

-   naïve T cells (CD4+CD45RA+ and CD8+CD45RA+),

-   NK cells, and

-   B cells

were monitored in the two pivotal studies, 711 and 712. Quantification
of counts was conducted at a central laboratory.

### Pharmacodynamics following One Course of Treatment in Patients with Chronic Plaque Psoriasis

The placebo groups in both pivotal studies showed a stable T cell
profile over time. Compared to placebo, treatment with alefacept
resulted in reductions in total lymphocytes (Display 5-1 shows total
lymphocyte counts over time for Study 712), CD4+ and CD8+ T cells, and
in CD4+ and CD8+ memory T cells. For the 10 and 15 mg alefacept IM doses
in Study 712 and the three IV doses evaluated in Study 708, the Phase 2,
dose-response study, the reduction in T cells was dose-dependent.

Consistent with its mechanism of action, treatment with alefacept
resulted in a markedly greater reduction in CD4+ and CD8+ memory T cells
compared to the reduction in CD4+ and CD8+ naïve T cells (Display 5-2).
For both routes of administration, the degree of T cell reduction was
greatest during the first 6 weeks of treatment, after which the rate of
reduction slowed and the T cell count gradually started to increase
after completion of the treatment course. Changes in CD4+ and CD8+
memory T cells are detectable as reductions in total CD4+ and total CD8+
T cells, which together cause reductions in total lymphocyte counts. As
measured by mean percentage change from baseline at 2 weeks post-dosing,
the greatest effects were evident in CD8+ and CD4+ T cells, followed by
total lymphocyte counts (Display 5-2). There was no significant effect
on NK cells or on B cells.

Display 5-1 Study 712: mean lymphocyte count by treatment and time

![](media/image1.wmf)

![](media/image2.wmf)Display 5-2 Study 712: mean percentage change from
baseline in total lymphocyte count and lymphocyte subsets at 2 weeks
post-dosing

The mean counts for total lymphocytes and T cell subsets were within
normal limits during a course of alefacept. However, it is important to
examine if any patients had one or more counts below the lower limit of
normal (LLN). Display 5-3 shows the number of patients who had a total
lymphocyte count, a CD4+ count, or a CD8+ count less than the LLN.

Display 5-3 Numbers of patients with counts \<LLN: 15 mg IM and 7.5 mg
IV

+--------------------------------------+--------------+---------------+
|                                      | 15 mg IM     | 7.5 mg IV     |
|                                      |              |               |
|                                      | (n=166)      | (n=366)       |
+--------------------------------------+--------------+---------------+
| Number (percentage) of patients with |              |               |
+--------------------------------------+--------------+---------------+
| total lymphocytes \<910 cells/uL     | 17 (10)      | 80 (22)       |
| (LLN)                                |              |               |
+--------------------------------------+--------------+---------------+
| total lymphocytes \<500 cells/uL     | 1 (\<1)      | 2 ( 1)        |
+--------------------------------------+--------------+---------------+
| CD4+ count \<404 cells/uL (LLN)      | 52 (31)      | 176 (48)      |
+--------------------------------------+--------------+---------------+
| CD4+ count \<200 cells/uL            | 4 ( 2)       | 11 ( 3)       |
+--------------------------------------+--------------+---------------+
| CD8+ count \<220 cells/uL (LLN)      | 78 (47)      | 217 (59)      |
+--------------------------------------+--------------+---------------+
| CD8+ count \<50 cells/uL             | 3 ( 2)       | 16 ( 4)       |
+--------------------------------------+--------------+---------------+

LLN: lower limit of normal.

*Recovery of T Cells upon Completion of a Course of Alefacept*

In Studies 711 and 712, lymphocytes and T cells were monitored for at
least 12 weeks after treatment. The longest follow-up time after
completion of a single course of treatment with alefacept is provided by
patients in Cohort 2 of Study 711. Patients in this cohort received
placebo as study drug during the second course, enabling the monitoring
of recovery of T cells for a period of 36 weeks following the last dose
of 7.5 mg alefacept IV. If a patient enrolled into Study 724, the
extension to Study 711 described in Section 3.2.2, and participated in
"interim visits" prior to dosing in Study 724, the period of follow-up
is even longer.

The percentage of patients who attained a total lymphocyte count greater
than 75% of baseline at all time points after the last alefacept dose in
Course 1 can be quantified. Display 5-4 shows that 90% of patients had
achieved a lymphocyte count greater than 75% of baseline by 162 days
relative to the visit at 2 weeks post-doing (the first visit after the
last dose). The count does not reach 100% because 8 patients were lost
to follow-up, and although 3 patients have not as yet achieved a count
greater than 75% of baseline, their counts are above the LLN.

As for total lymphocytes, detailed characterization of the rate of
return of the CD4+ T cell count during the follow-up period has also
been performed, in this case, to greater than the LLN (404 cells/μL).
Display 5-5 shows that almost 90% of patients had CD4+ T cell counts at
or above the LLN at 99 days relative to the visit at 2 weeks
post-dosing. Again, the count does not reach 100% because 9 patients
withdrew from the study and 5 patients have yet to reach the LLN.

Display 5-4 Study 711 Cohort 2 (alefacept/placebo): percentage of
patients above 75% of baseline for total lymphocytes

![](media/image3.wmf){width="6.103472222222222in"
height="2.879861111111111in"}

Days after the 2-week post-dosing visit in Course 1

Display 5-5 Study 711 Cohort 2 (alefacept/placebo): percentage of
patients with CD4+ T cell count \>LLN

![](media/image4.wmf){width="6.195833333333334in"
height="3.0097222222222224in"}

Days after the 2-week post-dosing visit in Course 1

### Pharmacodynamic Effects following Additional Courses of Therapy

The effects of alefacept on T cell subsets during the second course were
similar to those seen in the first course. Display 5-6 shows the mean
percentage change from baseline at 2 weeks post-treatment for each
course.

A second course of treatment with alefacept did not demonstrate a
cumulative decrease in total lymphocytes, CD4+ and CD8+ T cell counts.
This stabilization in T cell count is consistent with the more selective
reduction of the memory T cells by alefacept.

![](media/image2.wmf)Display 5-6 Study 711: mean percentage change from
baseline in total lymphocyte count and lymphocyte subsets at 2 weeks
post-dosing in each course

Further evidence of a lack of cumulative effect on lymphocytes and T
cells is provided by the numbers of patients with counts less than the
LLN. Display 5-7 shows these data for Courses 1 and 2 in Study 711. No
increase in the number of patients with counts less than the LLN is
apparent. Also, no evidence of cumulative pharmacodynamic effects after
three courses of 7.5 mg alefacept IV has been seen in an ongoing Phase 2
study (Study 714, Display 3-1).

Display 5-7 Study 711: numbers of patients with counts \<LLN in one and
two courses of 7.5 mg alefacept IV

+--------------------------------------+--------------+---------------+
|                                      | First course | Second course |
|                                      |              |               |
|                                      | (n=366)      | (n=154)       |
+--------------------------------------+--------------+---------------+
| Number (percentage) of patients with |              |               |
+--------------------------------------+--------------+---------------+
| total lymphocytes \<910 cells/uL     | 80 (22)      | 26 (17)       |
| (LLN)                                |              |               |
+--------------------------------------+--------------+---------------+
| total lymphocytes \<500 cells/uL     | 2 ( 1)       | 1 ( 1)        |
+--------------------------------------+--------------+---------------+
| CD4+ count \<404 cells/uL (LLN)      | 176 (48)     | 68 (44)       |
+--------------------------------------+--------------+---------------+
| CD4+ count \<200 cells/uL            | 11 ( 3)      | 4 ( 3)        |
+--------------------------------------+--------------+---------------+
| CD8+ count \<220 cells/uL (LLN)      | 217 (59)     | 86 (56)       |
+--------------------------------------+--------------+---------------+
| CD8+ count \<50 cells/uL             | 16 ( 4)      | 5 ( 3)        |
+--------------------------------------+--------------+---------------+

LLN: lower limit of normal.

## Correlations between Reductions in T Cells and Efficacy

The relationship between reductions in T cell subsets and clinical
response was analyzed. For these analyses, the area-under-the-effect
curve, E~AUC~, based on the percentage change from baseline, was used
(further details are provided in Appendix 2). E~AUC~ represents the
cumulative attrition of cells during the dosing period.

As shown in Display 5-8, an increase in response was seen for each
increasing quartile of E~AUC~ for both subsets of memory T cells. (Q1
denotes the least reduction in T cells while Q4 denotes the greatest
reduction). A similar correlation between E~AUC~ quartiles of memory T
cells and the other clinical outcome measures, i.e., PASI 50 and PGA
AC/C, was also demonstrated.

This correlation between the E~AUC~ of the memory T cells and clinical
response corresponds to that seen between intra-lesional IFNγ+T cells
and clinical response in Study 716 (Section 5.3). These observations are
the first time that targeted reduction of a T cell subset has been
correlated with clinical benefit in an autoimmune disease.

Display 5-8 PASI 75 response rates at 2 weeks post-dosing by E~AUC~
quartiles of memory T cells in Course 1 of Study 711 and Study 712

######## CD4+ memory cells {#cd4-memory-cells .unnumbered}

![](media/image3.wmf){width="5.583333333333333in"
height="1.773611111111111in"}

######## CD8+ memory cells {#cd8-memory-cells .unnumbered}

![](media/image4.wmf){width="5.471527777777778in"
height="1.9652777777777777in"}

Solid bar represents alefacept; open bar represents placebo

E~AUC~ represents the cumulative attrition of cells. E~AUC~ is
calculated for each patient. Those receiving alefacept (irrespective of
dose) are grouped into four "bins" defined by the quartiles. Q1, Q2, Q3,
and Q4 represent these "bins" in each study, with Q1 the lowest
quartile, and Q4 the highest. Patients who received placebo are grouped
according to the quartiles of the alefacept-treated patients.

## Action of Alefacept on Cutaneous T Cells

Study 716 evaluated the effect of alefacept on T cells in the skin and
correlated these changes with those in the periphery. Four patients in
this study had punch and keratome biopsies before and after a course of
7.5 mg alefacept IV. All 4 patients demonstrated a relative reduction of
*in situ* and circulating CD4+ and CD8+ T cells. In all 4 patients, the
percentage change in baseline PASI correlated with the percentage change
in the intra-lesional CD4+ and CD8+ T cells which expressed IFNγ+
(correlation coefficient of 0.68). Patients could be ranked in parallel
by percentage reduction in PASI score, intra-lesional IFNγ+ T cells, and
circulating CD8+ memory T cells. The three patients who had maintained
the greatest reductions in PASI scores had significant reductions in
IFNγ+ T cells at the end of treatment. The down-regulation of IFNγ+
secreting T cells corresponds with data suggesting a critical role of
the Th1 inflammatory cytokine in the keratinocyte hyperproliferation
(Bata-Csorgo *et al,* 1995, Austin *et al*, 1999, Friedrich *et al*,
2000). These data demonstrate that the peripheral lymphocyte reductions
induced by alefacept are associated with T cell reductions in psoriatic
plaques.

## Implications of Reductions in T Cells on Immune Function

While alefacept-mediated lymphocyte effects are predictable and
measurable, it is important to understand safety outcomes based upon
current knowledge of memory T cell function. The primary role of memory
T cells is preventing infections, especially opportunistic infections.
Infections such as pneumocystis carinii pneumonia, toxoplasmosis,
reactivation of herpetic infections, CMV infections, cryptosporidial
infections and a range of candidal disorders are very typically seen in
the context of memory T cell reduction. As described in Section 6, the
risk of infection was thoroughly explored in the alefacept program. The
data indicate no enhanced risk of infection nor a predisposition to
opportunistic infection. To date, no opportunistic infections have been
observed.

The major mechanism by which memory T cells protect from infection is to
amplify and increase the speed of an immune response after re-exposure
to a bacterial or viral antigen. This function was explored in two ways
in the alefacept program: (i) assessment of delayed-type
hypersensitivity (DTH) responses and, (ii) response to immunization in
alefacept-treated patients. In Study 708, the Phase 2, dose-response
study, DTH testing was performed for a range of antigens including
tuberculin, tetanus, and diptheria. Although many patients treated with
placebo exhibited loss of DTH response to one or more of the test
antigens, there was a trend towards a higher proportion losing response
in those treated with alefacept. The ability of patients to mount
humoral immune responses in the face of reductions in T cells was
assayed in Study 718.

Study 718 was conducted to evaluate humoral responses to a neo-antigen
(φX174) and a recall antigen (tetanus toxoid) in patients with chronic
plaque psoriasis treated with 7.5 mg alefacept IV for 12 weeks. Note
that memory T cell function is critical for responses to both antigens.
Patients were randomized to receive either alefacept or no treatment,
the latter group serving as a control (Display 5-9). Alefacept-treated
patients were immunized with φX174 at 6 and 12 weeks during dosing, and
at 8 and 14 weeks after the final dose. Patients were immunized with
tetanus toxoid 9 weeks after the final dose of alefacept. Patients in
the control group received φX174 immunization 6 and 12 weeks after
randomization and a tetanus toxoid immunization at 10 weeks after
randomization. After the vaccination period, patients in the control
group were offered treatment with alefacept.

![](media/image1.wmf)Display 5-9 Design of Study 718

The peak antibody responses following the primary and secondary φX174
immunizations were similar for the control group and the group treated
with alefacept. No patient in either treatment group failed to generate
an IgG anti-φX174 response. The percentage IgG fraction of the
anti-φX174 response after the secondary immunization was comparable
between the groups. The anti-φX174 responses in the alefacept-treated
group were durable as evidenced by a further rise in titer and
percentage IgG fraction following the tertiary immunization (Display
5-10).

![](media/image1.wmf)Display 5-10 Total anti-ϕX174 antibody titers

Baseline titers for anti-tetanus toxoid antibodies were measured both at
the first study visit for each group (study baseline) and immediately
prior to immunization with the tetanus toxoid (pre-immunization
baseline). A two-fold or greater rise in anti-tetanus toxoid response in
relation to the study baseline was demonstrated by 91% and 89% in the
control and alefacept-treated groups, respectively (p = 0.80).

These data demonstrate that immune function as assayed by the ability to

-   mount antibody responses to a new antigen,

-   mount IgG responses despite reductions in memory T cells, and

-   respond to a physiologically relevant antigen, such as tetanus
    toxoid

are preserved during alefacept therapy.

## Summary of Clinical Pharmacology

In summary, the clinical pharmacology data demonstrate the following:

-   Serum concentrations of alefacept are proportional to dose.
    Following IM administration, dose-adjusted bioavailability is
    approximately 70%. The disposition of alefacept is consistent and
    independent of dose. The elimination half-life of alefacept is
    approximately 11 days following IV and IM administration.

-   Treatment with alefacept results in a predictable, dose-dependent,
    mechanism-based reduction in total lymphocyte, CD4+ T cells, CD8+ T
    cells, and CD4+ and CD8+ memory T cells.

-   The maximum effect of alefacept is approximately 6 weeks, after
    which the rate of T cell reduction decreases and T cell counts
    stabilize.

-   There is no cumulative pharmacodynamic effect of alefacept with
    repeat courses of therapy.

-   Recovery of T cells occurs with withdrawal of alefacept treatment.

-   Recovery of T cells is similar with repeat administration of
    alefacept.

-   Treatment with alefacept does not interfere with the immune response
    to recall or neo-antigens.

-   The degree of T cell reduction, as measured by E~AUC~, is correlated
    with clinical efficacy. This correlation supports the hypothesis
    that clinical response results from targeted reduction of the CD4+
    and CD8+ memory T cells by alefacept.

# CLINICAL SAFETY

This section presents an integrated analysis of the safety profile of
alefacept in psoriasis following single and multiple courses of therapy.
The integrated database is comprised of data from ten clinical studies
of patients with psoriasis:

-   three Phase 2 dose-escalation studies, Studies 703, 705, and 709;

-   three double-blind, placebo-controlled studies: the Phase 2
    dose-response study (708), and the two Phase 3 studies, 711 and 712;

-   two extension studies, 710 and 714, where patients who had
    participated in the Phase 2 studies received additional courses of
    therapy; and

-   two extension studies, 717 and 724, where patients who had
    participated in the two Phase 3 studies received additional courses
    of therapy.

With the exception of Studies 703 and 705 where a total of 51 patients
were enrolled and received one infusion, one course of alefacept is
comprised of 12 weeks of once-weekly dosing and a minimum of 12 weeks of
follow-up. Since the duration of effect of alefacept is long, safety
events reported during the 12 weeks of follow-up are included. In total,
the safety profile of alefacept is based on 1056 patient-years of
exposure.

Safety data have been analyzed in two ways:

-   a comparison of the safety profile of alefacept with that of placebo
    from the placebo-controlled, single-course experience (413 patients
    received placebo and 876 received alefacept; Display 6-1), and

-   a comparison of the safety profiles of multiple courses of alefacept
    to allow an understanding of the long-term adverse event profile
    (Display 6-1).

In addition, the incidence of infections and the incidence of
malignancies, events of particular concern with products that affect the
immune system, are presented.

Display 6-1 Number of patients in analyses of safety

+-------------------------------------------+------------+------------+
|                                           | Placebo    | Alefacept  |
+-------------------------------------------+------------+------------+
| First-course exposure in                  | 413 (a)    | 876 (b)    |
| placebo-controlled studies                |            |            |
|                                           | NA         | 1357 (c)   |
| Number of patients who have received at   |            |            |
| least                                     | NA         | 756        |
|                                           |            |            |
| 1 course of alefacept                     | NA         | 199        |
|                                           |            |            |
| 2 courses of alefacept                    | NA         | 81         |
|                                           |            |            |
| 3 courses of alefacept                    | NA         | 46         |
|                                           |            |            |
| 4 courses of alefacept                    | NA         | 13         |
|                                           |            |            |
| 5 courses of alefacept                    |            |            |
|                                           |            |            |
| 6 courses of alefacept                    |            |            |
+-------------------------------------------+------------+------------+

NA: Not applicable. Patients in (a) and (b) are distinct. Patients in
(c) include those in (b),

and those in (a) who received alefacept for the first time in a
subsequent course.

## Non-serious Adverse Events

The most common adverse events reported by patients receiving alefacept
in placebo-controlled studies were headache (18% placebo *vs* 17%
alefacept), accidental injury (13% *vs* 15%), pharyngitis (13% *vs*
15%), infection (11% *vs* 11%), pruritus (8% *vs* 11%), and rhinitis
(10% *vs* 11%). The incidence of adverse events with the first course of
study drug was similar between alefacept and placebo in the controlled
studies (Display 6-2). The only adverse event that occurred at least 5%
higher in incidence among alefacept-treated patients compared to
placebo-treated patients in the first course was chills (1% placebo *vs*
6% alefacept). Episodes of chills were reported within 24 hours of study
drug infusion but their incidence did not increase with subsequent
courses of treatment (Display 6-3).

The incidence of adverse events did not increase with subsequent courses
of alefacept treatment: 83%, 74%, 64%, 72%, and 61% of patients had at
least one adverse event in the first, second, third, fourth and fifth
courses of alefacept, respectively (Display 6-3).

Display 6-2 Incidence of adverse events in the first course of
placebo-controlled studies experienced by at least 5% of patients who
received alefacept

+-----------------------------+--------------------+--------------------+
|                             | Placebo-controlled |                    |
|                             | studies            |                    |
+-----------------------------+--------------------+--------------------+
|                             | Placebo            | Alefacept          |
+-----------------------------+--------------------+--------------------+
| No. of patients dosed       | 413 (100)          | 876 (100)          |
+-----------------------------+--------------------+--------------------+
| No. with an event           | 327 ( 79)          | 730 ( 83)          |
+-----------------------------+--------------------+--------------------+
| Event                       | 74 ( 18)           | 151 ( 17)          |
|                             |                    |                    |
| Headache                    | 52 ( 13)           | 134 ( 15)          |
|                             |                    |                    |
| Accidental injury           | 55 ( 13)           | 130 ( 15)          |
|                             |                    |                    |
| Pharyngitis                 | 45 ( 11)           | 98 ( 11)           |
|                             |                    |                    |
| Infection                   | 34 ( 8)            | 97 ( 11)           |
|                             |                    |                    |
| Pruritus                    | 40 ( 10)           | 92 ( 11)           |
|                             |                    |                    |
| Rhinitis                    | 36 ( 9)            | 80 ( 9)            |
|                             |                    |                    |
| Flu syndrome                | 28 ( 7)            | 52 ( 6)            |
|                             |                    |                    |
| Viral infection             | 28 ( 7)            | 51 ( 6)            |
|                             |                    |                    |
| Asthenia                    | 5 ( 1)             | 50 ( 6)            |
|                             |                    |                    |
| Chills                      | 21 ( 5)            | 50 ( 6)            |
|                             |                    |                    |
| Pain                        | 22 ( 5)            | 48 ( 5)            |
|                             |                    |                    |
| Diarrhea                    | 13 ( 3)            | 44 ( 5)            |
|                             |                    |                    |
| Dizziness                   | 24 ( 6)            | 42 ( 5)            |
|                             |                    |                    |
| Arthralgia                  | 14 ( 3)            | 42 ( 5)            |
|                             |                    |                    |
| Nausea                      |                    |                    |
+-----------------------------+--------------------+--------------------+

NOTE: Numbers in parentheses are percentages.

Events are listed by decreasing incidence in those who received
alefacept.

Display 6-3 Incidence of adverse events experienced by at least 5% of
patients by course of alefacept

+------------------+---------+---------+---------+---------+---------+
|                  | Course  |         |         |         |         |
|                  | of      |         |         |         |         |
|                  | al      |         |         |         |         |
|                  | efacept |         |         |         |         |
+------------------+---------+---------+---------+---------+---------+
|                  | First   | Second  | Third   | Fourth  | Fifth   |
+------------------+---------+---------+---------+---------+---------+
| No. of patients  | 1357    | 756     | 199     | 81      | 46      |
| dosed            | (100)   | (100)   | (100)   | (100)   | (100)   |
+------------------+---------+---------+---------+---------+---------+
| No. with an      | 1121 (  | 560 (   | 128 (   | 58 (    | 28 (    |
| event            | 83)     | 74)     | 64)     | 72)     | 61)     |
+------------------+---------+---------+---------+---------+---------+
| Event            | 219 (   | 71 ( 9) | 15 ( 8) | 5 ( 6)  | 2 ( 4)  |
|                  | 16)     |         |         |         |         |
| Headache         |         | 130 (   | 18 ( 9) | 11 (    | 4 ( 9)  |
|                  | 218 (   | 17)     |         | 14)     |         |
| Accidental       | 16)     |         | 15 ( 8) |         | 1 ( 2)  |
| injury           |         | 92 (    |         | 6 ( 7)  |         |
|                  | 205 (   | 12)     | 15 ( 8) |         | 3 ( 7)  |
| Pharyngitis      | 15)     |         |         | 12 (    |         |
|                  |         | 76 (    | 14 ( 7) | 15)     | 1 ( 2)  |
| Infection        | 151 (   | 10)     |         |         |         |
|                  | 11)     |         | 7 ( 4)  | 4 ( 5)  | 2 ( 4)  |
| Rhinitis         |         | 66 ( 9) |         |         |         |
|                  | 145 (   |         | 5 ( 3)  | 8 ( 10) | 3 ( 7)  |
| Flu syndrome     | 11)     | 55 ( 7) |         |         |         |
|                  |         |         | 13 ( 7) | 4 ( 5)  | 1 ( 2)  |
| Pruritus         | 133 (   | 41 ( 5) |         |         |         |
|                  | 10)     |         | 15 ( 8) | 7 ( 9)  | 3 ( 7)  |
| Viral infection  |         | 51 ( 7) |         |         |         |
|                  | 116 (   |         | 5 ( 3)  | 5 ( 6)  | 1 ( 2)  |
| Pain             | 9)      | 38 ( 5) |         |         |         |
|                  |         |         | 1 (     | 0       | 0       |
| Asthenia         | 79 ( 6) | 23 ( 3) | \<1)    |         |         |
|                  |         |         |         | 0       | 0       |
| Chills           | 78 ( 6) | 11 ( 1) | 2 ( 1)  |         |         |
|                  |         |         |         | 0       | 0       |
| Diarrhea         | 74 ( 5) | 16 ( 2) | 6 ( 3)  |         |         |
|                  |         |         |         | 1 ( 1)  | 0       |
| Nausea           | 73 ( 5) | 20 ( 3) | 3 ( 2)  |         |         |
|                  |         |         |         | 1 ( 1)  | 1 ( 2)  |
| Arthralgia       | 71 ( 5) | 15 ( 2) | 11 ( 6) |         |         |
|                  |         |         |         | 0       | 3 ( 7)  |
| Sinusitis        | 68 ( 5) | 29 ( 4) | 0       |         |         |
|                  |         |         |         | 1 ( 1)  |         |
| Dyspepsia        | 65 ( 5) | 14 ( 2) |         |         |         |
|                  |         |         |         |         |         |
|                  | 56 ( 4) |         |         |         |         |
|                  |         |         |         |         |         |
|                  | 19 ( 1) |         |         |         |         |
+------------------+---------+---------+---------+---------+---------+

NOTE: Numbers in parentheses are percentages.

Events are listed by decreasing incidence in the first course.

Display 6-4 shows the incidence of common adverse events by route of
administration for the Phase 3 studies.

Of the events with an incidence of 5% or more, those that occurred more
frequently in patients receiving 7.5 mg alefacept IV compared to those
receiving 15 mg alefacept IM include accidental injury (7.5 mg alefacept
IV *vs* 15 mg alefacept IM: 20% *vs* 10%), rhinitis (12% *vs* 5%), and
chills (10% *vs* 2%).

Adverse events that occurred more frequently in patients receiving 15 mg
alefacept IM compared to those receiving 7.5 mg alefacept IV include
pruritus (15 mg alefacept IM *vs* 7.5 mg alefacept IV: 18% *vs* 11%),
infection (16% *vs* 10%), asthenia (11% *vs* 4%), injection site pain
(9% *vs* \<1%), injection site reaction (5% *vs* 0%), and injection site
inflammation (5% *vs* 0%). Injection site reactions were generally mild
in severity.

Display 6-4 Adverse events with an incidence of 5% or more in the first
course of phase 3 studies (by route of administration)

+---------------------+--------+--------+---+--------+--------+--------+
|                     | Phase  |        |   |        |        |        |
|                     | 3      |        |   |        |        |        |
|                     | s      |        |   |        |        |        |
|                     | tudies |        |   |        |        |        |
+---------------------+--------+--------+---+--------+--------+--------+
|                     | P      |        |   | Ale    |        |        |
|                     | lacebo |        |   | facept |        |        |
+---------------------+--------+--------+---+--------+--------+--------+
|                     | IV     | IM     |   | 7.5 mg | 10 mg  | 15 mg  |
|                     |        |        |   | IV     | IM     | IM     |
+---------------------+--------+--------+---+--------+--------+--------+
| No. of patients     | 186    | 168    |   | 367    | 173    | 166    |
| dosed               | (100)  | (100)  |   | (100)  | (100)  | (100)  |
+---------------------+--------+--------+---+--------+--------+--------+
| No. with an event   | 143 (  | 139 (  |   | 310 (  | 139 (  | 145 (  |
|                     | 77)    | 83)    |   | 84)    | 80)    | 87)    |
+---------------------+--------+--------+---+--------+--------+--------+
| Event               | 30 (   | 19 (   |   | 73 (   | 22 (   | 16 (   |
|                     | 16)    | 11)    |   | 20)    | 13)    | 10)    |
| Accidental injury   |        |        |   |        |        |        |
|                     | 38 (   | 26 (   |   | 62 (   | 34 (   | 30 (   |
| Headache            | 20)    | 15)    |   | 17)    | 20)    | 18)    |
|                     |        |        |   |        |        |        |
| Pharyngitis         | 23 (   | 15 (   |   | 52 (   | 20 (   | 20 (   |
|                     | 12)    | 9)     |   | 14)    | 12)    | 12)    |
| Rhinitis            |        |        |   |        |        |        |
|                     | 21 (   | 11 (   |   | 43 (   | 24 (   | 9 ( 5) |
| Pruritus            | 11)    | 7)     |   | 12)    | 14)    |        |
|                     |        |        |   |        |        | 30 (   |
| Chills              | 16 (   | 16 (   |   | 40 (   | 24 (   | 18)    |
|                     | 9)     | 10)    |   | 11)    | 14)    |        |
| Flu syndrome        |        |        |   |        |        | 4 ( 2) |
|                     | 2 ( 1) | 3 ( 2) |   | 37 (   | 1 (    |        |
| Infection           |        |        |   | 10)    | \<1)   | 14 (   |
|                     | 15 (   | 18 (   |   |        |        | 8)     |
| Viral infection     | 8)     | 11)    |   | 37 (   | 14 (   |        |
|                     |        |        |   | 10)    | 8)     | 26 (   |
| Pain                | 20 (   | 19 (   |   |        |        | 16)    |
|                     | 11)    | 11)    |   | 35 (   | 25 (   |        |
| Back pain           |        |        |   | 10)    | 14)    | 10 (   |
|                     | 12 (   | 16 (   |   |        |        | 6)     |
| Myalgia             | 6)     | 10)    |   | 29 (   | 13 (   |        |
|                     |        |        |   | 8)     | 8)     | 11 (   |
| Sinusitis           | 11 (   | 8 ( 5) |   |        |        | 7)     |
|                     | 6)     |        |   | 26 (   | 8 ( 5) |        |
| Arthralgia          |        | 8 ( 5) |   | 7)     |        | 4 ( 2) |
|                     | 5 ( 3) |        |   |        | 4 ( 2) |        |
| Diarrhea            |        | 4 ( 2) |   | 20 (   |        | 5 ( 3) |
|                     | 3 ( 2) |        |   | 5)     | 3 ( 2) |        |
| Arthritis           |        | 5 ( 3) |   |        |        | 4 ( 2) |
|                     | 10 (   |        |   | 20 (   | 6 ( 3) |        |
| Dizziness           | 5)     | 16 (   |   | 5)     |        | 10 (   |
|                     |        | 10)    |   |        | 8 ( 5) | 6)     |
| Asthenia            | 6 ( 3) |        |   | 19 (   |        |        |
|                     |        | 12 (   |   | 5)     | 11 (   | 8 ( 5) |
| Nausea              | 9 ( 5) | 7)     |   |        | 6)     |        |
|                     |        |        |   | 18 (   |        | 7 ( 4) |
| Hypertension        | 5 ( 3) | 4 ( 2) |   | 5)     | 4 ( 2) |        |
|                     |        |        |   |        |        | 6 ( 4) |
| Tooth disorder      | 6 ( 3) | 6 ( 4) |   | 18 (   | 6 ( 3) |        |
|                     |        |        |   | 5)     |        | 18 (   |
| Peripheral edema    | 9 ( 5) | 18 (   |   |        | 10 (   | 11)    |
|                     |        | 11)    |   | 17 (   | 6)     |        |
| Gastroenteritis     | 8 ( 4) |        |   | 5)     |        | 6 ( 4) |
|                     |        | 6 ( 4) |   |        | 13 (   |        |
| Injection site pain | 6 ( 3) |        |   | 17 (   | 8)     | 7 ( 4) |
|                     |        | 3 ( 2) |   | 5)     |        |        |
| Injection site      | 4 ( 2) |        |   |        | 8 ( 5) | 8 ( 5) |
| reaction            |        | 2 ( 1) |   | 16 (   |        |        |
|                     | 3 ( 2) |        |   | 4)     | 5 ( 3) | 2 ( 1) |
| Injection site      |        | 8 ( 5) |   |        |        |        |
| inflammation        | 6 ( 3) |        |   | 13 (   | 6 ( 3) | 1 (    |
|                     |        | 2 ( 1) |   | 4)     |        | \<1)   |
| Injection site      | 0      |        |   |        | 8 ( 5) |        |
| hemorrhage          |        | 4 ( 2) |   | 11 (   |        | 15 (   |
|                     | 0      |        |   | 3)     | 8 ( 5) | 9)     |
|                     |        | 1 (    |   |        |        |        |
|                     | 0      | \<1)   |   | 9 ( 2) | 1 (    | 9 ( 5) |
|                     |        |        |   |        | \<1)   |        |
|                     | 0      | 0      |   | 8 ( 2) |        | 8 ( 5) |
|                     |        |        |   |        | 5 ( 3) |        |
|                     |        | 10 (   |   | 6 ( 2) |        | 5 ( 3) |
|                     |        | 6)     |   |        | 11 (   |        |
|                     |        |        |   | 1 (    | 6)     |        |
|                     |        |        |   | \<1)   |        |        |
|                     |        |        |   |        |        |        |
|                     |        |        |   | 0      |        |        |
|                     |        |        |   |        |        |        |
|                     |        |        |   | 0      |        |        |
|                     |        |        |   |        |        |        |
|                     |        |        |   | 0      |        |        |
+---------------------+--------+--------+---+--------+--------+--------+

NOTE: Numbers in parentheses are percentages.

Events are listed by decreasing incidence in those who received 7.5 mg
alefacept IV.

## Deaths, Serious Adverse Events, and Adverse Events Leading to Discontinuation of Study Drug

### Deaths

Three deaths following treatment with alefacept have been reported. All
were considered by the principal investigator to be unrelated to study
drug.

-   A 34-year old man enrolled in Study 711 had a 26-year history of
    psoriasis with no known history of depression, psychiatric illness,
    or other chronic diseases, although there was a family history of
    suicide. The patient received 11 doses of 7.5 mg alefacept IV in
    Course 1 and withdrew from the study due to worsening of disease.
    Eleven weeks after his last dose of alefacept, the patient committed
    suicide.

-   A 47-year old man with a past history of coronary artery disease,
    hypertension, obesity (111 kg), smoking, and gout was enrolled into
    Study 714 and died due to myocardial infarction 6 weeks after his
    last dose of 7.5 mg alefacept IV.

-   A 53-year old man with a past history of diaphragmatic hernia and
    Barrett's esophagus received a course of 15 mg alefacept IM in Study
    712 and a further course of 15 mg IM in Study 717. He was diagnosed
    with an 8.5 cm poorly differentiated esophageal carcinoma 1 week
    after his last dose in Study 717. An abdominal CT scan was negative
    for metastatic disease. He was treated with palliative radiation
    therapy and stent placement. He was prematurely withdrawn from the
    study due to the event. The patient died 9 months after diagnosis
    due to esophageal adenocarcinoma.

One patient died of a myocardial infarction after being enrolled into,
and randomized in Study 712, but prior to receiving any study drug.

### Serious Adverse Events

The proportion of patients who experienced a serious adverse event was
similar between the placebo and alefacept treatment groups (Display
6-5). In placebo-controlled studies, 19 patients (5%) who received
placebo and 42 patients (5%) who received alefacept in the first course
experienced at least one serious adverse event.

Many of the current immunosuppressant therapies are associated with
disease flare or rebound after treatment is stopped that sometimes
necessitates hospitalization. The most common serious adverse event was
hospitalization for psoriasis experienced by 6 patients (1%) who
received placebo and by 2 alefacept-treated patients (\<1%). This
difference is important since the period of reporting serious adverse
events includes the 12 weeks of dosing and the 12 weeks of follow-up. No
patient who responded to alefacept experienced rebound of disease
requiring hospitalization.

The most frequently reported serious adverse events among
alefacept-treated patients were coronary artery disorder (4 patients),
cellulitis (3 patients), and myocardial infarction (3 patients). Each of
these serious adverse events were observed at a rate of \<1% in
alefacept-treated patients and were not observed in placebo-treated
patients. However, the number of patients exposed to placebo is less
than half of those treated with alefacept. No events in either the
alefacept or placebo groups were observed at an incidence of 1% or more.
The risk of serious adverse events did not increase with multiple
courses (Display 6-6).

Display 6-5 Incidence of serious adverse events in the first course of
placebo-controlled studies

+-----------------------------------+----------------+-----------------+
|                                   | Plac           |                 |
|                                   | ebo-controlled |                 |
|                                   | studies        |                 |
+-----------------------------------+----------------+-----------------+
|                                   | Placebo        | Alefacept       |
+-----------------------------------+----------------+-----------------+
| No. of patients dosed             | 413 (100)      | 876 (100)       |
+-----------------------------------+----------------+-----------------+
| No. with a serious event          | 19 ( 5)        | 42 ( 5)         |
+-----------------------------------+----------------+-----------------+
| Event                             | 0              | 4 ( \<1)        |
|                                   |                |                 |
| Coronary artery disorder          | 0              | 3 ( \<1)        |
|                                   |                |                 |
| Cellulitis                        | 0              | 3 ( \<1)        |
|                                   |                |                 |
| Myocardial infarct                | 0              | 2 ( \<1)        |
|                                   |                |                 |
| Accidental injury                 | 0              | 2 ( \<1)        |
|                                   |                |                 |
| Carcinoma                         | 1 ( \<1)       | 2 ( \<1)        |
|                                   |                |                 |
| Chest pain                        | 0              | 2 ( \<1)        |
|                                   |                |                 |
| Diabetes mellitus                 | 0              | 2 ( \<1)        |
|                                   |                |                 |
| Gastroenteritis                   | 1 ( \<1)       | 2 ( \<1)        |
|                                   |                |                 |
| Pancreatitis                      | 6 ( 1)         | 2 ( \<1)        |
|                                   |                |                 |
| Psoriasis                         | 0              | 1 ( \<1)        |
|                                   |                |                 |
| Abscess                           | 0              | 1 ( \<1)        |
|                                   |                |                 |
| Angioedema                        | 1 ( \<1)       | 1 ( \<1)        |
|                                   |                |                 |
| Arthritis                         | 0              | 1 ( \<1)        |
|                                   |                |                 |
| Asthma                            | 0              | 1 ( \<1)        |
|                                   |                |                 |
| Atrial fibrillation               | 0              | 1 ( \<1)        |
|                                   |                |                 |
| AV block complete                 | 0              | 1 ( \<1)        |
|                                   |                |                 |
| Back pain                         | 0              | 1 ( \<1)        |
|                                   |                |                 |
| Bursitis                          | 2 ( \<1)       | 1 ( \<1)        |
|                                   |                |                 |
| Cholelithiasis                    | 0              | 1 ( \<1)        |
|                                   |                |                 |
| Congestive heart failure          | 1 ( \<1)       | 1 ( \<1)        |
|                                   |                |                 |
| Infection                         | 1 ( \<1)       | 1 ( \<1)        |
|                                   |                |                 |
| Kidney calculus                   | 0              | 1 ( \<1)        |
|                                   |                |                 |
| Menorrhagia                       | 0              | 1 ( \<1)        |
|                                   |                |                 |
| Pleural effusion                  | 1 ( \<1)       | 1 ( \<1)        |
|                                   |                |                 |
| Prostatic carcinoma               | 0              | 1 ( \<1)        |
|                                   |                |                 |
| Skin carcinoma                    | 0              | 1 ( \<1)        |
|                                   |                |                 |
| Skin melanoma                     | 0              | 1 ( \<1)        |
|                                   |                |                 |
| Suicide attempt                   | 1 ( \<1)       | 0               |
|                                   |                |                 |
| Angina pectoris                   | 1 ( \<1)       | 0               |
|                                   |                |                 |
| Arthralgia                        | 1 ( \<1)       | 0               |
|                                   |                |                 |
| Bronchitis                        | 1 ( \<1)       | 0               |
|                                   |                |                 |
| Gastrointestinal disorder         | 1 ( \<1)       | 0               |
|                                   |                |                 |
| Gum hemorrhage                    | 2 ( \<1)       | 0               |
|                                   |                |                 |
| Hernia                            | 1 ( \<1)       | 0               |
|                                   |                |                 |
| Pain                              | 1 ( \<1)       | 0               |
|                                   |                |                 |
| Rectal hemorrhage                 | 1 ( \<1)       | 0               |
|                                   |                |                 |
| Syncope                           |                |                 |
+-----------------------------------+----------------+-----------------+

NOTE: Numbers in parentheses are percentages.

Events are listed by decreasing incidence in those who received
alefacept.

Display 6-6 Incidence of serious adverse events by course of alefacept

+---------------------+--------+--------+---------+---------+---------+
|                     | Course |        |         |         |         |
|                     | of     |        |         |         |         |
|                     | ale    |        |         |         |         |
|                     | facept |        |         |         |         |
+---------------------+--------+--------+---------+---------+---------+
|                     | First  | Second | Third   | Fourth  | Fifth   |
+---------------------+--------+--------+---------+---------+---------+
| No. of patients     | 1357   | 756    | 199     | 81      | 46      |
| dosed               | (100)  | (100)  | (100)   | (100)   | (100)   |
+---------------------+--------+--------+---------+---------+---------+
| No. with a serious  | 67 (   | 30 (   | 9 ( 5)  | 0       | 1 ( 2)  |
| event               | 5)     | 4)     |         |         |         |
+---------------------+--------+--------+---------+---------+---------+
| Event               | 5 (    | 5 (    | 1 (     | 0       | 0       |
|                     | \<1)   | \<1)   | \<1)    |         |         |
| Accidental injury   |        |        |         | 0       | 0       |
|                     | 5 (    | 0      | 0       |         |         |
| Psoriasis           | \<1)   |        |         | 0       | 0       |
|                     |        | 0      | 0       |         |         |
| Cellulitis          | 4 (    |        |         | 0       | 0       |
|                     | \<1)   | 0      | 0       |         |         |
| Coronary artery     |        |        |         | 0       | 0       |
| disorder            | 4 (    | 1 (    | 0       |         |         |
|                     | \<1)   | \<1)   |         | 0       | 0       |
| Skin carcinoma      |        |        | 0       |         |         |
|                     | 4 (    | 0      |         | 0       | 0       |
| Chest pain          | \<1)   |        | 0       |         |         |
|                     |        | 4 (    |         | 0       | 0       |
| Cholelithiasis      | 3 (    | \<1)   | 0       |         |         |
|                     | \<1)   |        |         | 0       | 1 ( 2)  |
| Diabetes mellitus   |        | 0      | 1 (     |         |         |
|                     | 3 (    |        | \<1)    | 0       | 0       |
| Myocardial infarct  | \<1)   | 0      |         |         |         |
|                     |        |        | 1 (     | 0       | 0       |
| Asthma              | 3 (    | 0      | \<1)    |         |         |
|                     | \<1)   |        |         | 0       | 0       |
| Carcinoma           |        | 1 (    | 0       |         |         |
|                     | 3 (    | \<1)   |         | 0       | 0       |
| Gastroenteritis     | \<1)   |        | 0       |         |         |
|                     |        | 1 (    |         | 0       | 0       |
| Hernia              | 2 (    | \<1)   | 0       |         |         |
|                     | \<1)   |        |         | 0       | 0       |
| Infection           |        | 0      | 1 (     |         |         |
|                     | 2 (    |        | \<1)    | 0       | 0       |
| Infection bacterial | \<1)   | 2 (    |         |         |         |
|                     |        | \<1)   | 0       | 0       | 0       |
| Pancreatitis        | 2 (    |        |         |         |         |
|                     | \<1)   | 0      | 0       | 0       | 0       |
| Suicide attempt     |        |        |         |         |         |
|                     | 2 (    | 0      | 0       | 0       | 0       |
| Abscess             | \<1)   |        |         |         |         |
|                     |        | 0      | 0       | 0       | 0       |
| Acute kidney        | 2 (    |        |         |         |         |
| failure             | \<1)   | 0      | 0       | 0       | 0       |
|                     |        |        |         |         |         |
| Angioedema          | 2 (    | 0      | 0       | 0       | 0       |
|                     | \<1)   |        |         |         |         |
| Arthritis           |        | 0      | 0       | 0       | 0       |
|                     | 2 (    |        |         |         |         |
| Atrial fibrillation | \<1)   | 1 (    | 0       | 0       | 0       |
|                     |        | \<1)   |         |         |         |
| AV block complete   | 2 (    |        | 0       | 0       | 0       |
|                     | \<1)   | 0      |         |         |         |
| Back pain           |        |        | 0       | 0       | 0       |
|                     | 1 (    | 0      |         |         |         |
| Bursitis            | \<1)   |        | 0       | 0       | 0       |
|                     |        | 0      |         |         |         |
| Cerebrovascular     | 1 (    |        | 0       | 0       | 0       |
| accident            | \<1)   | 0      |         |         |         |
|                     |        |        | 0       | 0       | 0       |
| Cholecystitis       | 1 (    | 0      |         |         |         |
|                     | \<1)   |        | 0       | 0       | 0       |
| Congestive heart    |        | 2 (    |         |         |         |
| failure             | 1 (    | \<1)   | 0       | 0       | 0       |
|                     | \<1)   |        |         |         |         |
| Duodenal ulcer      |        | 0      | 0       | 0       | 0       |
| hemorrhage          | 1 (    |        |         |         |         |
|                     | \<1)   | 0      | 1 (     | 0       | 0       |
| Dysuria             |        |        | \<1)    |         |         |
|                     | 1 (    | 0      |         | 0       | 0       |
| Gastrointestinal    | \<1)   |        | 0       |         |         |
| disorder            |        | 1 (    |         | 0       | 0       |
|                     | 1 (    | \<1)   | 0       |         |         |
| Kidney calculus     | \<1)   |        |         | 0       | 0       |
|                     |        | 0      | 0       |         |         |
| Menorrhagia         | 1 (    |        |         | 0       | 0       |
|                     | \<1)   | 0      | 0       |         |         |
| Obesity             |        |        |         | 0       | 0       |
|                     | 1 (    | 2 (    | 0       |         |         |
| Ovarian disorder    | \<1)   | \<1)   |         | 0       | 0       |
|                     |        |        | 0       |         |         |
| Pain                | 1 (    | 0      |         | 0       | 0       |
|                     | \<1)   |        | 0       |         |         |
| Pleural effusion    |        | 0      |         | 0       | 0       |
|                     | 1 (    |        | 0       |         |         |
| Prostatic carcinoma | \<1)   | 0      |         | 0       | 0       |
|                     |        |        | 0       |         |         |
| Pruritus            | 1 (    | 0      |         | 0       | 0       |
|                     | \<1)   |        | 0       |         |         |
| Rectal hemorrhage   |        | 0      |         | 0       | 0       |
|                     | 1 (    |        | 0       |         |         |
| Scleritis           | \<1)   | 0      |         | 0       | 0       |
|                     |        |        | 0       |         |         |
| Shock               | 1 (    | 0      |         | 0       | 0       |
|                     | \<1)   |        | 0       |         |         |
| Skin melanoma       |        | 0      |         | 0       | 0       |
|                     | 1 (    |        | 0       |         |         |
| Angina pectoris     | \<1)   | 0      |         | 0       | 0       |
|                     |        |        | 1 (     |         |         |
| Bone disorder       | 1 (    | 1 (    | \<1)    | 0       | 0       |
|                     | \<1)   | \<1)   |         |         |         |
| Bronchitis          |        |        | 1 (     | 0       | 0       |
|                     | 1 (    | 1 (    | \<1)    |         |         |
| Carcinoma of lung   | \<1)   | \<1)   |         | 0       | 0       |
|                     |        |        | 0       |         |         |
| Coronary occlusion  | 1 (    | 0      |         | 0       | 0       |
|                     | \<1)   |        | 0       |         |         |
| Drug dependence     |        | 0      |         | 0       | 0       |
|                     | 1 (    |        | 0       |         |         |
| Gastrointestinal    | \<1)   | 1 (    |         |         |         |
| carcinoma           |        | \<1)   | 0       |         |         |
|                     | 1 (    |        |         |         |         |
| Hemorrhage          | \<1)   | 1 (    | 1 (     |         |         |
|                     |        | \<1)   | \<1)    |         |         |
| Hemorrhage of colon | 1 (    |        |         |         |         |
|                     | \<1)   | 1 (    | 0       |         |         |
| Herpes simplex      |        | \<1)   |         |         |         |
|                     | 1 (    |        |         |         |         |
|                     | \<1)   | 1 (    |         |         |         |
|                     |        | \<1)   |         |         |         |
|                     | 1 (    |        |         |         |         |
|                     | \<1)   | 0      |         |         |         |
|                     |        |        |         |         |         |
|                     | 1 (    | 1 (    |         |         |         |
|                     | \<1)   | \<1)   |         |         |         |
|                     |        |        |         |         |         |
|                     | 1 (    |        |         |         |         |
|                     | \<1)   |        |         |         |         |
|                     |        |        |         |         |         |
|                     | 1 (    |        |         |         |         |
|                     | \<1)   |        |         |         |         |
|                     |        |        |         |         |         |
|                     | 0      |        |         |         |         |
|                     |        |        |         |         |         |
|                     | 0      |        |         |         |         |
|                     |        |        |         |         |         |
|                     | 0      |        |         |         |         |
|                     |        |        |         |         |         |
|                     | 0      |        |         |         |         |
|                     |        |        |         |         |         |
|                     | 0      |        |         |         |         |
|                     |        |        |         |         |         |
|                     | 0      |        |         |         |         |
|                     |        |        |         |         |         |
|                     | 0      |        |         |         |         |
|                     |        |        |         |         |         |
|                     | 0      |        |         |         |         |
|                     |        |        |         |         |         |
|                     | 0      |        |         |         |         |
|                     |        |        |         |         |         |
|                     | 0      |        |         |         |         |
+---------------------+--------+--------+---------+---------+---------+

NOTE: Numbers in parentheses are percentages.

Events are listed by decreasing incidence in the first course.

Display 6-6 Incidence of serious adverse events by course of alefacept
(continued)

+---------------------+--------+--------+---------+---------+---------+
|                     | Course |        |         |         |         |
|                     | of     |        |         |         |         |
|                     | ale    |        |         |         |         |
|                     | facept |        |         |         |         |
+---------------------+--------+--------+---------+---------+---------+
|                     | First  | Second | Third   | Fourth  | Fifth   |
+---------------------+--------+--------+---------+---------+---------+
| No. of patients     | 1357   | 756    | 199     | 81      | 46      |
| dosed               | (100)  | (100)  | (100)   | (100)   | (100)   |
+---------------------+--------+--------+---------+---------+---------+
| No. with a serious  | 67 (   | 30 (   | 9 ( 5)  | 0       | 1 ( 2)  |
| event               | 5)     | 4)     |         |         |         |
+---------------------+--------+--------+---------+---------+---------+
| Event               | 0      | 1 (    | 0       | 0       | 0       |
|                     |        | \<1)   |         |         |         |
| Hyperglycemia       | 0      |        | 1 (     | 0       | 0       |
|                     |        | 0      | \<1)    |         |         |
| Lung fibrosis       | 0      |        |         | 0       | 0       |
|                     |        | 1 (    | 0       |         |         |
| Nasal septum        | 0      | \<1)   |         | 0       | 0       |
| disorder            |        |        | 0       |         |         |
|                     | 0      | 1 (    |         | 0       | 0       |
| Peripheral vascular |        | \<1)   | 0       |         |         |
| disorder            | 0      |        |         | 0       | 0       |
|                     |        | 1 (    | 1 (     |         |         |
| Peritonitis         | 0      | \<1)   | \<1)    | 0       | 0       |
|                     |        |        |         |         |         |
| Pneumonia           | 0      | 2 (    | 0       | 0       | 0       |
|                     |        | \<1)   |         |         |         |
| Pulmonary           | 0      |        | 0       | 0       | 0       |
| hypertension        |        | 1 (    |         |         |         |
|                     | 0      | \<1)   | 0       | 0       | 0       |
| Skin disorder       |        |        |         |         |         |
|                     |        | 1 (    | 0       |         |         |
| Thrombophlebitis    |        | \<1)   |         |         |         |
|                     |        |        |         |         |         |
| Urinary             |        | 1 (    |         |         |         |
| incontinence        |        | \<1)   |         |         |         |
|                     |        |        |         |         |         |
|                     |        | 1 (    |         |         |         |
|                     |        | \<1)   |         |         |         |
+---------------------+--------+--------+---------+---------+---------+

NOTE: Numbers in parentheses are percentages.

Events are listed by decreasing incidence in the first course.

In the first course of placebo-controlled studies, more cardiovascular
events were reported in the alefacept-treated group than in the group
who received placebo. Specifically, there were three episodes of
myocardial infarction and four episodes of coronary artery disease in
the alefacept group, but none in placebo patients. There was one report
of angina pectoris in the placebo group but none in the alefacept group.
Review of these cardiovascular events did not reveal any unusual
presentations. The majority of these events occurred in men 51 years of
age or older, and each had one or more classical risk factors associated
with ischemic heart disease.

In all studies, a total of five patients were diagnosed with a total of
five myocardial infarctions. The incidence rate per person-years treated
with alefacept was 5 events per 1056 person-years, or 4.7 per 1000
person-years with a 95% confidence interval (CI) of 1.6 to 11.7 per 1000
person-years. In the first course of placebo-controlled studies, the
corresponding rates were 7.5 per 1000 person-years (3 events per 401
person-years; 95% CI: 3.5 to 15.8) for the alefacept-treated patients,
and 0 per 1000 person-years (0 event per 178 person-years; 95% CI: 0 to
20.7) for the placebo-treated patients. The background rates for first
myocardial infarction in white men in the 45-54 year age range has been
estimated as 4 per 1000 person-years (Centers for Disease Control and
Prevention, 2001). Thus, in an analysis by person-years exposure, the
incidence was consistent with the rate expected in the study population.

One patient who was enrolled into Study 708 experienced a serious
adverse event of angioedema. The patient's symptoms occurred 1 week
after his last dose of alefacept and responded to IV steroids. He had
two additional minor recurrences at 2 and 8 weeks after the initial
presentation and again he responded promptly to therapy. The patient had
a past history of allergies.

### Discontinuations from Study Drug due to Adverse Events

Overall, very few patients discontinued study drug due to an adverse
event. In placebo-controlled studies, 6 (1%) patients who received
placebo and 17 (2%) alefacept-treated patients discontinued study drug
due to an adverse event (Display 6-7). From multiple-course exposure
(Display 6-8), events accounting for discontinuation of treatment in
more than one patient in the first course were headache (3 patients),
nausea (3 patients), cholecystitis (2 patients), dizziness (2 patients),
and psoriasis (2 patients). Single occurrences of events led to
discontinuation in subsequent courses. There was no single adverse event
consistently accounting for discontinuation of study drug. The spectrum
of adverse events leading to treatment discontinuation was diverse, and
the proportion of patients who discontinued study drug during subsequent
courses did not increase.

Display 6-7 Incidence of adverse events leading to discontinuation of
study drug in the first course of placebo-controlled studies

+---------------------------------+-----------------+-----------------+
|                                 | Pla             |                 |
|                                 | cebo-controlled |                 |
|                                 | studies         |                 |
+---------------------------------+-----------------+-----------------+
|                                 | Placebo         | Alefacept       |
+---------------------------------+-----------------+-----------------+
| No. of patients dosed           | 413 (100)       | 876 (100)       |
+---------------------------------+-----------------+-----------------+
| No. with an adverse event       | 6 ( 1)          | 17 ( 2)         |
| leading to discontinuation of   |                 |                 |
| study drug                      |                 |                 |
+---------------------------------+-----------------+-----------------+
| Event                           | 0               | 3 ( \<1)        |
|                                 |                 |                 |
| Headache                        | 1 ( \<1)        | 2 ( \<1)        |
|                                 |                 |                 |
| Nausea                          | 0               | 1 ( \<1)        |
|                                 |                 |                 |
| Angioedema                      | 0               | 1 ( \<1)        |
|                                 |                 |                 |
| Arthritis                       | 0               | 1 ( \<1)        |
|                                 |                 |                 |
| Bronchitis                      | 0               | 1 ( \<1)        |
|                                 |                 |                 |
| Cholecystitis                   | 0               | 1 ( \<1)        |
|                                 |                 |                 |
| Cholelithiasis                  | 0               | 1 ( \<1)        |
|                                 |                 |                 |
| Coronary artery disorder        | 0               | 1 ( \<1)        |
|                                 |                 |                 |
| Dehydration                     | 0               | 1 ( \<1)        |
|                                 |                 |                 |
| Dizziness                       | 0               | 1 ( \<1)        |
|                                 |                 |                 |
| Flu syndrome                    | 0               | 1 ( \<1)        |
|                                 |                 |                 |
| GI neoplasia                    | 0               | 1 ( \<1)        |
|                                 |                 |                 |
| Infection                       | 0               | 1 ( \<1)        |
|                                 |                 |                 |
| Nausea and vomiting             | 1 ( \<1)        | 1 ( \<1)        |
|                                 |                 |                 |
| Pancreatitis                    | 0               | 1 ( \<1)        |
|                                 |                 |                 |
| Pleural effusion                | 0               | 1 ( \<1)        |
|                                 |                 |                 |
| Prostatic carcinoma             | 1 ( \<1)        | 1 ( \<1)        |
|                                 |                 |                 |
| Psoriasis                       | 0               | 1 ( \<1)        |
|                                 |                 |                 |
| Syncope                         | 0               | 1 ( \<1)        |
|                                 |                 |                 |
| Urticaria                       | 1 ( \<1)        | 0               |
|                                 |                 |                 |
| Accidental injury               | 1 ( \<1)        | 0               |
|                                 |                 |                 |
| Asthenia                        | 1 ( \<1)        | 0               |
|                                 |                 |                 |
| Fever                           | 1 ( \<1)        | 0               |
|                                 |                 |                 |
| Neoplasm                        | 1 ( \<1)        | 0               |
|                                 |                 |                 |
| Rash                            | 1 ( \<1)        | 0               |
|                                 |                 |                 |
| Skin benign neoplasm            |                 |                 |
+---------------------------------+-----------------+-----------------+

NOTE: Numbers in parentheses are percentages.

Events are listed by decreasing incidence in those who received
alefacept.

Display 6-8 Incidence of adverse events leading to discontinuation of
study drug by course of alefacept

+---------------------+--------+--------+---------+---------+---------+
|                     | Course |        |         |         |         |
|                     | of     |        |         |         |         |
|                     | ale    |        |         |         |         |
|                     | facept |        |         |         |         |
+---------------------+--------+--------+---------+---------+---------+
|                     | First  | Second | Third   | Fourth  | Fifth   |
+---------------------+--------+--------+---------+---------+---------+
| No. of patients     | 1357   | 756    | 199     | 81      | 46      |
| dosed               | (100)  | (100)  | (100)   | (100)   | (100)   |
+---------------------+--------+--------+---------+---------+---------+
| No. with an adverse | 24 (   | 5 (    | 2 ( 1)  | 1 ( 1)  | 0       |
| event leading to    | 2)     | \<1)   |         |         |         |
| discontinuation of  |        |        |         |         |         |
| study drug          |        |        |         |         |         |
+---------------------+--------+--------+---------+---------+---------+
| Event               | 3 (    | 0      | 0       | 0       | 0       |
|                     | \<1)   |        |         |         |         |
| Headache            |        | 0      | 0       | 0       | 0       |
|                     | 3 (    |        |         |         |         |
| Nausea              | \<1)   | 0      | 0       | 0       | 0       |
|                     |        |        |         |         |         |
| Cholecystitis       | 2 (    | 0      | 0       | 0       | 0       |
|                     | \<1)   |        |         |         |         |
| Dizziness           |        | 0      | 0       | 0       | 0       |
|                     | 2 (    |        |         |         |         |
| Psoriasis           | \<1)   | 0      | 0       | 0       | 0       |
|                     |        |        |         |         |         |
| Angioedema          | 2 (    | 0      | 0       | 0       | 0       |
|                     | \<1)   |        |         |         |         |
| Arthralgia          |        | 0      | 0       | 0       | 0       |
|                     | 1 (    |        |         |         |         |
| Arthritis           | \<1)   | 0      | 0       | 0       | 0       |
|                     |        |        |         |         |         |
| Asthenia            | 1 (    | 0      | 0       | 0       | 0       |
|                     | \<1)   |        |         |         |         |
| Bronchitis          |        | 0      | 0       | 0       | 0       |
|                     | 1 (    |        |         |         |         |
| Chills              | \<1)   | 0      | 0       | 0       | 0       |
|                     |        |        |         |         |         |
| Cholelithiasis      | 1 (    | 0      | 0       | 0       | 0       |
|                     | \<1)   |        |         |         |         |
| Coronary artery     |        | 0      | 0       | 0       | 0       |
| disorder            | 1 (    |        |         |         |         |
|                     | \<1)   | 0      | 0       | 0       | 0       |
| Dehydration         |        |        |         |         |         |
|                     | 1 (    | 0      | 0       | 0       | 0       |
| Flu syndrome        | \<1)   |        |         |         |         |
|                     |        | 0      | 0       | 1 ( 1)  | 0       |
| GI neoplasia        | 1 (    |        |         |         |         |
|                     | \<1)   | 0      | 0       | 0       | 0       |
| Herpes zoster       |        |        |         |         |         |
|                     | 1 (    | 0      | 0       | 0       | 0       |
| Infection           | \<1)   |        |         |         |         |
|                     |        | 0      | 0       | 0       | 0       |
| Injection site      | 1 (    |        |         |         |         |
| reaction            | \<1)   | 0      | 0       | 0       | 0       |
|                     |        |        |         |         |         |
| Nausea and vomiting | 1 (    | 0      | 0       | 0       | 0       |
|                     | \<1)   |        |         |         |         |
| Pancreatitis        |        | 0      | 0       | 0       | 0       |
|                     | 1 (    |        |         |         |         |
| Pleural effusion    | \<1)   | 0      | 0       | 0       | 0       |
|                     |        |        |         |         |         |
| Prostatic carcinoma | 1 (    | 0      | 0       | 0       | 0       |
|                     | \<1)   |        |         |         |         |
| Scleritis           |        | 0      | 0       | 0       | 0       |
|                     | 1 (    |        |         |         |         |
| Syncope             | \<1)   | 0      | 0       | 0       | 0       |
|                     |        |        |         |         |         |
| Urticaria           | 1 (    | 1 (    | 0       | 0       | 0       |
|                     | \<1)   | \<1)   |         |         |         |
| Vertigo             |        |        | 1 (     | 0       | 0       |
|                     | 1 (    | 0      | \<1)    |         |         |
| Allergic reaction   | \<1)   |        |         | 0       | 0       |
|                     |        | 1 (    | 0       |         |         |
| Carcinoma of lung   | 1 (    | \<1)   |         | 0       | 0       |
|                     | \<1)   |        | 0       |         |         |
| Conjunctivitis      |        | 1 (    |         | 0       | 0       |
|                     | 1 (    | \<1)   | 1 (     |         |         |
| Infection bacterial | \<1)   |        | \<1)    | 0       | 0       |
|                     |        | 0      |         |         |         |
| Lung fibrosis       | 1 (    |        | 0       | 0       | 0       |
|                     | \<1)   | 1 (    |         |         |         |
| Pneumonia           |        | \<1)   | 0       |         |         |
|                     | 1 (    |        |         |         |         |
| Pulmonary           | \<1)   | 1 (    |         |         |         |
| hypertension        |        | \<1)   |         |         |         |
|                     | 1 (    |        |         |         |         |
|                     | \<1)   |        |         |         |         |
|                     |        |        |         |         |         |
|                     | 1 (    |        |         |         |         |
|                     | \<1)   |        |         |         |         |
|                     |        |        |         |         |         |
|                     | 1 (    |        |         |         |         |
|                     | \<1)   |        |         |         |         |
|                     |        |        |         |         |         |
|                     | 0      |        |         |         |         |
|                     |        |        |         |         |         |
|                     | 0      |        |         |         |         |
|                     |        |        |         |         |         |
|                     | 0      |        |         |         |         |
|                     |        |        |         |         |         |
|                     | 0      |        |         |         |         |
|                     |        |        |         |         |         |
|                     | 0      |        |         |         |         |
|                     |        |        |         |         |         |
|                     | 0      |        |         |         |         |
|                     |        |        |         |         |         |
|                     | 0      |        |         |         |         |
+---------------------+--------+--------+---------+---------+---------+

NOTE: Numbers in parentheses are percentages.

Events are listed by decreasing incidence in the first course.

## Infections

### All Infections

Because alefacept targets T cells, the frequency and severity of
infections in the safety database were analyzed. Investigators recorded
whether or not each adverse event represented a new or ongoing
infection. The COSTART dictionary used to code adverse events throughout
this Briefing Document allows for specific terms such as "viral
infection" and "infection bacterial," provided that investigators give
sufficient information. However, the COSTART term "infection" is a more
general term and so can include different types of infections without a
great degree of specificity. To better clinically evaluate and interpret
the nature of all infections, all events that were coded to the
non-specific COSTART term "infection" have also been coded using the
MedDRA dictionary.

The proportion of patients who reported infections was similar between
the placebo- and alefacept-treated patients in the placebo-controlled
studies: 43% and 45%, respectively (Display 6-9). In both treatment
groups, the most frequently reported infections, i.e., with an incidence
of 5% or more, were pharyngitis, nasopharyngitis (cold), flu syndrome,
and viral infection. With additional courses of alefacept, the
proportion of patients with these types of infections was similar
although there appears to be a slight increase in viral infections. The
incidence of infection did not increase during subsequent courses with
alefacept (Display 6-10).

Display 6-9 Incidence of infections in the first course of
placebo-controlled studies experienced by at least 5% of patients who
received alefacept

+----------------------------------+-----------------+-----------------+
|                                  | Pla             |                 |
|                                  | cebo-controlled |                 |
|                                  | studies         |                 |
+----------------------------------+-----------------+-----------------+
|                                  | Placebo         | Alefacept       |
+----------------------------------+-----------------+-----------------+
| No. of patients dosed            | 413 (100)       | 876 (100)       |
+----------------------------------+-----------------+-----------------+
| No. with an infection            | 176 ( 43)       | 393 ( 45)       |
+----------------------------------+-----------------+-----------------+
| Event                            | 44 ( 11)        | 95 ( 11)        |
|                                  |                 |                 |
| Infection                        | 28 ( 7)         | 66 ( 8)         |
|                                  |                 |                 |
| Nasopharyngitis (a)              | 42 ( 10)        | 89 ( 10)        |
|                                  |                 |                 |
| Pharyngitis                      | 21 ( 5)         | 64 ( 7)         |
|                                  |                 |                 |
| Flu syndrome                     | 27 ( 7)         | 52 ( 6)         |
|                                  |                 |                 |
| Viral infection                  |                 |                 |
+----------------------------------+-----------------+-----------------+

NOTE: Numbers in parentheses are percentages.

Events are listed by decreasing incidence in those who received
alefacept.

\(a\) MedDRA term.

Display 6-10 Incidence of infections experienced by at least 5% of
patients by course of alefacept

+---------------------+--------+--------+---------+---------+---------+
|                     | Course |        |         |         |         |
|                     | of     |        |         |         |         |
|                     | ale    |        |         |         |         |
|                     | facept |        |         |         |         |
+---------------------+--------+--------+---------+---------+---------+
|                     | First  | Second | Third   | Fourth  | Fifth   |
+---------------------+--------+--------+---------+---------+---------+
| No. of patients     | 1357   | 756    | 199     | 81      | 46      |
| dosed               | (100)  | (100)  | (100)   | (100)   | (100)   |
+---------------------+--------+--------+---------+---------+---------+
| No. with an         | 633 (  | 327 (  | 63 (    | 33 (    | 12 (    |
| infection           | 47)    | 43)    | 32)     | 41)     | 26)     |
+---------------------+--------+--------+---------+---------+---------+
| Event               | 147 (  | 76 (   | 15 ( 8) | 12 (    | 3 ( 7)  |
|                     | 11)    | 10)    |         | 15)     |         |
| Infection           |        |        | 9 ( 5)  |         | 3 ( 7)  |
|                     | 103 (  | 57 (   |         | 6 ( 7)  |         |
| Nasopharyngitis (a) | 8)     | 8)     | 2 ( 1)  |         | 0       |
|                     |        |        |         | 2 ( 2)  |         |
| Tooth infection (a) | 8 (    | 2 (    | 2 ( 1)  |         | 0       |
|                     | \<1)   | \<1)   |         | 2 ( 2)  |         |
| Skin infection NOS  |        |        | 10 ( 5) |         | 1 ( 2)  |
| (a)                 | 6 (    | 2 (    |         | 4 ( 5)  |         |
|                     | \<1)   | \<1)   | 3 ( 2)  |         | 1 ( 2)  |
| Pharyngitis         |        |        |         | 6 ( 7)  |         |
|                     | 144 (  | 62 (   | 12 ( 6) |         | 1 ( 2)  |
| Flu syndrome        | 11)    | 8)     |         | 7 ( 9)  |         |
|                     |        |        | 10 ( 5) |         | 1 ( 2)  |
| Viral infection     | 107 (  | 44 (   |         | 0       |         |
|                     | 8)     | 6)     |         |         |         |
| Sinusitis           |        |        |         |         |         |
|                     | 79 (   | 51 (   |         |         |         |
|                     | 6)     | 7)     |         |         |         |
|                     |        |        |         |         |         |
|                     | 47 (   | 26 (   |         |         |         |
|                     | 3)     | 3)     |         |         |         |
+---------------------+--------+--------+---------+---------+---------+

NOTE: Numbers in parentheses are percentages.

NOS: Not otherwise specified.

\(a\) MedDRA term.

### Serious Infections

The proportion of patients with serious infections was \<1% for both the
alefacept- and placebo-treated patients during the first course of
therapy in the placebo-controlled studies (Display 6-11).

Display 6-11 Incidence of serious infections in the first course of
placebo-controlled studies

+---------------------------------+------------------+-----------------+
|                                 | Pl               |                 |
|                                 | acebo-controlled |                 |
|                                 | studies          |                 |
+---------------------------------+------------------+-----------------+
|                                 | Placebo          | Alefacept       |
+---------------------------------+------------------+-----------------+
| No. of patients dosed           | 413 (100)        | 876 (100)       |
+---------------------------------+------------------+-----------------+
| No. with a serious infection    | 2 ( \<1)         | 8 ( \<1)        |
+---------------------------------+------------------+-----------------+
| Body as a whole                 | 0                | 5 ( \<1)        |
|                                 |                  |                 |
| Cellulitis                      | 0                | 3 ( \<1)        |
|                                 |                  |                 |
| Abscess                         | 0                | 1 ( \<1)        |
|                                 |                  |                 |
| Infection                       | 0                | 1 ( \<1)        |
|                                 |                  |                 |
| Wound infection NEC (a)         | 0                | 1 ( \<1)        |
|                                 |                  |                 |
| Digestive System                | 1 ( \<1)         | 2 ( \<1)        |
|                                 |                  |                 |
| Gastroenteritis                 | 0                | 2 ( \<1)        |
|                                 |                  |                 |
| Pancreatitis                    | 1 ( \<1)         | 0               |
|                                 |                  |                 |
| Respiratory System              | 1 ( \<1)         | 1 ( \<1)        |
|                                 |                  |                 |
| Asthma                          | 0                | 1 ( \<1)        |
|                                 |                  |                 |
| Pneumonia                       | 1 ( \<1)         | 0               |
+---------------------------------+------------------+-----------------+

NOTE: Numbers in parentheses are percentages.

NEC: Not elsewhere classified.

\(a\) MedDRA term.

Serious infections occurring in more than one patient in the first
course of alefacept include cellulitis (3 patients), bacterial infection
(2 patients), and gastroenteritis (2 patients). In subsequent courses, 5
patients (\<1%) in the second course, 3 patients (2%) in the third
course, and none in the fourth and fifth courses experienced a serious
infection (Display 6-12). Pneumonia was observed in three patients.
There is no suggestion that multi-course exposure to alefacept increased
the risk of experiencing a serious infection.

All serious infections were typical in the population studied in terms
of presentation, course, and outcome. No unusual or opportunistic
infections were observed. No deaths occurred due to an infection.

Display 6-12 Incidence of serious infections by course of alefacept

+-----------------------+--------+--------+--------+--------+--------+
|                       | Course |        |        |        |        |
|                       | of     |        |        |        |        |
|                       | ale    |        |        |        |        |
|                       | facept |        |        |        |        |
+-----------------------+--------+--------+--------+--------+--------+
|                       | First  | Second | Third  | Fourth | Fifth  |
+-----------------------+--------+--------+--------+--------+--------+
| No. of patients dosed | 1357   | 756    | 199    | 81     | 46     |
|                       | (100)  | (100)  | (100)  | (100)  | (100)  |
+-----------------------+--------+--------+--------+--------+--------+
| No. with a serious    | 10 (   | 5 (    | 3 ( 2) | 0      | 0      |
| infection             | \<1)   | \<1)   |        |        |        |
+-----------------------+--------+--------+--------+--------+--------+
| Body as a whole       | 7 (    | 2 (    | 1 (    | 0      | 0      |
|                       | \<1)   | \<1)   | \<1)   |        |        |
| Cellulitis            |        |        |        | 0      | 0      |
|                       | 3 (    | 0      | 0      |        |        |
| Infection bacterial   | \<1)   |        |        | 0      | 0      |
|                       |        | 0      | 0      |        |        |
| Abscess               | 2 (    |        |        | 0      | 0      |
|                       | \<1)   | 0      | 0      |        |        |
| Infection             |        |        |        | 0      | 0      |
|                       | 1 (    | 2 (    | 1 (    |        |        |
| Burn infection (a)    | \<1)   | \<1)   | \<1)   | 0      | 0      |
|                       |        |        |        |        |        |
| Appendicitis (a)      | 1 (    | 0      | 0      | 0      | 0      |
|                       | \<1)   |        |        |        |        |
| Postoperative wound   |        | 0      | 1 (    | 0      | 0      |
| infection (a)         | 1 (    |        | \<1)   |        |        |
|                       | \<1)   | 1 (    |        | 0      | 0      |
| Wound infection NEC   |        | \<1)   | 0      |        |        |
| (a)                   | 0      |        |        | 0      | 0      |
|                       |        | 1 (    | 0      |        |        |
| Digestive system      | 0      | \<1)   |        | 0      | 0      |
|                       |        |        | 0      |        |        |
| Gastroenteritis       | 0      | 0      |        | 0      | 0      |
|                       |        |        | 0      |        |        |
| Respiratory System    | 2 (    | 0      |        | 0      | 0      |
|                       | \<1)   |        | 2 ( 1) |        |        |
| Asthma                |        | 2 (    |        | 0      | 0      |
|                       | 2 (    | \<1)   | 0      |        |        |
| Bronchitis            | \<1)   |        |        | 0      | 0      |
|                       |        | 0      | 1 (    |        |        |
| Pneumonia             | 1 (    |        | \<1)   | 0      | 0      |
|                       | \<1)   | 0      |        |        |        |
| Skin and appendages   |        |        | 1 (    | 0      | 0      |
|                       | 1 (    | 2 (    | \<1)   |        |        |
| Herpes simplex        | \<1)   | \<1)   |        |        |        |
|                       |        |        | 0      |        |        |
|                       | 0      | 1 (    |        |        |        |
|                       |        | \<1)   | 0      |        |        |
|                       | 0      |        |        |        |        |
|                       |        | 1 (    |        |        |        |
|                       | 0      | \<1)   |        |        |        |
|                       |        |        |        |        |        |
|                       | 0      |        |        |        |        |
+-----------------------+--------+--------+--------+--------+--------+

NOTE: Numbers in parentheses are percentages.

NEC: Not elsewhere classified.

\(a\) MedDRA term.

### The Lack of Relationship between Infections and Low T Cell Counts 

The occurrence of infections relative to the degree of reduction in T
cell counts was evaluated in several ways. In the first analysis, the
cumulative depression in lymphocytes was measured as a function of the
total lymphocyte count area under the effect curve (E~AUC~) (Appendix
2). Overall, the rate of infections did not increase by E~AUC~ quartile
in the Phase 3 studies. When analyzed by each type of infection, there
were slightly more cases of pharyngitis in the highest quartile in
alefacept-treated patients during the second course in Study 711. The
majority of these cases were mild to moderate in severity.

The incidence of infections was also analyzed in patients with CD4+ T
cell counts \<250 cells/μL or ≥250 cells/μL. In this analysis,
comparison to placebo is difficult because only 2 patients treated with
placebo had CD4+ T cell counts \<250 cells/μL. Among patients treated
with alefacept in the placebo-controlled trials, there was no difference
in the occurrence of infections between patients with CD4+ T cell counts
\<250 cells/μL and those with counts ≥250 cells/μL. The incidence of
infection did not increase in patients who developed CD4+ T cell counts
\<250 cells/μL with continued exposure to alefacept. It is important to
note that no patient in the safety database, regardless of CD4+ T cell
count, experienced an opportunistic infection. A similar analysis
investigating the incidence of infection and CD8+ T cell counts did not
reveal a relationship.

## Malignancies

The rate of malignancies in the alefacept safety database was low. Two
patients (\<1%) in the placebo group and 10 patients (1%) in the
alefacept group had malignancies diagnosed during the first course of
study drug in placebo-controlled studies (Display 6-13). The incidence
of malignancies did not increase with repeat courses of alefacept
(Display 6-14). The incidence rate of malignancies per person-years is
20.8 per 1000 person-years (95% CI: 13.0 to 32.1), a rate that is
consistent with that reported by Margolis *et al* (2001)(29 per 1000
person-years).

Display 6-13 Incidence of malignancies experienced in the first course
of placebo-controlled studies

+-----------------------------+-------------------+-------------------+
|                             | P                 |                   |
|                             | lacebo-controlled |                   |
|                             | studies           |                   |
+-----------------------------+-------------------+-------------------+
|                             | Placebo           | Alefacept         |
+-----------------------------+-------------------+-------------------+
| No. of patients dosed       | 413 (100)         | 876 (100)         |
+-----------------------------+-------------------+-------------------+
| No. with a malignancy       | 2 ( \<1)          | 10 ( 1)           |
+-----------------------------+-------------------+-------------------+
| Event                       | 1 ( \<1)          | 6 ( \<1)          |
|                             |                   |                   |
| Skin carcinoma              | 0                 | 2 ( \<1)          |
|                             |                   |                   |
| Carcinoma (a)               | 1 ( \<1)          | 1 ( \<1)          |
|                             |                   |                   |
| Prostatic carcinoma         | 0                 | 1 ( \<1)          |
|                             |                   |                   |
| Skin melanoma               |                   |                   |
+-----------------------------+-------------------+-------------------+

NOTE: Numbers in parentheses are percentages.

Events are listed by decreasing incidence in those who received
alefacept.

\(a\) Includes one case of testicular cancer and one case of renal cell
cancer.

Display 6-14 Incidence of malignancies by course of alefacept

+--------------------+--------+--------+--------+---------+---------+
|                    | Course |        |        |         |         |
|                    | of     |        |        |         |         |
|                    | ale    |        |        |         |         |
|                    | facept |        |        |         |         |
+--------------------+--------+--------+--------+---------+---------+
|                    | First  | Second | Third  | Fourth  | Fifth   |
+--------------------+--------+--------+--------+---------+---------+
| No. of patients    | 1357   | 756    | 199    | 81      | 46      |
| dosed              | (100)  | (100)  | (100)  | (100)   | (100)   |
+--------------------+--------+--------+--------+---------+---------+
| No. with a         | 16 (   | 4 (    | 4 ( 2) | 1 ( 1)  | 1 ( 2)  |
| malignancy         | 1)     | \<1)   |        |         |         |
+--------------------+--------+--------+--------+---------+---------+
| Event              | 11 (   | 2 (    | 2 ( 1) | 1 ( 1)  | 1 ( 2)  |
|                    | \<1)   | \<1)   |        |         |         |
| Skin carcinoma     |        |        | 0      | 0       | 0       |
|                    | 2 (    | 1 (    |        |         |         |
| Carcinoma (a)      | \<1)   | \<1)   | 0      | 0       | 0       |
|                    |        |        |        |         |         |
| Skin melanoma      | 2 (    | 0      | 0      | 0       | 0       |
|                    | \<1)   |        |        |         |         |
| Prostatic          |        | 0      | 1 (    | 0       | 0       |
| carcinoma          | 1 (    |        | \<1)   |         |         |
|                    | \<1)   | 0      |        | 0       | 0       |
| Carcinoma of lung  |        |        | 1 (    |         |         |
|                    | 0      | 1 (    | \<1)   | 0       | 0       |
| Gastrointestinal   |        | \<1)   |        |         |         |
| carcinoma          | 0      |        | 1 (    |         |         |
|                    |        | 0      | \<1)   |         |         |
| GI neoplasia (b)   | 0      |        |        |         |         |
+--------------------+--------+--------+--------+---------+---------+

NOTE: Numbers in parentheses are percentages.

Events are listed by decreasing incidence in the first course.

\(a\) Includes one case of testicular cancer, one case of renal cell
cancer, and one case of optic nerve melanoma.

\(b\) One patient with colonic adenomas.

The most common malignancy was skin carcinoma that occurred in 6
alefacept-treated patients (\<1%) compared to 1 patient (\<1%) who
received placebo. The term "skin carcinoma" included both squamous cell
and basal cell carcinoma. Patients with psoriasis are known to be at an
increased risk for skin cancers. Examination of medical histories
revealed that greater proportions of alefacept-treated patients relative
to those who received placebo had prior histories of squamous cell skin
cancer (11/876 (1%) *vs* 1/413 (\<1%)) and basal cell carcinoma (13/876
(1%) *vs* 6/413 (1%)).

Data collected between 1976 and 1985 have shown that the rate of
invasive squamous cell skin carcinomas in patients with low exposure to
PUVA is 10 per 1000 person-years, and for those with high exposure to
PUVA the rate is 38 per 1000 person-years (Display 6-15). Current rates
are believed to be higher. In the first course of placebo-controlled
studies, the corresponding rates for alefacept- and placebo-treated
patients were 12.5 per 1000 person-years (95% CI: 6.9 to 22.2) and 0 per
1000 person-years (95% CI: 0 to 20.7), respectively. For total alefacept
exposure, the rate was 13.3 per 1000 person-years (95% CI: 6.9 to 22.2).
The observed rates, therefore, are consistent with the rate expected in
this patient population.

With respect to basal cell carcinoma, in the first course of
placebo-controlled studies, the rate in the alefacept-treated patients
was 5.0 per 1000 patient years (95% CI: 1.6 to 11.7) and that for
placebo-treated patients was 5.6 per 1000 patient years (95% CI: 2.2 to
13.1). No information on background rates is available.

Display 6-15 Observed and expected rates of non-melanoma skin cancer

+-------------------------+---------------------+---------------------+
|                         | Observed rate       | Expected rate       |
|                         |                     |                     |
|                         | (/1000              | in psoriasis        |
|                         | person-years)       | patients            |
|                         |                     |                     |
|                         |                     | (/1000              |
|                         |                     | person-years)       |
+-------------------------+---------------------+---------------------+
| Squamous cell cancer    | 13.3                | 10 to 38 (a)        |
+-------------------------+---------------------+---------------------+
| Basal cell cancer       | 5                   | Not available       |
+-------------------------+---------------------+---------------------+

\(a\) From Stern *et al* (1997); Marcil and Stern (2001).

Two patients were diagnosed with melanoma (Display 6-14). One patient
had significant prior treatment with PUVA/UVB and the second patient had
the lesion noted at screening. One case was minimally invasive to 0.25
mm and the other was melanoma *in situ*. Each was less than 1 cm in
greatest dimension. Both were treated successfully with local excision
without sequelae.

The types and incidence of malignancies observed in the alefacept
database are consistent with what would be expected in this patient
population.

At the time of writing, a 68 year-old patient in an alefacept
re-treatment study had a presumptive diagnosis of B cell non-Hodgkins
lymphoma. Definitive immunohistological and molecular classifications
are pending. The expected rate of lymphoma in the adult population is
0.2 to 0.3 per 1000 person-years. Given the elevated incidence cited by
Margolis *et al* (2001), the expected rate would be 1.4 to 2.1 per 1000
person-years. Thus, with the size of the alefacept safety database, the
observation is likely within expected limits.

As recently demonstrated by Margolis *et al*, patients with moderate to
severe psoriasis are at increased risk of developing malignancies
(Display 6-16). Indeed, relative to a group of patients with
hypertension, patients with severe psoriasis are 1.78 times more likely
to develop any type of malignancy (95% CI: 1.32 to 2.40), and 7.95 times
more likely to develop a lymphoproliferative malignancy (95% CI: 4.94 to
12.79).

Display 6-16 Incidence of malignancies in psoriasis and control
populations

+--------------------------+---------------------+---------------------+
|                          | Relative rate ratio | Relative rate ratio |
|                          | (95% CI)            | (95% CI)            |
|                          |                     |                     |
|                          | for all             | for                 |
|                          | malignancies        | lymphoproliferative |
|                          |                     | malignancies        |
+--------------------------+---------------------+---------------------+
| Hypertension             | 1.00 (reference)    | 1.00 (reference)    |
|                          |                     |                     |
| Severe psoriasis         | 1.78 (1.32 -- 2.40) | 7.95 (4.94 --       |
|                          |                     | 12.79)              |
| Less severe psoriasis    | 1.13 (1.03 -- 1.25) |                     |
|                          |                     | 2.11 (1.63 -- 2.74) |
| Severe eczema            | 1.04 (0.85 -- 1.28) |                     |
|                          |                     | 1.70 (0.99 -- 2.95) |
| Organ transplant (heart, | 2.12 (1.80 -- 2.50) |                     |
| liver, or kidney)        |                     | 3.35 (2.23 -- 5.03) |
+--------------------------+---------------------+---------------------+

From Margolis *et al* (2001).

Rate ratios are adjusted for age, state of origin, and sex.

## Immunogenicity

Antibodies to alefacept were measured at baseline and in the follow-up
period of each course. The proportion of patients testing positive for
anti-alefacept antibodies at baseline and post-baseline during each
course of treatment was low (0 to 2%), and the proportion of patients
with detectable antibody did not increase with repeat courses of
alefacept (Display 6-17).

A total of 35 patients have tested positive for anti-alefacept antibody
in an alefacept course, of whom 6 remained positive during subsequent
courses.

No safety issues associated with antibody development were identified.

Display 6-17 Incidence of antibodies to alefacept by course of alefacept

+-------------+----------+----------+----------+----------+----------+
|             | Course   |          |          |          |          |
|             | of       |          |          |          |          |
|             | a        |          |          |          |          |
|             | lefacept |          |          |          |          |
+-------------+----------+----------+----------+----------+----------+
|             | First    | Second   | Third    | Fourth   | Fifth    |
+-------------+----------+----------+----------+----------+----------+
| Number of   | 1306     | 756      | 199      | 81       | 46       |
| patients    |          |          |          |          |          |
| dosed       |          |          |          |          |          |
+-------------+----------+----------+----------+----------+----------+
| Baseline    | 4/1289   | 7/756    | 3/199 (  | 0/81     | 0/46     |
|             | (\<1)    | (\<1)    | 2)       |          |          |
| During      |          |          |          | 0/68     | 0/46     |
| course      | 31/1269  | 10/663 ( | 1/152    |          |          |
|             | ( 2)     | 2)       | (\<1)    |          |          |
+-------------+----------+----------+----------+----------+----------+

NOTE: Entries are number of patients testing positive/number evaluated
(percentage).

## Laboratory Test Abnormalities

During the clinical development of alefacept, the hematology and
chemistry values were monitored. Extensive analyses of chemistry values
showed no significant effects of alefacept treatment compared to
placebo. The effect of alefacept upon lymphocytes is discussed in
Section 5.2. A greater proportion of alefacept-treated patients had a
decrease in the total white blood cell count after treatment compared to
placebo (2% placebo *vs* 7% alefacept) that can be attributed to the
reduction in lymphocyte counts. There were no differences in the other
hematologic cell lines, (i.e., red blood cell count, neutrophils,
eosinophils, basophils, monocytes, and platelets) between alefacept- and
placebo-treated patients.

In placebo-controlled studies, 10% and 11% of patients in the placebo
and alefacept groups, respectively, had elevations in aspartate
aminotransferase (AST) at baseline, and 15% and 18% respectively, had
baseline elevations in alanine aminotransferase (ALT). The incidence of
shifts from baseline to high in transaminases were similar in alefacept
and placebo groups. More than 90% of the elevations in liver function
tests in the alefacept-treated patients ranged from 1 to 3 times the
upper limit of normal. Isolated elevations to 5 times the upper limit of
normal were observed in the context of baseline elevations. Only one
patient discontinued due to liver function test abnormalities. No
patient developed overt clinical hepatitis.

## Summary of Clinical Safety

-   During clinical development, over 1350 patients with chronic plaque
    psoriasis have received a course of treatment with alefacept.
    Analysis of the clinical safety database demonstrates that alefacept
    treatment is well-tolerated. Overall, the proportions of patients
    with adverse events or serious adverse events were low and
    comparable between alefacept and placebo in the controlled clinical
    trials. Among the serious adverse events, more patients treated with
    alefacept experienced a cardiovascular event. These events occurred
    in patients with one or more risk factors for heart disease. In
    particular, the rate of myocardial infarctions is consistent with
    that expected in the study population.

-   Despite the effect of alefacept on T cell counts, the incidence of
    infections, including serious infections, was comparable between
    alefacept- and placebo-treated patients. The occurrence of
    infections, including serious infections, did not increase in
    patients with low CD4+ T cell counts. No patient experienced an
    opportunistic infection.

-   In the clinical studies, the incidence of squamous cell skin
    carcinoma was slightly higher in alefacept- compared to
    placebo-treated patients but the numbers are too low to allow
    definite conclusions. Patients with psoriasis are known to be at
    risk for squamous cell skin carcinoma. It is possible that increased
    clearance of the skin lesions may allow easier and earlier detection
    of carcinoma. Furthermore, the incidence rate of squamous cell skin
    carcinoma is consistent with that expected in the study population.

-   There is no suggestion of increased risk with multiple-course
    exposure to alefacept.

# BENEFITS AND RISKS

## Benefits

The clearest demonstration of a need for new treatment of moderate to
severe psoriasis is the current treatment pattern of the disease: the
use of agents with collateral organ toxicities as primary therapy for
psoriasis. These current therapies may cause severe short-term adverse
events in some patients, and all cause significant morbidity with
long-term use. Even with the use of these treatments, psoriasis is
rarely cleared. Patients with psoriasis and their physicians seek new,
more targeted, safer yet effective approaches to treat the disease. In
the meantime, because of the tremendous impact of psoriasis on patients'
lives, patients and their physicians choose to use potential toxic
treatments for this disorder.

Alefacept is designed to target the reduction of the memory T cells by
binding to CD2 and causing apoptosis of the activated memory T cell.
This targeted reduction in the memory T cells results in suppression of
the inflammatory process in psoriatic lesions.

The clinical benefit of alefacept was demonstrated in two pivotal
trials, each supporting either an IV or IM route of administration. In
these trials, a significantly greater proportion of patients treated
with alefacept compared to placebo experienced clinical benefit as
measured by PASI 75. Demonstration of clinical response by PASI 75 was
supported by clinical response as measured by PGA AC/C and PASI 50 both
at 2 weeks after treatment or at any time during a course of alefacept
treatment. In conjunction with the improvement of the signs and symptoms
of disease activity, the clinical significance to patients was confirmed
by the patients' improved quality of life as measured by the validated
DLQI. Clinical response was consistent across demographic and baseline
disease characteristics.

The clinical response following treatment with alefacept is durable.
Most currently available systemic agents have associated rebound or
flare of psoriasis with discontinuation of treatment. The long remission
of disease activity associated with elimination of activated memory
dermal T cells defines alefacept as the first remittive systemic therapy
for treatment of chronic plaque psoriasis.

The efficacy data also demonstrate that patients have additional
clinical benefit with subsequent courses of alefacept. A greater
proportion of patients experience significant clinical response with a
second course of alefacept.

## Risks

Treatment with alefacept is well-tolerated. The most common adverse
events were headache, pharyngitis, injury, infection, rhinitis, and
pruritus. The majority of these events were mild and all occurred with
similar frequency in both alefacept- and placebo-treated patients. The
only difference in adverse events between the IM and IV routes of
administration was an increased number of chills with the IV route and
an increased number of injection site reactions with the IM route. In
addition, there were few serious adverse events reported and the
reporting rates of specific serious adverse events were similar between
alefacept- and placebo-treated patients.

Because of its mechanism of action, patients treated with alefacept have
a decrease in their total lymphocyte count, CD4+ and CD8+ T cell counts.
Despite the reduction in lymphocytes with treatment with alefacept, the
proportion of patients who experienced infections, including serious
infections, was similar between the alefacept- and placebo-treated
groups. The types of infections reported were comparable and included
upper respiratory, i.e., pharyngitis, flu syndrome, and nasopharyngitis.
Most of these infections were mild. Serious infections occurred in \<1%
of patients treated with alefacept. The occurrence of infections,
including serious infections, was no higher in patients with low CD4+ T
cell counts and did not increase with repeat courses of alefacept. No
patient developed an opportunistic infection.

The overall low incidence of infections, including serious infections,
in patients treated with alefacept may be related to its targeted
reduction of memory T cells and the redundancy of the immune system.
Treatment with alefacept causes greater reduction in the memory T cells
compared to the naïve T cells, thereby leaving intact the immunological
response to new antigens. The ability of the immune system to maintain
its functionality is reflected by the results of Study 718 where
alefacept-treated patients demonstrated normal primary antibody response
and memory response. In addition, the reduction in the CD4+ and CD8+
memory T cells in the circulation may not correlate to the population of
these cells in the lymphoid and non-lymphoid tissues where the majority
of memory T cells reside. Lymph node biopsy of non-human primates
exposed to alefacept demonstrated follicular hyperplasia with normal
lymph node architecture. Thus, sufficient memory T cells may be
available to respond to immunological challenge in patients treated with
alefacept.

The long-term risks of targeting the activated memory T cells involved
in the pathogenesis of psoriasis are not yet known. Current therapies,
such as methotrexate and cyclosporine, also work through immune
inhibition and both are less specific inhibitors of immune function and
are associated with collateral organ toxicity. As such, the long-term
toxicity of the more targeted approach is expected to be less than that
of currently used treatments. Moreover, the lack of both opportunistic
infections and detectable effects on the immune response to antigens
supports the safety of alefacept. Finally, effects of alefacept on T
cells can be monitored and are reversible. The ability to monitor T cell
counts and to stop treatment provides a degree of safety not seen with
other immune inhibitors.

To definitively address the issue of long-term risk, Biogen Inc.
envisages a robust and well-powered approach to detect potentially
important safety issues. The existing database will be supplemented with
data from:

-   safety extension trials - Phase 2 and Phase 3 re-treatment studies
    are ongoing in approximately over 800 patients;

-   a safety surveillance study (500 patient open-label study) that will
    be initiated in 2002 in order to enhance the total number of
    patients exposed to alefacept; and

-   a safety registry study proposed to evaluate long-term outcomes
    (e.g. serious infection, malignancy) in patients with any prior or
    ongoing exposure to alefacept. Detailed prior treatment histories
    will allow for more precise evaluation of the contribution of
    alefacept to the risk of events.

A specific goal of any post-approval evaluation of safety will be to
develop enhanced data collection methodologies that specifically
identify detailed information for adverse events of interest reported to
Biogen Inc., e.g. collection of skin type, past medical history,
histologic type, anatomical location, exposure to other carcinogenic
agents for patients reported to have developed skin cancer.

## Conclusion

Chronic plaque psoriasis is a life-long inflammatory disorder of the
skin. It is associated with significant physical, psychological, and
social morbidity. Although existing systemic therapies and phototherapy
are fairly effective, they are associated with poor tolerability and
significant short- and long-term organ-system toxicities. Treatment with
alefacept is a more targeted approach aimed at the memory T cells
involved in the pathogenesis of psoriasis. The reduction in these memory
T cells provides improvement in the signs and symptoms of psoriasis. The
clinical benefit with alefacept treatment is prolonged and associated
with improvement in quality of life. Alefacept is well-tolerated.
Despite the reduction in T cells, the incidence of infections, including
serious infections, was low. Overall, the rate of occurrence of
malignancies was low and consistent with the rate expected in this
patient population. Thus, the benefit to risk assessment favors the use
of alefacept in the treatment of chronic plaque psoriasis.

# REFERENCES {#references .unnumbered}

Al Suwaidan SN, Feldman SR. Clearance is not a realistic expectation of
psoriasis treatment. *J Am Acad Dermatol* 2000; 42(5):796-802.

Austin LM, Ozawa M, Kikuchi T, *et al*. The majority of epidermal T
cells in Psoriasis vulgaris lesions can produce type 1 cytokines,
interferon-gamma, interleukin-2, and tumor necrosis factor-alpha,
defining TC1 (cytotoxic T lymphocyte) and TH1 effector populations: a
type 1 differentiation bias is also measured in circulating blood T
cells in psoriatic patients. *J Invest Dermatol* 1999; 113(5):752-759.

Bata-Csorgo Z, Hammerberg C, Voorhees JJ, *et al*. Kinetics and
regulation of human keratinocyte stem cell growth in short-term primary
ex vivo culture. Cooperative growth factors from psoriatic lesional T
lymphocytes stimulate proliferation among psoriatic uninvolved, but not
normal, stem keratinocytes. *J Clin Invest* 1995; 95(1):317-327.

Boyd AS, Neldner KH. Hydroxyurea therapy. *J Am Acad Dermatol* 1991;
25(3):518-524.

Centers for Disease Control and Prevention. Mortality from coronary
heart disease and acute myocardial infarction -- United States, 1998.
*Morbidity and Mortality Weekly Report* 2001; 50(6):90-93.

Coven TR, Burack LH, Gilleaudeau R, *et al*. Narrowband UV-B produces
superior clinical and histopathological resolution of moderate to severe
psoriasis in patients compared with broadband UV-B. *Arch Dermatol*
1997; 133(12):1514-1522.

daSilva AJ, Brickelmaier M, Majeau GR, *et al*. Alefacept, an
immunomodulatory recombinant LFA-3/IgG1 fusion protein, induces CD16
signaling and CD2/CD16-dependent apoptosis of CD2+ cells. In press.

Devrimci-Ozguven H, Kundakci TN, Kumbasar H, *et al*. The depression,
anxiety, life satisfaction and affective expression levels in psoriasis
patients. *J Eur Acad Dermatol Venereol* 2000; 14(4):267-271.

Dooren-Greebe RJ, Kuijpers AL, Mulder J, *et al*. Methotrexate
revisited: effects of long-term treatment in psoriasis. *Br J Dermatol*
1994; 130(2):204-210.

Dooren-Greebe RJ, Kuijpers AL, Termorshuizen F, *et al*. Interruption of
long-term methotrexate treatment in psoriasis. Evaluation of clinical
course and laboratory parameters after discontinuation and
reintroduction of weekly oral methotrexate. *Acta Derm Venereol* 1995;
75(5):393-396.

Ellis CN, Fradin MS, Hamilton TA, *et al*. Duration of remission during
maintenance cyclosporine therapy for psoriasis. Relationship to
maintenance dose and degree of improvement during initial therapy. *Arch
Dermatol* 1995; 131(7):791-795.

Ellis CN, Fradin MS, Messana JM, *et al*. Cyclosporine for plaque-type
psoriasis. Results of a multidose, double-blind trial. *N Engl J Med*
1991; 324(5):277-284.

Ellis CN, Krueger GG. Treatment of chronic plaque psoriasis by selective
targeting of memory effector T lymphocytes. *N Engl J Med* 2001;
345(4):248-255.

Feldman SR. Psoriasis treatment. *Curr Prob Dermatol* 1998; 10:1-40.

Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)\--a simple
practical measure for routine clinical use. *Clin Exp Dermatol* 1994;
19(3):210-216.

Fredriksson T, Pettersson U. Severe psoriasis - oral therapy with a new
retinoid. *Dermatologica* 1978; 157(4):238-244.

Friedrich M, Krammig S, Henze M, *et al*. Flow cytometric
characterization of lesional T cells in psoriasis: intracellular
cytokine and surface antigen expression indicates an activated,
memory/effector type 1 immunophenotype. *Arch Dermatol Res* 2000;
292(10):519-521.

Fuhlbrigge RC, Kieffer JD, Armerding D, *et al*. Cutaneous lymphocyte
antigen is a specialized form of PSGL-1 expressed on skin-homing T
cells. *Nature* 1997; 389(6654):978-981.

Gordon PM, Diffey BL, Matthews JN, Farr PM. A randomized comparison of
narrow-band TL-01 phototherapy and PUVA photochemotherapy for psoriasis.
*J Am Acad Dermatol* 1999; 41(5 pt 1):728-732.

Griffiths CE, Voorhees JJ. Psoriasis, T cells and autoimmunity. *J R Soc
Med* 1996; 89(6):315-319.

Gupta MA, Gupta AK. Depression and suicidal ideation in dermatology
patients with acne, alopecia areata, atopic dermatitis and psoriasis.
*Br J Dermatol* 1998; 139(5):846-850.

Henseler T, Christophers E. Disease concomitance in psoriasis. *J Am
Acad Dermatol* 1995; 32(6):982-986.

Hesse G, Wichmann-Hesse AC, Bercher M. PUVA\--therapy with low UV-A
dose. *Z Hautkr* 1987; 62(12):927-6.

Jegasothy BV, Ackerman CD, Todo S, *et al*. Tacrolimus (FK 506) -- a new
therapeutic agent for severe recalcitrant psoriasis. *Arch Dermatol*
1992; 128(6):781-785.

Kanik KS, Cash JM. Does methotrexate increase the risk of infection or
malignancy? *Rheum Dis Clin Morth Am* 1997; 23(4):955-967.

Kaplan RP, Russell DH, Lowe NJ. Etretinate therapy for psoriasis:
clinical responses, remission times, epidermal DNA and polyamine
responses. *J Am Acad Dermatol* 1983; 8(1):95-102.

Kirby B, Richards HL, Woo P, *et al*. Physical and psychologic measures
are necessary to assess overall psoriasis severity. *J Am Acad Dermatol*
2001; 45(1):72-76.

Krueger G, Koo J, Lebwohl M, *et al*. The impact of psoriasis on quality
of life: results of a 1998 National Psoriasis Foundation
patient-membership survey. *Arch Dermatol* 2001; 137(3):280-284.

Krueger GG, Feldman SR, Camisa C, *et al*. Two considerations for
patients with psoriasis and their clinicians: What defines mild,
moderate, and severe psoriasis? What constitutes a clinically
significant improvement when treating psoriasis? *J Am Acad Dermatol*
2000; 43:281-285.

Lebwohl M, Ali S. Treatment of psoriasis. Part 1: topical therapy and
phototherapy. *J Am Acad Dermatol* 2001; 45(4):487-498.

Lebwohl M, Ali S. Treatment of psoriasis. Part 2: systemic therapies. *J
Am Acad Dermatol* 2001; 45(5):649-661.

Lebwohl M, Ellis C, Gottlieb A, *et al*. Cyclosporine consensus
conference with emphasis on the treatment of psoriasis. *J Am Acad
Dermatol* 1998; 39(3):464-475.

Lowe NJ, Wieder JM, Rosenbach A, *et al*. Long-term low-dose
cyclosporine therapy for severe psoriasis: effects on renal function and
structure. *J Am Acad Dermatol* 1996; 35 (5 Pt 1):710-719.

Lundberg L, Johannesson M, Silverdahl M, *et al*. Health-related quality
of life in patients with psoriasis and atopic dermatitis measured with
SF-36, DLQI and a subjective measure of disease activity. *Acta Derm
Venereol* 2000; 80(6):430-434.

Majeau GR, Meier W, Jimmo B, *et al*. Mechanism of lymphocyte
function-associated molecule 3-Ig fusion proteins inhibition of T cell
responses. Structure/function analysis in vitro and in human CD2
transgenic mice. *J Immunol* 1994; 152(6):2753-2767.

Marcil I, Stern RS. Squamous-cell cancer of the skin in patients given
PUVA and ciclosporin: nested cohort crossover study. Lancet 2001;
358:1042-1045.

Margolis D, Bilker W, Hennessy S, *et al*. The risk of malignancy
associated with psoriasis. *Arch Dermatol* 2001; 137(6):778-783.

Mason C, Krueger GG. Thioguanine for refractory psoriasis: a 4-year
experience. *J Am Acad Dermatol* 2001; 44(1):67-72.

Menter MA, See JA, Amend WJ, *et al*. Proceedings of the psoriasis
combination and rotation therapy conference. Deer Valley, Utah, Oct 7-9,
1994. *J Am Acad Dermatol* 1996; 34(2 Pt 1):315-321.

Morison WL, Baughman RD, Day RM, *et al*. Consensus workshop on the
toxic effects of long-term PUVA therapy. *Arch Dermatol* 1998;
134(5):595-598.

Nall M, Farber E. World epidemiology of psoriasis. Psoriasis:
proceedings of the second International Symposium. New York: Yorke
Medical Books, 1977.

O\'Neill P, Kelly P. Postal questionnaire study of disability in the
community associated with psoriasis. *BMJ* 1996; 313(7062):919-921.

Ozawa A, Sugai J, Ohkido M, *et al*. Cyclosporin in psoriasis:
continuous monotherapy versus intermittent long-term therapy. *Eur J
Dermatol* 1999; 9(3):218-223.

Rapp SR, Exum ML, Reboussin DM, *et al*. The physical, psychological and
social impact of psoriasis. *J Health Psychol* 1997; 2:525-537.

Rapp SR, Feldman SR, Exum ML, *et al*. Psoriasis causes as much
disability as other major medical diseases. *J Am Acad Dermatol* 1999;
41(3 Pt 1):401-407.

Robert C, Kupper TS. Inflammatory skin diseases, T cells, and immune
surveillance. *N Engl J Med* 1999; 341(24):1817-1828.

Roenigk HH, Auerbach R, Maibach H, *et al*. Methotrexate in psoriasis:
consensus conference. *J Am Acad Dermatol* 1998; 38(3):478-485.

Shupack J, Abel E, Bauer E, *et al*. Cyclosporine as maintenance therapy
in patients with severe psoriasis. *J Am Acad Dermatol* 1997; 36(3 Pt
1):423-432.

Stern RS, Lunder EJ. Risk of squamous cell carcinoma and methoxsalen
(psoralen) and UV-A radiation (PUVA). A meta-analysis. *Arch Dermatol*
1998; 134 (12):1582-1585.

Stern RS, Nichols KT, Vakeva LH. Malignant melanoma in patients treated
for psoriasis with methoxsalen (psoralen) and ultraviolet A radiation
(PUVA). The PUVA Follow-Up Study. *N Engl J Med* 1997;
336(15):1041-1045.

Szabo SK, Hammerberg C, Yoshida Y, *et al*. Identification and
quantitation of interferon-gamma producing T cells in psoriatic lesions:
localization to both CD4+ and CD8+ subsets. *J Invest Dermatol* 1998;
111(6):1072-1078.

van de Kerkhof PC, Steegers-Theunissen RP, Kuipers MV. Evaluation of
topical drug treatment in psoriasis. *Dermatology* 1998; 197(1):31-36.

Yosipovitch G, Goon A, Wee J, *et al*. The prevalence and clinical
characteristics of pruritus among patients with extensive psoriasis. *Br
J Dermatol* 2000; 143 (5):969-973.

Zachariae H, Kragballe K, Hansen HE, *et al*. Renal biopsy findings in
long-term cyclosporine treatment of psoriasis. *Br J Dermatol* 1997;
136(4):531-535.

Zackheim HS, Glogau RG, Fisher DA, Maibach HI. 6-thioguanine treatment
and psoriasis: experience in 81 patients. *J Am Acad Dermatol* 1994;
30(3):452-458.

# APPENDIX 1: PASI, PGA, and DLQI {#appendix-1-pasi-pga-and-dlqi .unnumbered}

The calculation of the Psoriasis Area and Severity Index (PASI), the
seven-point Physician's Global Assessment (PGA), and the Dermatology
Life Quality Index (DLQI) are described.

**PASI**

Four anatomic sites − head, upper extremities, trunk, and lower
extremities − are assessed for erythema, induration, and desquamation
using a 5-point scale:

-   0 = no symptoms

-   1 = slight

-   2 = moderate

-   3 = marked

-   4 = very marked.

Based on the extent of lesions in a given anatomic site, the area
affected is assigned a numerical value:

-   1 = \<10%

-   2 = 10-29%

-   3 = 30-49%

-   4 = 50-69%

-   5 = 70-89%

-   6 = 90-100%.

Since the head, upper extremities, trunk, and lower extremities
correspond to approximately 10, 20, 30, and 40% of body surface area,
respectively, the PASI score is calculated using the formula

PASI = 0.1(*E~h~* + *I~h~* +*D~h~*)*A~h~* + 0.2(*E~u~* + *I~u~* +
*D~u~*)*A~u~* + 0.3(*E~t~* + *I~t~* + *D~t~*)*A~t~* + 0.4(*E~l~* +*I~l~*
+*D~l~*)*A~l~*

where *E*, *I*, *D*, and *A* denote erythema, induration, desquamation,
and area, respectively, and *h*, *u*, *t*, and *l* denote head, upper
extremities, trunk, and lower extremities, respectively. PASI ranges
from 0.0 to 72.0, with the highest score representing complete
erythroderma of the severest possible degree. Typically, scores of 3 or
less represent mild disease, scores over 3 and up to and including 15
represent moderate disease, and scores over 15 are considered to be
associated with severe disease (Fleischer *et al*, 1996).

**PGA**

The PGA is a 7-point scale used to measure the severity of disease at
the time of the physician's evaluation:

-   severe: very marked plaque elevation, scaling, and/or erythema

-   moderate to severe: marked plaque elevation, scaling, and/or
    erythema

-   moderate: moderate plaque elevation, scaling, and/or erythema

-   mild to moderate: intermediate between moderate and mild

-   mild: slight plaque elevation, scaling, and/or erythema

-   almost clear: intermediate between mild and clear

-   clear: no signs of psoriasis (post-inflammatory hypopigmentation or
    hyperpigmentation could be present).

**DLQI**

DLQI is captured on a patient questionnaire as shown below.

+----------------------------------------------------------+-----------+
| Question                                                 | Response  |
+----------------------------------------------------------+-----------+
| Over the last week, how itchy, sore, painful or stinging | Very much |
| has your skin been?                                      |           |
|                                                          | A lot     |
|                                                          |           |
|                                                          | A little  |
|                                                          |           |
|                                                          | Not at    |
|                                                          | all       |
+----------------------------------------------------------+-----------+
| Over the last week, how embarrassed or self-conscious    | Very much |
| have you been because of your skin?                      |           |
|                                                          | A lot     |
|                                                          |           |
|                                                          | A little  |
|                                                          |           |
|                                                          | Not at    |
|                                                          | all       |
+----------------------------------------------------------+-----------+
| Over the last week, how much has your skin interfered    | Very much |
| with you going shopping or looking after your home or    |           |
| garden?                                                  | A lot     |
|                                                          |           |
|                                                          | A little  |
|                                                          |           |
|                                                          | Not at    |
|                                                          | all       |
|                                                          |           |
|                                                          | Not       |
|                                                          | relevant  |
+----------------------------------------------------------+-----------+
| Over the last week, how much has your skin influenced    | Very much |
| the clothes you wear?                                    |           |
|                                                          | A lot     |
|                                                          |           |
|                                                          | A little  |
|                                                          |           |
|                                                          | Not at    |
|                                                          | all       |
|                                                          |           |
|                                                          | Not       |
|                                                          | relevant  |
+----------------------------------------------------------+-----------+
| Over the last week, how much has your skin affected any  | Very much |
| social or leisure activities?                            |           |
|                                                          | A lot     |
|                                                          |           |
|                                                          | A little  |
|                                                          |           |
|                                                          | Not at    |
|                                                          | all       |
|                                                          |           |
|                                                          | Not       |
|                                                          | relevant  |
+----------------------------------------------------------+-----------+
| Over the last week, how much has your skin made it       | Very much |
| difficult for you to do any sport?                       |           |
|                                                          | A lot     |
|                                                          |           |
|                                                          | A little  |
|                                                          |           |
|                                                          | Not at    |
|                                                          | all       |
|                                                          |           |
|                                                          | Not       |
|                                                          | relevant  |
+----------------------------------------------------------+-----------+
| Over the last week, has your skin prevented you from     | Yes       |
| working or studying?                                     |           |
|                                                          | No        |
|                                                          |           |
|                                                          | Not       |
|                                                          | relevant  |
+----------------------------------------------------------+-----------+
| If "no", over the last week how much has your skin been  | A lot     |
| a problem at work or studying?                           |           |
|                                                          | A little  |
|                                                          |           |
|                                                          | Not at    |
|                                                          | all       |
+----------------------------------------------------------+-----------+
| Over the last week, how much has your skin created       | Very much |
| problems with your partner or any of your close friends  |           |
| or relatives?                                            | A lot     |
|                                                          |           |
|                                                          | A little  |
|                                                          |           |
|                                                          | Not at    |
|                                                          | all       |
|                                                          |           |
|                                                          | Not       |
|                                                          | relevant  |
+----------------------------------------------------------+-----------+
| Over the last week, how much has your skin caused any    | Very much |
| sexual difficulties?                                     |           |
|                                                          | A lot     |
|                                                          |           |
|                                                          | A little  |
|                                                          |           |
|                                                          | Not at    |
|                                                          | all       |
|                                                          |           |
|                                                          | Not       |
|                                                          | relevant  |
+----------------------------------------------------------+-----------+
| Over the last week, how much of a problem has the        | Very much |
| treatment for your skin been, for example by making your |           |
| home messy, or by taking up time?                        | A lot     |
|                                                          |           |
|                                                          | A little  |
|                                                          |           |
|                                                          | Not at    |
|                                                          | all       |
|                                                          |           |
|                                                          | Not       |
|                                                          | relevant  |
+----------------------------------------------------------+-----------+

# APPENDIX 2: Calculation of E~AUC~ {#appendix-2-calculation-of-eauc .unnumbered}

To provide a summary measure of the magnitude of change in lymphocyte
counts and the duration of such an effect, the area-under-the-effect
curve, E~AUC~, was calculated for each patient and each cell type as
described below.

For each patient, the percentage change from baseline count at each time
point during the period after the first injection to 2 weeks after the
last injection in each treatment course is calculated. The percentage
change can be plotted against the actual time the sample was drawn and
the points joined to form a polygon. The area between the resulting
polygon and the line of no change (the zero percent line) can then be
calculated using the trapezoidal rule (Display A2-1). The E~AUC~ can be
thought as representing the "cumulative attrition" of counts.

![](media/image2.wmf){width="4.0in"
height="2.4208333333333334in"}Display A2-1 Calculation of E~AUC~

For a patient whose count is greater than baseline, the area above the
line of no change is not included in the calculation. For instance, in
Display A2-2, the second sample after baseline provided a count above
baseline. The area above the line of no change is not included in the
calculation, but the two triangles (shaded) are counted in the
calculation of the E~AUC~. The intersections with the line of no change
are calculated by interpolation.

![](media/image3.wmf){width="3.9in"
height="2.6055555555555556in"}Display A2-2 Calculation of E~AUC~ when
counts are greater than baseline

# appendix 3: publication of phase 2 dose-response study (708): Ellis CN, Krueger GG. Treatment of chronic plaque psoriasis by selective targeting of memory effector t lymphocytes. *N Engl J Med* 2001; 345(4):248-255 {#appendix-3-publication-of-phase-2-dose-response-study-708-ellis-cn-krueger-gg.-treatment-of-chronic-plaque-psoriasis-by-selective-targeting-of-memory-effector-t-lymphocytes.-n-engl-j-med-2001-3454248-255 .unnumbered}

![](media/image4.png){width="5.995138888888889in"
height="8.463194444444444in"}

![](media/image5.png)

![](media/image6.png){width="6.0in" height="8.529166666666667in"}

![](media/image7.png){width="5.995138888888889in"
height="8.247916666666667in"}

![](media/image8.png){width="5.990972222222222in"
height="8.422222222222222in"}

![](media/image9.png){width="5.990972222222222in"
height="8.468055555555555in"}

![](media/image10.png){width="6.0in" height="8.541666666666666in"}

![](media/image11.png){width="5.990972222222222in"
height="8.468055555555555in"}