DERMATOLOGIC AND OPHTHALMIC DRUGS\
ADVISORY COMMITTEE MEETING

9 SEPTEMBER 2003

RAPTIVA (Efalizumab)

Genentech, Inc.\
1 DNA Way\
South San Francisco, CA 94080‑4990

*Available for Public Disclosure without Redaction*

TABLE OF CONTENTS

Page

1\. EXECUTIVE SUMMARY 3

1.1 Proposed Indication 4

1.2 Efficacy 4

1.3 Safety 7

1.4 Conclusions 9

2\. OVERVIEW 10

2.1 Background 10

2.2 Pathophysiology of Psoriasis 10

2.3 Mechanism of Action of Raptiva 11

3\. PHARMACOLOGY 14

3.1 Clinical Pharmacology of Raptiva 14

3.1.1 Raptiva Pharmacodynamics 14

3.1.2 Raptiva Pharmacokinetics 17

3.1.3 Raptiva Immunology and Immunocompetence 19

3.2 Nonclinical Pharmacology Toxicology Data 20

4\. OVERVIEW OF CLINICAL TRIALS 22

5\. CLINICAL EFFICACY 26

5.1 Overview of Study 2390 26

5.1.1 Study 2390 26

5.2 Supportive Studies Providing Additional Efficacy Data 39

5.2.1 Study 2600 39

5.2.2 Study 2058 40

5.2.3 Study 2059 42

5.3 Comparison of Results in Subpopulations 44

5.4 Treatment beyond 12 Weeks 46

5.5 Clinical Efficacy Conclusions 50

TABLE OF CONTENTS (cont'd)

Page

6\. CLINICAL SAFETY 52

6.1 Overview 52

6.2 Clinical Results 53

6.2.1 Demographics and Baseline Characteristics 53

6.2.2 Subject Disposition (Phase III Studies) 55

6.2.3 Drug Exposure (Phase III Studies) 56

6.2.4 Common Adverse Events (Phase III Studies) 57

6.2.5 Drug‑Related Adverse Events (Phase III Studies) 59

6.2.6 Acute Adverse Reactions (Phase III Studies) 60

6.2.7 Deaths and Other Serious Adverse Events 62

6.2.8 Malignancies (All Psoriasis Studies) 65

6.2.9 Infection‑Related Adverse Events (Phase III Studies) 69

6.2.10 Thrombocytopenia (All Psoriasis Studies) 71

6.2.11 Adverse Events of Psoriasis (Phase III Studies) 75

6.2.12 Arthritis (Phase III Studies) 78

6.2.13 Hypersensitivity‑Related Adverse Events\
(Phase III Studies) 78

6.2.14 Injection‑Site Adverse Events (Phase III Studies) 80

6.2.15 Audiologic Assessments 80

6.3 Laboratory Safety Tests (Phase III Studies) 80

6.4 Long‑Term Clinical Results 81

6.5 Retreatment Results 85

6.6 Withdrawal Results 86

6.7 Drug--Drug and Drug--Demographic Interactions 88

6.7.1 Drug--Drug Interactions 88

6.7.2 Drug--Demographic Interactions 89

6.8 Drug Abuse, Overdose, and Withdrawal Effects 89

6.9 Self‑Administration of Subcutaneous Raptiva 89

6.10 Safety Data from Other Indications 90

6.11 Clinical Safety Summary and Conclusions 91

TABLE OF CONTENTS (cont'd)

Page

7\. BENEFITS AND RISKS 92

7.1 Unmet Medical Need 92

7.2 Benefit--Risk Conclusions 93

REFERENCE LIST 94

TABLES AND FIGURES

Table 1: Abbreviations and Terms 1

Table 2: Overall Maximal Effects for Down‑Modulation of CD11a Expression
and Saturation of Available CD11a Binding Sites on Leukocyte
Subpopulations by Raptiva during Weekly Treatment in the Clinical
Studies 14

Table 3: Clinical Development of Raptiva: Completed Psoriasis Studies 23

Table 4: Clinical Development of Raptiva: Ongoing Psoriasis Studies 25

Table 5: Demographic and Baseline Characteristics of Randomized Subjects
in Study 2390 29

Table 6: Baseline Psoriasis Characteristics of Treated Subjects in
Study 2390 30

Table 7: Subject Disposition and Reasons for Discontinuation of
Treatment in Study 2390 31

Table 8: PASI‑75 Response to Treatment at 12 Weeks for Randomized
Subjects in Study 2390 32

Table 9: PASI Response at 12 Weeks as Percent Improvement from Baseline
in Study 2390 33

Table 10: PGA Response at 12 Weeks for Subjects in Study 2390 35

Table 11: Improvement from Baseline in Overall DLQI Score at Week 12 in
Study 2390 36

Table 12: Mean (SD) Improvement from Baseline in the Itching Scale at
Week 12 in Study 2390 38

Table 13: Efficacy Results at 12 Weeks for Randomized Subjects in
Study 2600 40

Table 14: PASI‑75 and PASI‑50 Responses after 24 Weeks of Continuous
Treatment for Subjects: Study 2391 47

TABLE OF CONTENTS (cont'd)

Page

TABLES AND FIGURES (cont'd)

Table 15: Treatment beyond 24 Weeks, Overview of Efficacy by PASI
Response in Study 2243: PASI Response from Baseline during First and
Extended Treatment (\> 12 Weeks) with Raptiva 48

Table 16: Baseline Demographics for Subjects in the Phase III,
Placebo‑Controlled Studies 2390, 2600, 2058, and 2059 54

Table 17: Baseline Psoriasis Characteristics for Subjects in the Phase
III, Placebo‑Controlled Studies 2390, 2600, 2058, and 2059 55

Table 18: Subject Disposition and Reasons for Premature Discontinuation
for Subjects during the First 12 Weeks of Treatment in the Phase III,
Placebo‑Controlled Studies 2390, 2600, 2058, and 2059 56

Table 19: Extent of Exposure to Study Drug for Subjects during the First
12 Weeks of Treatment in the Placebo‑Controlled Studies 2390, 2600,
2058, and 2059 57

Table 20: Adverse Events That Occurred in ≥ 5% of Subjects in Any
Raptiva or Placebo‑Treated Group during the First 12 Weeks of Treatment
in the Placebo‑Controlled Studies 58

Table 21: Study Drug--Related Adverse Events That Occurred in ≥ 5% of
Subjects in Any Raptiva or Placebo‑Treated Group during the First 12
Weeks of Treatment in the Placebo‑Controlled Studies 60

Table 22: Acute Adverse Reactions Experienced by Subjects during the
First 12 Weeks of Treatment in the Placebo‑Controlled Studies 61

Table 23: Deaths 63

Table 24: Serious Adverse Events That Occurred during the First 12 Weeks
of Treatment in the Placebo‑Controlled Studies 64

Table 25: Incidence Rates for Malignancies in the Psoriasis Clinical
Trials 66

Table 26: Observed versus Expected Rates of Malignancies:
Raptiva‑Treated Subjects 68

Table 27: Adverse Events Diagnostic of Infection That Occurred during
the First 12 Weeks of Treatment in the Placebo‑Controlled Studies 70

Table 28: Observed versus Expected Infections Requiring Hospitalization
71

Table 29: NCI‑CTC Grade 3 or 4 Thrombocytopenia Events or
Thrombocytopenia Occurrences Classified by the Investigators as Serious
72

Table 30: Thrombocytopenia during the First 12 Weeks of Treatment in the
Placebo‑Controlled Studies 74

TABLE OF CONTENTS (cont'd)

Page

TABLES AND FIGURES (cont'd)

Table 31: Psoriasis Adverse Events Experienced by Subjects Previously
Treated with Raptiva during Washout 76

Table 32: Psoriasis Adverse Events by Medication Received during Washout
for Evaluable Subjects from Studies HUPS254, HUPS256, 2058, 2059, 2142,
2243, and 2062 77

Table 33: Rate of Adverse Events of Psoriasis, Excluding Mild and
Guttate Psoriasis, by Concomitant Therapy during Washout 77

Table 34: Hypersensitivity Adverse Events That Occurred during the First
12 Weeks of Treatment in the Placebo‑Controlled Studies 79

Table 35: Adverse Events Experienced by ≥ 5% of Subjects by 12‑Week
Course of Raptiva Treatment 83

Table 36: Serious Adverse Events Reported for 2 or More Subjects Treated
with Raptiva within Any 12‑Week Treatment Period of the
Placebo‑Controlled and Open‑Label Studies 84

Table 37: Adverse Events Experienced by ≥ 5% of Subjects Treated with
Raptiva following a Period of Non‑Treatment 85

Table 38: Serious Adverse Events Reported for 2 or More Subjects during
the First or Second Raptiva Treatment Course in the Placebo‑Controlled
and Open‑Label Studies 86

Table 39: Home Dosing: Subjects without PASI‑75 Response during the
First 12 Weeks of Treatment Achieving PASI‑75 during the Second 12 Weeks
of Treatment 90

Figure 1a: PASI Response at 12 Weeks of Treatment in Study 2390 6

Figure 1b: PASI Response following 12 and 24 Weeks of Treatment in
Studies 2390 and 2391 6

Figure 2: Psoriasis 11

Figure 3: Raptiva's Mechanism of Action 12

Figure 4: Mean Serum Raptiva Concentration (PK), CD11a Expression, and
Available CD11a Binding Sites and Absolute Lymphocyte Counts (PD)
following Administration of 1.0 mg/kg/wk Raptiva for 12 Weeks in
Study 2142 16

Figure 5: Study 2390 26

Figure 6: Mean ± SEM Percent Improvement in PASI Score over Time in
Study 2390 34

TABLE OF CONTENTS (cont'd)

Page

TABLES AND FIGURES (cont'd)

Figure 7: Mean ± SEM Improvement in DLQI over Time in Study 2390 37

Figure 8: Study 2058 41

Figure 9: Study 2059 43

Figure 10: Raptiva Minus Placebo PASI‑75 Rates at Day 84 by Demographic
Subgroups (95% CI) 45

Figure 11: Raptiva Minus Placebo PASI‑75 Rates at Day 84 by
Disease‑Related Subgroups (95% CI) 46

Figure 12: Acute Adverse Reactions Experienced by Subjects during the
First 12 Weeks of Treatment in Placebo‑Controlled Studies 62

Figure 13: Percent PASI Improvement during Raptiva Treatment and Washout
for Two Cohorts in Study 2059 87

APPENDICES

Appendix A: Proposed Package Insert

Appendix B: Psoriasis Area and Severity Index

Appendix C: Physicians Global Assessment (Formerly known as the Overall
Lesion Severity Scale)

Appendix D: Physician's Global Assessment of Change

Appendix E: Copies of Publications

The abbreviations used in this document are defined in Table 1 below.

+----------------------+-----------------------------------------------+
| Table 1              |                                               |
|                      |                                               |
| Abbreviations and    |                                               |
| Terms                |                                               |
+----------------------+-----------------------------------------------+
| Abbreviation         | Definition                                    |
+----------------------+-----------------------------------------------+
| APC                  | Antigen‑presenting cells                      |
+----------------------+-----------------------------------------------+
| BLA                  | Biologics License Application                 |
+----------------------+-----------------------------------------------+
| BMI                  | Body mass index                               |
+----------------------+-----------------------------------------------+
| BSA                  | Body surface area                             |
+----------------------+-----------------------------------------------+
| CI                   | Confidence interval                           |
+----------------------+-----------------------------------------------+
| COPD                 | Chronic obstructive pulmonary disease         |
+----------------------+-----------------------------------------------+
| CRP                  | C‑reactive protein                            |
+----------------------+-----------------------------------------------+
| DLQI                 | Dermatology Life Quality Index                |
+----------------------+-----------------------------------------------+
| F                    | Female                                        |
+----------------------+-----------------------------------------------+
| FDA                  | Food and Drug Administration                  |
+----------------------+-----------------------------------------------+
| FE                   | First Exposure (first 12 weeks of Raptiva     |
|                      | treatment)                                    |
+----------------------+-----------------------------------------------+
| FT                   | First 12‑week treatment period of controlled  |
|                      | studies (2058, 2059, 2390, and 2600)          |
+----------------------+-----------------------------------------------+
| GI                   | Gastrointestinal                              |
+----------------------+-----------------------------------------------+
| HLA‑DR               | Human leukocyte antigen‑DR                    |
+----------------------+-----------------------------------------------+
| HUVEC                | Human vein endothelial cell                   |
+----------------------+-----------------------------------------------+
| ICAM                 | Intercellular adhesion molecule               |
+----------------------+-----------------------------------------------+
| IL‑2                 | Interleukin‑2                                 |
+----------------------+-----------------------------------------------+
| ITT                  | Intent to treat                               |
+----------------------+-----------------------------------------------+
| IV                   | Intravenous                                   |
+----------------------+-----------------------------------------------+
| LFA‑1                | Lymphocyte function--associated antigen‑1     |
+----------------------+-----------------------------------------------+
| M                    | Male                                          |
+----------------------+-----------------------------------------------+
| MOA                  | Mechanism of action                           |
+----------------------+-----------------------------------------------+
| NA                   | Not applicable                                |
+----------------------+-----------------------------------------------+
| NCI‑CTC              | National Cancer Institute Common Toxicity     |
|                      | Criteria                                      |
+----------------------+-----------------------------------------------+
| NK                   | Natural killer                                |
+----------------------+-----------------------------------------------+
| NMSC                 | Non‑melanomatous skin cancer                  |
+----------------------+-----------------------------------------------+
| NOS                  | Not otherwise specified                       |
+----------------------+-----------------------------------------------+
| OLS                  | Overall Lesion Severity (now referred to as   |
|                      | Physicians Global Assessment)                 |
+----------------------+-----------------------------------------------+

+----------------------+-----------------------------------------------+
| Table 1 (cont'd)     |                                               |
|                      |                                               |
| Abbreviations and    |                                               |
| Terms                |                                               |
+----------------------+-----------------------------------------------+
| Abbreviation         | Definition                                    |
+----------------------+-----------------------------------------------+
| PASI                 | Psoriasis Area and Severity Index             |
+----------------------+-----------------------------------------------+
| PASI‑50              | 50% improvement in PASI score relative to     |
|                      | Day 0 of the first 12‑week treatment period   |
+----------------------+-----------------------------------------------+
| PASI‑75              | \< 75% improvement in PASI score relative to  |
|                      | Day 0 of the first 12‑week treatment period   |
+----------------------+-----------------------------------------------+
| PGA of Change        | Physician's Global Assessment of Change       |
+----------------------+-----------------------------------------------+
| PD                   | Pharmacodynamics                              |
+----------------------+-----------------------------------------------+
| PK                   | Pharmacokinetics                              |
+----------------------+-----------------------------------------------+
| PBMC                 | Peripheral blood mononuclear cell             |
+----------------------+-----------------------------------------------+
| PSA                  | Psoriasis Symptom Assessment                  |
+----------------------+-----------------------------------------------+
| PTLD                 | Post‑transplant lymphoproliferative disorder  |
+----------------------+-----------------------------------------------+
| qow                  | Every other week                              |
+----------------------+-----------------------------------------------+
| SC                   | Subcutaneous                                  |
+----------------------+-----------------------------------------------+
| SD                   | Standard deviation                            |
+----------------------+-----------------------------------------------+
| SEER                 | Surveillance, Epidemiology and End Results    |
+----------------------+-----------------------------------------------+
| SEM                  | Standard error of mean                        |
+----------------------+-----------------------------------------------+
| SH                   | Saskatchewan Health                           |
+----------------------+-----------------------------------------------+
| TCP                  | Thrombocytopenia                              |
+----------------------+-----------------------------------------------+
| UHC                  | UnitedHealthcare                              |
+----------------------+-----------------------------------------------+
| WBC                  | White blood cell                              |
+----------------------+-----------------------------------------------+

1\. EXECUTIVE SUMMARY

Raptiva represents a novel approach to the treatment of moderate to
severe psoriasis. It is a recombinant humanized monoclonal antibody that
binds to lymphocyte cell surface marker CD11a, and it inhibits
activation and trafficking of T‑cells.

Raptiva has been extensively studied in 13 psoriasis clinical trials in
which 2,762 subjects were treated with Raptiva. Four of the studies were
placebo‑controlled, randomized, Phase III trials. Subjects treated with
Raptiva experienced rapid, clinically meaningful, and statistically
significant benefits across every measured endpoint in all Phase II and
III clinical studies. Subjects receiving Raptiva had fewer psoriatic
skin lesions, less itching, and improved quality‑of‑life as well as
sustained benefits while on therapy. Few subjects experienced serious
adverse effects from Raptiva therapy; most adverse events were mild and
transient. Below is a list of key conclusions drawn from the Raptiva
clinical studies:

-   Raptiva improves signs and symptoms of psoriasis:

After 12 weeks of Raptiva treatment, 27% of subjects had PASI‑75
improvement and 59% of subjects had PASI‑50 improvement compared with
placebo rates of 4% and 14%, respectively.

All other secondary endpoints, including global psoriasis assessment
(PGA), quality‑of‑life scale (DLQI), and itching scale, showed
statistically and clinically significant benefit.

-   Raptiva has an early onset of action, with reduction in PASI score
    demonstrated 4 weeks after the start of treatment.

-   The beneficial effects of Raptiva are consistent across patient
    subgroups.

-   The efficacy of Raptiva improves with continuous treatment past
    12 weeks.

After 24 weeks of Raptiva treatment, 44% of subjects had PASI‑75
improvement and 66% of subjects had PASI‑50 improvement.

-   Raptiva is well tolerated, and its overall safety profile is
    favorable:

The rate of serious adverse events was low (2% in the proposed
to‑be‑marketed 1 mg/kg/wk dose group) and similar to the rate in
placebo‑treated subjects.

The most common adverse events were mild, self‑limited, and associated
with the first two doses. These events included headache, chills,
nausea, fever, myalgia, and asthenia.

A small number of subjects (\~1 in 500) had NCI Grade 3 or 4
thrombocytopenia that was reversible upon discontinuation of Raptiva. A
causal relationship with Raptiva could not be ruled out.

There is no evidence to suggest that Raptiva affects the overall rate of
malignancies and infections compared with placebo.

-   Withdrawal of Raptiva results in a loss of benefit. In some subjects
    (\~13%), rapid return of disease or a change in morphology was
    observed. Transition to other therapies after discontinuation
    largely reduces the occurrence of these adverse events.

-   Raptiva maintains its favorable safety profile even with extended
    treatment.

1.1 Proposed indication

Raptiva is indicated for the treatment of adult patients (18 years or
older) with moderate to severe plaque psoriasis.

1.2 Efficacy

Primary support for the efficacy of Raptiva in moderate to severe plaque
psoriasis is provided by the adequate and well‑controlled Phase III
study (2390) in subjects with moderate to severe plaque psoriasis.
Supportive data come from the randomized, double‑blind,
placebo‑controlled studies (2600, 2058, and 2059), which used the same
basic eligibility criteria and design of the first 12‑week treatment
course as Study 2390.

Subjects participating in the Phase III, placebo‑controlled studies all
had a diagnosis of moderate to severe plaque psoriasis as defined by a
score of at least 12 on the Psoriasis Area and Severity Index (PASI) and
psoriatic involvement of at least 10% of body surface area (BSA).
Subjects were required to be candidates for systemic psoriasis treatment
or had to have received prior therapy with systemic treatments.

Raptiva treatment commenced with an initial dose of 0.7 mg/kg, followed
by 11 weekly doses of 1.0 mg/kg. In Studies 2058 and 2059, subjects were
also randomized to receive 2.0 mg/kg Raptiva weekly during the first
12‑week treatment period.

The primary efficacy endpoint was the proportion of subjects who
achieved 75% or greater improvement from baseline in PASI (referred to
as PASI‑75) on Day 84. Secondary efficacy variables included the
PASI‑50, Physician's Global Assessments, a validated quality‑of‑life
assessment---the Dermatology Life Quality Index (DLQI)---and other
subject‑reported assessments focusing on symptoms and itching.

In the pivotal study (2390), the PASI‑75 and PASI‑50 responses were
statistically significantly higher for the Raptiva‑treated group
compared with the placebo‑treated group (p\<0.001; see Figure 1a). In
all three supportive studies, the benefit of Raptiva treatment was
consistent with that seen in Study 2390 and was statistically
significant.

The efficacy of continuous treatment with 1.0 mg/kg/wk Raptiva beyond
12 weeks is demonstrated by data from the open‑label extension
study (2391), which allowed subjects who completed Study 2390 to
continue Raptiva treatment for a further 12 weeks. The PASI‑75 response
rate increased from 27% at the end of 12 weeks of treatment to 44% at
the end of 24 weeks of treatment (p\<0.001; see Figure 1b). The
percentage of subjects achieving a PASI‑50 was also increased with a
further 12 weeks of treatment.

**Figure 1a**\
PASI Response at 12 Weeks of Treatment in Study 2390

![](media/image1.wmf)

**Figure 1b**\
PASI Response following 12 and 24 Weeks of Treatment\
in Studies 2390 and 2391

![](media/image2.wmf)

The placebo rate for 24 weeks is not available because placebo‑treated
patients rolled over to Raptiva at 12 weeks.

The efficacy of Raptiva was consistent across patient subgroups. In
particular, Raptiva appears to be equally effective in patients with
moderate, severe, or very severe disease.

Raptiva has a rapid onset of action. In Study 2390, at Day 28 the mean
PASI percent improvement from baseline was significantly greater
(p \< 0.001) in the Raptiva 1.0 mg/kg group compared with the
placebo‑treated group.

In addition, early response to treatment was observed in the
quality‑of‑life measure, the DLQI: the mean improvement from baseline in
DLQI was significantly greater (p \< 0.001) by Day 28 (the first
post‑baseline assessment) in the Raptiva‑treated group compared with the
placebo‑treated group. Further, for the Raptiva‑treated subjects, the
improvement at Day 28 had reached 70% of the total DLQI improvement
achieved by Day 84, indicating a substantial early quality‑of‑life
benefit.

1.3 Safety

Raptiva was studied in 2,762 subjects with psoriasis. Of these, 1,620
subjects were treated in the placebo‑controlled, randomized Phase III
trials.

During the first 12‑week, placebo‑controlled treatment period, the
overall rate of adverse events was slightly higher for the
Raptiva‑treated groups compared with the placebo‑treated group (73.6% in
the placebo‑treated group, 82.4% in the Raptiva 1.0 mg/kg/wk group, and
87.0% in the Raptiva 2.0 mg/kg/wk group). Headache, chills, fever,
nausea, and myalgia were among the most frequently reported adverse
events in the Raptiva‑treated subjects. These events were part of "acute
adverse reactions" that were predefined in the clinical program. The
reactions were generally mild, self‑limited, and short‑lived and
occurred most often with the initial two doses.

During the first 12‑week, placebo‑controlled treatment period, the
overall rate of serious adverse events was low and similar between the
placebo‑treated group (1.7%) and the Raptiva 1.0 mg/kg/wk group (2.0%).
Most types of serious adverse events were reported for a single subject,
and no pattern of serious adverse events suggestive of toxicity was
noted.

Overall rates of adverse events leading to discontinuation of treatment
were low (2.5% for the 1.0 mg/kg/wk group compared with 2.0% for the
placebo‑treated group) over the first 12 weeks.

Malignancies were reported infrequently and occurred at comparable rates
between the placebo‑treated and Raptiva‑treated groups. The overall
incidence rate of malignancies per 100 subject‑years was 1.62 in the
placebo‑treated group and 1.68 in the Raptiva‑treated group.

The overall frequency of infections during the first 12 weeks was
comparable between the placebo‑treated group (26.3%) and the 1.0
mg/kg/wk Raptiva‑treated group (28.9%). The rates of serious infections
requiring hospitalization were low and relatively similar between the
Raptiva‑ and placebo‑treated groups (1.61 per 100 subject‑years vs. 1.18
per 100 subject‑years, respectively), and were consistent with the
expected background rate based on external epidemiological data.

Clinical trials were designed such that Raptiva was discontinued without
taper or transition to other therapies in the clinical program. In
addition, use of other psoriasis medications was usually restricted even
when subjects experienced return of psoriasis. Adverse events of
psoriasis were experienced by 13.0% of the subjects during the 12‑week
period following discontinuation of Raptiva, most of which were mild to
moderate in severity. Only 6 (0.5%) of 1,166 subjects who underwent
Raptiva washout experienced a serious adverse event of psoriasis. In the
subset of subjects who initiated psoriasis medications during treatment
withdrawal, the rate of psoriasis adverse events was substantially
lower.

Out of the 2,762 Raptiva‑treated subjects in the clinical program, there
were six reports of reversible NCI Grade 3 or 4 thrombocytopenia (TCP)
that were consistent with a possible drug‑induced effect. Four of the
6 subjects had received medications or had concurrent medical conditions
that could have contributed or predisposed subjects to the onset of TCP.
Although causality has not been established, these results suggest that
reversible thrombocytopenia may occur infrequently (approximately 1 in
500 patients) in patients treated with Raptiva. However, the overall
rate of TCP observed during Raptiva treatment appears less than that
reported with other treatments used in patients with moderate to severe
psoriasis (e.g., NEORAL^^ \[package insert\]).

During the Raptiva program, there were no clinically significant
differences in laboratory abnormalities observed between the Raptiva‑
and placebo‑treated subjects. A total of 6.3% of the subjects developed
anti‑Raptiva antibodies, but almost all had extremely low titers. There
were no clinically relevant safety or efficacy effects associated with
the antibodies. Preliminary vaccination data suggest that secondary
response to immunization may be reduced by Raptiva treatment. Studies
are currently ongoing to evaluate immune responses during and following
administration of weekly SC doses of Raptiva. The current recommendation
is to hold Raptiva treatment for 4--8 weeks before an immunization.

Raptiva was well tolerated over the treatment periods beyond the initial
12 weeks. An examination of adverse events for subjects treated with
Raptiva beyond the initial 12 weeks of treatment up to 1 year indicates
no increase in the percentage of subjects reporting adverse events with
longer Raptiva exposure and no change in the rate of serious adverse
events.

1.4 Conclusions

Raptiva has been demonstrated to be safe and effective for the treatment
of psoriasis. Raptiva has a rapid onset of action and is well tolerated
over long durations of treatment. Extended therapy with Raptiva provides
increased clinical efficacy with no increase in adverse events. Overall,
there were few serious adverse events associated with Raptiva therapy,
no evidence of organ toxicity, and no evidence of increased malignancies
or infections.

Raptiva provides a significant new, safe, and efficacious alternative
for patients with moderate to severe plaque psoriasis.

2\. OVERVIEW

1.  BACKGROUND

The clinical development of Raptiva was performed collaboratively by
XOMA (Berkeley, CA) and Genentech, Inc. (South San Francisco, CA).

In December 2002, a Biologics License Application (BLA) was submitted.
In May 2003, a Safety Update was provided to the Food and Drug
Administration (FDA). Except where otherwise noted, the data in this
briefing document are drawn from the BLA and the Safety Update.

2.  Pathophysiology of Psoriasis

Psoriasis is a T cell--mediated, inflammatory disease characterized by
accumulation of activated T lymphocytes in the epidermis and dermis that
stimulate hyperproliferation of keratinocytes to produce psoriatic
lesions (see Figure 2) (Griffiths et al. 1995; Gottlieb 1998; Austin
et al. 1999; Bos and De Rie 1999; Nickoloff 1999). The antigen that
causes psoriasis is unknown, but the pathophysiology has been studied
extensively, particularly with regard to T cells. In order to mediate
the cellular changes in the dermis that lead to psoriasis, T lymphocytes
first undergo three key interactions with other cell types.

**Step 1:** Antigen‑presenting cells (APCs) must first be activated in
the epidermis, where antigen is internalized, enzymatically processed,
and presented on the APC surface. Activated APCs then travel to the
regional lymph nodes, where they interact with naive T lymphocytes,
resulting in T‑lymphocyte activation.

**Step 2:** T‑lymphocyte binding to venous endothelial cells occurs,
followed by trafficking into dermal and epidermal tissue.

**Step 3:** T‑lymphocyte reactivation by a second exposure to the
specific antigen, which occurs in the dermis or epidermis. This leads to
release of pro‑inflammatory cytokines and other inflammatory mediators,
which stimulate the increased keratinocyte proliferation.

Whereas Step 1 occurs only once, it is followed by proliferation of the
activated T cells, providing an amplification of the process. Steps 2
and 3 occur in an iterative fashion, causing the persistence of the
disease.

A large number of integrins and selectins on T lymphocytes contribute in
their interaction with APCs or endothelial cells.

Figure 2

Psoriasis

![](media/image3.jpeg){width="5.99375in" height="3.4604166666666667in"}

Schematic based on Krueger JG. J Am Acad Dermatol 2002;46(1):1--23.

2.3 MECHANISM OF ACTION OF Raptiva

LFA‑1 (lymphocyte function--associated antigen‑1, a leukocyte cell
surface protein) is an adhesion molecule whose expression is limited to
leukocytes. LFA‑1 is composed of two subunits: CD11a and CD18. Whereas
CD18 is also part of other adhesion molecules, CD11a is unique to LFA‑1.
This restricted expression of CD11a limits the potential effects of
Raptiva to cells that express LFA‑1. Although LFA‑1 is a key adhesion
molecule, leukocytes express multiple other members of the integrin and
selectin families. Variation in distribution of these multiple adhesion
molecules leads to variation in the relative functional importance of
LFA‑1. Binding of Raptiva to the CD11a subunit of LFA‑1 inhibits LFA‑1
function. Raptiva does not induce apoptosis or mediate cell killing.
Effects of Raptiva on lymphocytes and other cell types are reversible.

LFA‑1 binds to members of the ICAM (intercelluar adhesion molecule)
family. ICAM is expressed by APCs and is up‑regulated on endothelial
cells and keratinocytes in psoriasis plaques. Inhibition of LFA‑1
function by Raptiva interferes in several key steps of psoriasis
pathophysiology.

Raptiva inhibits adhesion of T lymphocytes to other cell types by
inhibiting the binding of LFA‑1 to ICAM‑1 (see Figure 3). This mechanism
of action (MOA) has a number of effects, depending on the cell type,
including the following:

-   Inhibition of T‑lymphocyte activation (proliferation, cytokine
    release)

-   Inhibition of T‑lymphocyte trafficking and extravasation

-   Inhibition of T‑lymphocyte interactions with tissue‑specific cells
    (keratinocytes)

Figure 3

Raptiva's Mechanism of Action

![](media/image4.jpeg){width="5.99375in"
height="3.4604166666666667in"}![](media/image5.wmf){width="1.05in"
height="0.525in"}![](media/image5.wmf){width="1.05in" height="0.525in"}

Treatment with Raptiva can potentially interfere at several critical
points in the pathophysiology of psoriasis:

-   Inhibition of initial activation of naive T cells in regional lymph
    nodes

-   Inhibition of T‑lymphocyte proliferation and interleukin‑2 (IL‑2)
    receptor expression

-   Inhibition of T‑lymphocyte trafficking to psoriatic lesions

-   Inhibition of secondary T‑lymphocyte activation in the dermis and
    epidermis

-   Inhibition of T‑lymphocyte interactions with keratinocytes

-   Inhibition of T‑lymphocyte release of cytokines that drive further
    inflammation within the psoriatic plaque

Projected actions of Raptiva were verified in skin biopsies from
moderate to severe psoriasis subjects participating in the clinical
trials. The number of infiltrating T cells in both the dermis and
epidermis was decreased by Raptiva treatment. This was accompanied by
decreased expression of inflammatory markers (decreased ICAM‑1 and
HLA‑DR) and normalization of keratinocyte differentiation as reflected
by keratin 16 expression. Epidermal and dermal thickness returned to the
normal range. Raptiva treatment produced full morphological and
immunohistochemical normalization of lesional psoriatic skin.

3\. PHARMACOLOGY

3.1 clinical pharmAcology of Raptiva

3.1.1 Raptiva Pharmacodynamics

Binding of CD11a by Raptiva results in saturation of available CD11a
binding sites on lymphocytes, down‑modulation of cell surface CD11a
expression on lymphocytes and elevation of peripheral blood lymphocytes.
As documented in the Phase I dose‑ranging studies, the extent and
duration of these effects was dose‑dependent.

At the proposed marketed dose of 1.0 mg/kg/wk SC, Raptiva produced
maximal effects on pharmacodynamic markers, throughout the dosing
interval i.e., reduced CD11a expression to \~15%--30% of baseline and
saturated CD11a on T lymphocytes in the peripheral blood to \< 5% of
baseline available binding sites. After cessation of treatment, CD11a
expression returned to baseline as Raptiva was eliminated from the body.
Similarly, Raptiva also affects other leukocyte populations, although
the extent of maximal effect is different for the different
subpopulations and less than that on T lymphocytes (see Table 2).

+-----------------+-------------------------+-------------------------+
| Table 2         |                         |                         |
|                 |                         |                         |
| Overall Maximal |                         |                         |
| Effects for     |                         |                         |
| Down‑Modulation |                         |                         |
| of CD11a        |                         |                         |
| Expression and  |                         |                         |
| Saturation of   |                         |                         |
| Available CD11a |                         |                         |
| Binding Sites   |                         |                         |
| on Leukocyte    |                         |                         |
| Subpopulations\ |                         |                         |
| by Raptiva      |                         |                         |
| during Weekly   |                         |                         |
| Treatment in    |                         |                         |
| the Clinical    |                         |                         |
| Studies         |                         |                         |
+-----------------+-------------------------+-------------------------+
| Cell Type       | CD11a Down‑Modulation\  | CD11a Saturation        |
|                 | Measured by CD11a       | Measured by Available   |
|                 | Expression\             | CD11a Binding Sites\    |
|                 | (Percent Baseline) ^a^  | (Percent Baseline)      |
+-----------------+-------------------------+-------------------------+
| T lymphocyte    | 15%−30%                 | \< 5%                   |
| (CD3^ + ^)      |                         |                         |
+-----------------+-------------------------+-------------------------+
| > CD4^ + ^      | 10%−20%                 | \< 5%                   |
| > phenotype     |                         |                         |
+-----------------+-------------------------+-------------------------+
| CD8^ + ^        | 20%−25%                 | \< 5%                   |
| phenotype       |                         |                         |
+-----------------+-------------------------+-------------------------+
| B lymphocytes   | 25%−50%                 | \< 10%                  |
+-----------------+-------------------------+-------------------------+
| NK cells        | 35%−50%                 | \< 5%                   |
+-----------------+-------------------------+-------------------------+
| Monocytes       | 60%−75%                 | \< 10%                  |
+-----------------+-------------------------+-------------------------+
| Neutrophils     | 45%−65%                 | \< 10%                  |
+-----------------+-------------------------+-------------------------+
| NK = natural    |                         |                         |
| killer.         |                         |                         |
|                 |                         |                         |
| ^a^ Ranges      |                         |                         |
| represent mean  |                         |                         |
| data from the   |                         |                         |
| last dosing     |                         |                         |
| interval in     |                         |                         |
| several         |                         |                         |
| multiple‑dose   |                         |                         |
| studies.        |                         |                         |
+-----------------+-------------------------+-------------------------+

Reduction in CD11a expression was rapid after intravenous (IV) and SC
administration. The full effect on pharmacodynamic markers following SC
administration was seen after 24--48 hours.

Multiple weekly IV doses of ≥ 0.3 mg/kg were required to maintain CD11a
down‑modulation between doses, whereas weekly IV doses of ≥ 0.6 mg/kg
were required to maintain full CD11a saturation between weekly doses.

Multiple weekly SC doses of 1.0 mg/kg were required to maintain both
CD11a down‑modulation and saturation between doses. Limited data are
available at SC doses of \< 1.0 mg/kg/wk.

Following the 12th and last dose of 1.0 mg/kg/wk SC, CD11a expression
returned to baseline as Raptiva was cleared from circulation. Between
5 and 8 weeks following the last dose, mean CD11a expression was within
25% of baseline values (see Figure 4).

Figure 4

Mean Serum Raptiva Concentration (PK), CD11a Expression, and Available
CD11a Binding Sites and Absolute Lymphocyte Counts (PD) following
Administration of 1.0 mg/kg/wk Raptiva for 12 Weeks in Study 2142

![](media/image6.wmf)

PD = pharmacodynamics; PK = pharmacokinetics.

Increases in the absolute counts of circulating leukocytes were observed
following administration of Raptiva. Absolute white blood cell (WBC)
counts increased by 2.5--3.5 × 10^3^ cells/μL following 1.0 and 2.0
mg/kg/wk Raptiva to \~10 × 10^3^ cells/μL. The largest change occurred
in the absolute count of circulating lymphocytes. T‑lymphocyte and
B‑lymphocyte counts approximately doubled, whereas natural killer (NK)
cell counts increased by \~50%. Increased counts were apparent within
24 hours of the first dose.

Leukocyte counts remained elevated with weekly dosing and returned to
baseline after treatment cessation. The time course of the changes was
closely related to the effects of Raptiva on CD11a expression and
available CD11a binding sites. After administration of 1.0 mg/kg/wk for
12 weeks, lymphocyte levels returned to within 10% of baseline by
8 weeks following the last dose. Similar to the maximum effects on CD11a
expression, maximum circulating leukocyte counts were comparable at
doses of 1.0 and 2.0 mg/kg/wk.

3.1.2 Raptiva Pharmacokinetics

Raptiva showed dose‑dependent nonlinear pharmacokinetics, which can be
explained by its saturable specific binding to its cell surface
receptor, CD11a.

Mean maximum concentration of drug was 12.4 and 30.9 μg/mL for the
1.0 and 2.0 mg/kg/wk doses, respectively; at steady state, peak
concentrations were achieved by \~2 days after SC doses. The mean time
from last dose to the time when Raptiva plasma concentrations fell below
the limit of detection (0.019 μg/mL) was 25 and 44 days for the 1.0 and
2.0 mg/kg/wk doses, respectively.

With SC doses of 1.0 mg/kg/wk, relative bioavailability of Raptiva was
\~50%.

Steady‑state trough levels were achieved 4 weeks following
administration of 1.0 mg/kg/wk and 8 weeks following administration of
2.0 mg/kg/wk, as assessed from Raptiva serum trough levels after weekly
dosing.

In the Phase III Study 2390, mean ± standard deviation (SD) steady‑state
Raptiva trough levels at Day 84 were 11.1 ± 7.9 μg/mL (n = 275)
following 12 weekly SC doses of Raptiva at 1.0 mg/kg. In subjects from
this study, Raptiva reduced CD11a expression to 19% of baseline and
saturated CD11a to \< 5% of baseline available binding sites on
T lymphocytes in the peripheral blood. Maximal effects observed in this
study indicate that subjects achieved adequate exposure to Raptiva.

Consistent trough levels measured during five consecutive 12‑week
treatment periods in the 3‑year extension study (2243) indicate that
there was no unexpected accumulation during long‑term treatment.

There was a 6.3% (67/1063 subjects) incidence of anti‑Raptiva antibodies
in subjects for whom serum samples were available during the follow‑up
period after elimination of Raptiva from serum. Anti‑Raptiva antibody
titers were low. There was an apparent decrease in efalizumab serum
levels in subjects who had anti‑Raptiva antibodies. Anti‑Raptiva
antibodies interfere with the efalizumab serum assay; therefore this
decrease could be an artifact. Anti‑Raptiva antibodies did not affect
the pharmacodynamics since the peripheral blood lymphocytes stayed
elevated and lymphocyte CD11a saturation was maintained. There was no
impact on efficacy or safety (see Section 6.3).

Through population pharmacokinetic analyses, weight was found to be the
most significant covariate affecting Raptiva SC clearance, confirming
the validity of weight‑based dosing. The population pharmacokinetic
model indicated that the clearance of Raptiva was 24% lower at a dose
level of 2.0 mg/kg/wk compared with 1.0 mg/kg/wk, consistent with
dose‑dependent nonlinear pharmacokinetics. The other pathophysiologic
covariates of baseline PASI, baseline lymphocyte count, and age had only
modest effects on clearance; sex and race had no effect on Raptiva
clearance.

CD11a expression and saturation in peripheral blood are good biologic
markers for adequate dosing based on three factors: 1) integration of
CD11a expression in peripheral blood; 2) CD11a expression in skin
(immunohistology); and 3) psoriasis disease assessment by PASI
improvement. Mechanistically, the pharmacodynamic effect is related to
maximal saturation of CD11a on peripheral blood T lymphocytes.

At Phase III doses (1.0 and 2.0 mg/kg/wk for 12 weeks SC), maximal
effects were seen on these pharmacodynamic markers (i.e., CD11a was
fully down‑modulated and saturated).

No clinically meaningful relationship was found between steady‑state
Raptiva level (summarized by quartiles) and any measure of overall
efficacy or safety events in the Phase III studies, which used doses of
1.0 and 2.0 mg/kg/wk.

3.1.3 Raptiva Immunology and Immunocompetence

T‑lymphocyte proliferation was not impaired in vitro in the mixed
lymphocyte reaction when using peripheral blood mononuclear cells
(PBMCs) obtained from subjects receiving Raptiva treatment. The
preparation of such PBMCs included washing procedures that removed
Raptiva from T cells, suggesting that T lymphocytes rapidly regain their
normal activation potential after drug removal or clearance.

A transient increase of CD69 expression (an early activation marker) on
a small percentage of circulating T lymphocytes was observed after the
first IV or SC dose of Raptiva and after subsequent IV doses when the
previous dose was too low to maintain saturation of CD11a. No
concomitant up‑regulation of CD25 (a second early activation marker) or
increases in cytokines typically produced by activated T lymphocytes
were noted, suggesting that the CD69^+^ T lymphocytes were not fully
activated.

Adverse events (e.g., fever, chills, etc.) observed after the initial
administration of Raptiva (first‑dose effects) were accompanied by small
transient increases in plasma levels of acute phase reactants such as
IL‑6, C‑reactive protein, and fibrinogen. These changes were not
associated with T‑lymphocyte activation.

In a Phase I study (HU9602), subjects were vaccinated with bacteriophage
φX174 1 day after receiving a single dose of Raptiva. The data from this
study suggest that that secondary response to immunization may not be
effective during Raptiva treatment, particularly at dose levels of
\> 0.6 mg/kg IV (Gottlieb 1998).

Subjects did not experience a decrease or increase in preexisting serum
concentrations of anti‑cytomegalovirus or anti‑tetanus toxoid antibodies
after treatment. Secondary booster vaccinations in humans during Raptiva
treatment are currently under investigation. The safety and efficacy of
vaccines, specifically live or live‑attenuated vaccines, administered to
patients being treated with Raptiva have not been studied.

To study immune responses in greater detail, a Phase I, randomized,
placebo‑controlled, single‑blind, parallel‑group, single‑center study
(2244) is in progress. Study 2244 is designed to evaluate immune
responses during and following administration of 12 weekly SC doses of
1.0 mg/kg Raptiva in 60 adult subjects with moderate plaque psoriasis.

3.2 NonClinical Pharmacology Toxicology Data

Because of the species specificity of Raptiva in humans and chimpanzees
and the limited availability of chimpanzees, a chimeric rat/mouse
anti--mouse CD11a antibody (muM17), was developed and evaluated as a
surrogate for Raptiva. Safety studies were performed with Raptiva in
chimpanzees and with muM17, an anti--mouse CD11a antibody, in mice to
provide a comprehensive safety evaluation.

The nonclinical pharmacology, pharmacokinetics, and toxicology of
Raptiva are consistent with the binding of the antibody to its ligand,
CD11a. All safety signals observed in the nonclinical safety evaluation
of Raptiva or muM17 can be explained by the known immunomodulatory
effects of these antibodies. These effects occurred at doses
approximately equivalent to the clinical dose of 1.0 mg/kg/wk Raptiva.

Consistent with the pharmacologic activity of these antibodies, CD11a
expression was greatly reduced on T cells in chimpanzees and mice
treated with Raptiva and muM17, respectively. Similar effects have been
seen in humans. The clinical relevance of the occasional overexpression
of CD11a following clearance of Raptiva from the serum is unknown
because no safety signals were observed in animals during this period of
overexpression.

Both Raptiva and muM17 appear to alter the trafficking of lymphocytes
such that there is a reduction in the cellularity of the lymph nodes,
increased spleen weights (evaluable with muM17 in mice only), and
increases in the circulating WBC count (noted with both Raptiva in
chimpanzees and humans and with muM17 in mice). These changes do not
appear to have any adverse toxicologic consequences.

In a developmental toxicity study conducted in mice using muM17, no
evidence of maternal toxicity, embryotoxicity, or teratogenicity was
observed. No adverse effects on behavioral, reproductive, or growth
parameters were observed in offspring of female mice exposed to an
anti‑mouse CD11a antibody during gestation and lactation. At 11 weeks of
age, the offspring had intact cell‑mediated immunity and a reduction in
the primary antibody response. At 25 weeks of age, the offspring had a
normal primary antibody response.

In a fertility and general reproduction study with muM17, no adverse
effects were noted on mating, fertility, or reproduction parameters in
male and female mice.

A 6‑month study was conducted in TSG‑p53^^ wild‑type mice, a strain
shown to be susceptible to lymphoma development. Additionally,
cyclosporine has been shown to produce lymphomas in this strain when
mice were treated for a period of 6 months (Storer et al. 2001). The
study was conducted to address the chronic safety of muM17 and to
determine the potential for treatment‑related effects on lymphoma
development. Results of this study indicated that treatment of mice for
6 months with muM17 was well tolerated; there was no treatment‑related
increase in lymphomas whereas one lymphoma was observed in
placebo‑treated mice. Expected findings, including increased spleen
weight and lymphoid organ changes, were consistent with
trafficking/demargination changes related to the pharmacologic activity
of the antibody. Additional long‑term animal studies have not been
conducted to evaluate the carcinogenic potential of Raptiva.

Raptiva was considered to be generally well tolerated in chimpanzees at
doses of up to 40 mg/kg/wk IV for 6 months, providing an exposure ratio
of 339‑fold based on cumulative dose and 174‑fold based on the
cumulative area under the curve compared with a clinical dose of
1.0 mg/kg/wk for 12 weeks. The surrogate antibody, muM17, was also well
tolerated in mice at doses up to 30 mg/kg/wk SC for 6 months, providing
an exposure ratio of 10‑ to 25‑fold based on plasma concentration
compared with the clinical dose of Raptiva.

4\. OVERVIEW OF CLINICAL TRIALS

Early evaluation of Raptiva was conducted in seven Phase I and II
clinical studies. Data on the safety and efficacy of Raptiva were
subsequently obtained from the pivotal study, 2390, which used the
to‑be‑marketed product. This trial was conducted in adults (≥18 years
old) with moderate to severe plaque psoriasis who were candidates for
systemic therapy and who had a baseline PASI score of ≥12.0, with plaque
psoriasis covering ≥ 10% of total BSA (Krueger et al. 2000). Extensive
supportive data are provided in three additional Phase III
placebo‑controlled studies (2600, 2058, and 2059). Support for the
long‑term use of Raptiva is provided by the open‑label study, 2391,
which provides extended treatment for subjects treated in Study 2390,
and also by Studies 2058 and 2059 and the ongoing open‑label study,
2243. Support for retreatment and additional long‑term continuous
treatment data were obtained from Study 2062, which provided Raptiva
treatment for subjects who had participated in earlier clinical trials.

There were five Phase I studies (HU9602, HUPS249, HUPSS254, HUPS256, and
2142) and one Phase II study (HUPS252) performed using Raptiva in the
treatment of psoriasis. Two of the Phase I studies (HU9602 and HUPS249)
and the Phase II study (HUPS252) used an IV formulation of Raptiva; the
safety data for these three studies are not reviewed in this document
except in the discussion of malignancy events. The safety data from
three of the remaining four Phase I studies (HUPS254, HUPS256, and
2142), which used an SC formulation of Raptiva, are part of the pool of
data from subjects in the first 12‑week treatment period of the
open‑label and placebo‑controlled studies. Table 3 summarizes the
completed Phase I, II, and III psoriasis studies. Table 4 summarizes the
ongoing studies.

+----+---+-----+--------------+--------+---------+----+----------+-----+
| T  |   |     |              |        |         |    |          |     |
| ab |   |     |              |        |         |    |          |     |
| le |   |     |              |        |         |    |          |     |
| 3  |   |     |              |        |         |    |          |     |
|    |   |     |              |        |         |    |          |     |
| Cl |   |     |              |        |         |    |          |     |
| in |   |     |              |        |         |    |          |     |
| ic |   |     |              |        |         |    |          |     |
| al |   |     |              |        |         |    |          |     |
| D  |   |     |              |        |         |    |          |     |
| ev |   |     |              |        |         |    |          |     |
| el |   |     |              |        |         |    |          |     |
| op |   |     |              |        |         |    |          |     |
| me |   |     |              |        |         |    |          |     |
| nt |   |     |              |        |         |    |          |     |
| of |   |     |              |        |         |    |          |     |
| Ra |   |     |              |        |         |    |          |     |
| pt |   |     |              |        |         |    |          |     |
| iv |   |     |              |        |         |    |          |     |
| a: |   |     |              |        |         |    |          |     |
| C  |   |     |              |        |         |    |          |     |
| om |   |     |              |        |         |    |          |     |
| pl |   |     |              |        |         |    |          |     |
| et |   |     |              |        |         |    |          |     |
| ed |   |     |              |        |         |    |          |     |
| P  |   |     |              |        |         |    |          |     |
| so |   |     |              |        |         |    |          |     |
| ri |   |     |              |        |         |    |          |     |
| as |   |     |              |        |         |    |          |     |
| is |   |     |              |        |         |    |          |     |
| S  |   |     |              |        |         |    |          |     |
| tu |   |     |              |        |         |    |          |     |
| di |   |     |              |        |         |    |          |     |
| es |   |     |              |        |         |    |          |     |
+----+---+-----+--------------+--------+---------+----+----------+-----+
| Ty |   | Stu | Stud         | St     | R       | Nu | In       | Du  |
| pe |   | dy\ | y Objectives | udy De | oute(s) | mb | dication | rat |
| of |   | Num |              | sign/\ | of\     | er |          | ion |
| S  |   | ber |              | Type   | Adminis | of |          | of  |
| tu |   |     |              | of     | tration | Su |          | Tre |
| dy |   |     |              | C      |         | bj |          | atm |
|    |   |     |              | ontrol |         | ec |          | ent |
|    |   |     |              |        |         | ts |          |     |
|    |   |     |              |        |         | ^  |          |     |
|    |   |     |              |        |         | a^ |          |     |
+----+---+-----+--------------+--------+---------+----+----------+-----+
| P  |   | HU9 | Safety,      | Open‑  | IV      | 31 | Moderate | Sin |
| ha |   | 602 | pharm        | label, |         |    | to       | gle |
| se |   |     | acokinetics, | singl  |         |    | severe   | d   |
| I  |   |     | and biologic | e‑dose |         |    | plaque   | ose |
|    |   |     | activity     |        |         |    | p        |     |
|    |   |     |              |        |         |    | soriasis |     |
+----+---+-----+--------------+--------+---------+----+----------+-----+
| P  |   | H   | Safety,      | Open‑  | IV      | 39 | Moderate | 7   |
| ha |   | UPS | pharm        | label, |         |    | to       | We  |
| se |   | 249 | acokinetics, | m      |         |    | severe   | eks |
| I  |   |     | and biologic | ultipl |         |    | plaque   |     |
|    |   |     | activity     | e‑dose |         |    | p        |     |
|    |   |     |              |        |         |    | soriasis |     |
+----+---+-----+--------------+--------+---------+----+----------+-----+
| P  |   | H   | Safety and   | P      | IV      | 1  | Moderate | 8   |
| ha |   | UPS | efficacy     | lacebo |         | 45 | to       | We  |
| se |   | 252 |              | ‑contr |         |    | severe   | eks |
| II |   |     |              | olled, |         |    | plaque   |     |
|    |   |     |              | d      |         |    | p        |     |
|    |   |     |              | ouble‑ |         |    | soriasis |     |
|    |   |     |              | blind, |         |    |          |     |
|    |   |     |              | rand   |         |    |          |     |
|    |   |     |              | omized |         |    |          |     |
+----+---+-----+--------------+--------+---------+----+----------+-----+
| P  |   | H   | Safety and   | Open‑l | SC      | 57 | Moderate | Sin |
| ha |   | UPS | efficacy     | abel,\ |         |    | to       | gle |
| se |   | 254 |              | s      |         |    | severe   | d   |
| I  |   |     |              | ingle‑ |         |    | plaque   | ose |
|    |   |     |              | and    |         |    | p        | and |
|    |   |     |              | m      |         |    | soriasis | 8   |
|    |   |     |              | ultipl |         |    |          |  we |
|    |   |     |              | e‑dose |         |    |          | eks |
+----+---+-----+--------------+--------+---------+----+----------+-----+
| P  |   | H   | Safety,      | Open‑  | SC and  | 77 | Moderate | 12  |
| ha |   | UPS | pharm        | label, | IV      |    | to       | We  |
| se |   | 256 | acokinetics, | rand   |         |    | severe   | eks |
| I  |   |     | and biologic | omized |         |    | plaque   |     |
|    |   |     | activity     |        |         |    | p        |     |
|    |   |     |              |        |         |    | soriasis |     |
+----+---+-----+--------------+--------+---------+----+----------+-----+
| P  |   | 2   | Efficacy,    | P      | SC      | 4  | Moderate | 12- |
| ha |   | 058 | safety, and  | lacebo |         | 98 | to       | -24 |
| se |   |     | tolerability | ‑contr |         |    | severe   | We  |
| I  |   |     |              | olled, |         |    | plaque   | eks |
| II |   |     |              | d      |         |    | p        |     |
|    |   |     |              | ouble‑ |         |    | soriasis |     |
|    |   |     |              | blind, |         |    |          |     |
|    |   |     |              | rand   |         |    |          |     |
|    |   |     |              | omized |         |    |          |     |
+----+---+-----+--------------+--------+---------+----+----------+-----+
| P  |   | 2   | Efficacy,    | P      | SC      | 5  | Moderate | 12- |
| ha |   | 059 | safety, and  | lacebo |         | 97 | to       | -24 |
| se |   |     | tolerability | ‑contr |         |    | severe   | We  |
| I  |   |     |              | olled, |         |    | plaque   | eks |
| II |   |     |              | d      |         |    | p        |     |
|    |   |     |              | ouble‑ |         |    | soriasis |     |
|    |   |     |              | blind, |         |    |          |     |
|    |   |     |              | rand   |         |    |          |     |
|    |   |     |              | omized |         |    |          |     |
+----+---+-----+--------------+--------+---------+----+----------+-----+
| P  |   | 2   | Safety and   | Open   | SC      | 5  | Moderate | 12  |
| ha |   | 062 | tolerability | ‑label |         | 36 | to       | We  |
| se |   |     | of           |        |         |    | severe   | eks |
| I  |   |     | retreatment  |        |         |    | plaque   |     |
| II |   |     |              |        |         |    | p        |     |
|    |   |     |              |        |         |    | soriasis |     |
+----+---+-----+--------------+--------+---------+----+----------+-----+
| ^  |   |     |              |        |         |    |          |     |
| a^ |   |     |              |        |         |    |          |     |
| In |   |     |              |        |         |    |          |     |
| cl |   |     |              |        |         |    |          |     |
| ud |   |     |              |        |         |    |          |     |
| es |   |     |              |        |         |    |          |     |
| a  |   |     |              |        |         |    |          |     |
| ll |   |     |              |        |         |    |          |     |
| s  |   |     |              |        |         |    |          |     |
| tu |   |     |              |        |         |    |          |     |
| dy |   |     |              |        |         |    |          |     |
| pa |   |     |              |        |         |    |          |     |
| rt |   |     |              |        |         |    |          |     |
| ic |   |     |              |        |         |    |          |     |
| ip |   |     |              |        |         |    |          |     |
| an |   |     |              |        |         |    |          |     |
| ts |   |     |              |        |         |    |          |     |
| t  |   |     |              |        |         |    |          |     |
| re |   |     |              |        |         |    |          |     |
| at |   |     |              |        |         |    |          |     |
| ed |   |     |              |        |         |    |          |     |
| wi |   |     |              |        |         |    |          |     |
| th |   |     |              |        |         |    |          |     |
| R  |   |     |              |        |         |    |          |     |
| ap |   |     |              |        |         |    |          |     |
| ti |   |     |              |        |         |    |          |     |
| va |   |     |              |        |         |    |          |     |
| or |   |     |              |        |         |    |          |     |
| pl |   |     |              |        |         |    |          |     |
| ac |   |     |              |        |         |    |          |     |
| eb |   |     |              |        |         |    |          |     |
| o. |   |     |              |        |         |    |          |     |
| So |   |     |              |        |         |    |          |     |
| me |   |     |              |        |         |    |          |     |
| su |   |     |              |        |         |    |          |     |
| bj |   |     |              |        |         |    |          |     |
| ec |   |     |              |        |         |    |          |     |
| ts |   |     |              |        |         |    |          |     |
| pa |   |     |              |        |         |    |          |     |
| rt |   |     |              |        |         |    |          |     |
| ic |   |     |              |        |         |    |          |     |
| ip |   |     |              |        |         |    |          |     |
| at |   |     |              |        |         |    |          |     |
| ed |   |     |              |        |         |    |          |     |
| in |   |     |              |        |         |    |          |     |
| mo |   |     |              |        |         |    |          |     |
| re |   |     |              |        |         |    |          |     |
| th |   |     |              |        |         |    |          |     |
| an |   |     |              |        |         |    |          |     |
| o  |   |     |              |        |         |    |          |     |
| ne |   |     |              |        |         |    |          |     |
| st |   |     |              |        |         |    |          |     |
| ud |   |     |              |        |         |    |          |     |
| y. |   |     |              |        |         |    |          |     |
|    |   |     |              |        |         |    |          |     |
| ^  |   |     |              |        |         |    |          |     |
| b^ |   |     |              |        |         |    |          |     |
| An |   |     |              |        |         |    |          |     |
| ad |   |     |              |        |         |    |          |     |
| di |   |     |              |        |         |    |          |     |
| ti |   |     |              |        |         |    |          |     |
| on |   |     |              |        |         |    |          |     |
| al |   |     |              |        |         |    |          |     |
| s  |   |     |              |        |         |    |          |     |
| ub |   |     |              |        |         |    |          |     |
| je |   |     |              |        |         |    |          |     |
| ct |   |     |              |        |         |    |          |     |
| w  |   |     |              |        |         |    |          |     |
| as |   |     |              |        |         |    |          |     |
| r  |   |     |              |        |         |    |          |     |
| an |   |     |              |        |         |    |          |     |
| do |   |     |              |        |         |    |          |     |
| mi |   |     |              |        |         |    |          |     |
| ze |   |     |              |        |         |    |          |     |
| d, |   |     |              |        |         |    |          |     |
| b  |   |     |              |        |         |    |          |     |
| ut |   |     |              |        |         |    |          |     |
| n  |   |     |              |        |         |    |          |     |
| ot |   |     |              |        |         |    |          |     |
| tr |   |     |              |        |         |    |          |     |
| ea |   |     |              |        |         |    |          |     |
| te |   |     |              |        |         |    |          |     |
| d. |   |     |              |        |         |    |          |     |
+----+---+-----+--------------+--------+---------+----+----------+-----+
| T  |   |     |              |        |         |    |          |     |
| ab |   |     |              |        |         |    |          |     |
| le |   |     |              |        |         |    |          |     |
| 3  |   |     |              |        |         |    |          |     |
| (c |   |     |              |        |         |    |          |     |
| on |   |     |              |        |         |    |          |     |
| t' |   |     |              |        |         |    |          |     |
| d) |   |     |              |        |         |    |          |     |
|    |   |     |              |        |         |    |          |     |
| Cl |   |     |              |        |         |    |          |     |
| in |   |     |              |        |         |    |          |     |
| ic |   |     |              |        |         |    |          |     |
| al |   |     |              |        |         |    |          |     |
| D  |   |     |              |        |         |    |          |     |
| ev |   |     |              |        |         |    |          |     |
| el |   |     |              |        |         |    |          |     |
| op |   |     |              |        |         |    |          |     |
| me |   |     |              |        |         |    |          |     |
| nt |   |     |              |        |         |    |          |     |
| of |   |     |              |        |         |    |          |     |
| Ra |   |     |              |        |         |    |          |     |
| pt |   |     |              |        |         |    |          |     |
| iv |   |     |              |        |         |    |          |     |
| a: |   |     |              |        |         |    |          |     |
| C  |   |     |              |        |         |    |          |     |
| om |   |     |              |        |         |    |          |     |
| pl |   |     |              |        |         |    |          |     |
| et |   |     |              |        |         |    |          |     |
| ed |   |     |              |        |         |    |          |     |
| P  |   |     |              |        |         |    |          |     |
| so |   |     |              |        |         |    |          |     |
| ri |   |     |              |        |         |    |          |     |
| as |   |     |              |        |         |    |          |     |
| is |   |     |              |        |         |    |          |     |
| S  |   |     |              |        |         |    |          |     |
| tu |   |     |              |        |         |    |          |     |
| di |   |     |              |        |         |    |          |     |
| es |   |     |              |        |         |    |          |     |
+----+---+-----+--------------+--------+---------+----+----------+-----+
| Ty | S |     | Stud         | St     | R       | Nu | In       | Du  |
| pe | t |     | y Objectives | udy De | oute(s) | mb | dication | rat |
| of | u |     |              | sign/\ | of\     | er |          | ion |
| S  | d |     |              | Type   | Adminis | of |          | of  |
| tu | y |     |              | of     | tration | Su |          | Tre |
| dy | \ |     |              | C      |         | bj |          | atm |
|    | N |     |              | ontrol |         | ec |          | ent |
|    | u |     |              |        |         | ts |          |     |
|    | m |     |              |        |         | ^  |          |     |
|    | b |     |              |        |         | a^ |          |     |
|    | e |     |              |        |         |    |          |     |
|    | r |     |              |        |         |    |          |     |
+----+---+-----+--------------+--------+---------+----+----------+-----+
| P  | 2 |     | Pharm        | Open   | SC      | 70 | Moderate | 12  |
| ha | 1 |     | acokinetics, | ‑label |         |    | to       | We  |
| se | 4 |     | pharm        |        |         |    | severe   | eks |
| I  | 2 |     | acodynamics, |        |         |    | plaque   |     |
|    |   |     | safety, and  |        |         |    | p        |     |
|    |   |     | tolerability |        |         |    | soriasis |     |
|    |   |     | of Genentech |        |         |    |          |     |
|    |   |     | Raptiva      |        |         |    |          |     |
+----+---+-----+--------------+--------+---------+----+----------+-----+
| P  | 2 |     | Efficacy,    | P      | SC      | 5  | Moderate | 12  |
| ha | 3 |     | safety, and  | lacebo |         | 55 | to       | We  |
| se | 9 |     | tolerability | ‑contr |         | ^  | severe   | eks |
| I  | 0 |     | of 1.0 mg/kg | olled, |         | b^ | plaque   |     |
| II |   |     |              | d      |         |    | p        |     |
|    |   |     |              | ouble‑ |         |    | soriasis |     |
|    |   |     |              | blind, |         |    |          |     |
|    |   |     |              | rand   |         |    |          |     |
|    |   |     |              | omized |         |    |          |     |
+----+---+-----+--------------+--------+---------+----+----------+-----+
| P  | 2 |     | Safety of    | Open‑  | SC      | 5  | Moderate | 24  |
| ha | 3 |     | 1.0 mg/kg/wk | label\ |         | 16 | to       | We  |
| se | 9 |     | in subjects  | (ext   |         |    | severe   | eks |
| I  | 1 |     | who were     | ension |         |    | plaque   |     |
| II |   |     | previously   | of     |         |    | p        |     |
|    |   |     | treated with | Study  |         |    | soriasis |     |
|    |   |     | Raptiva or   |  2390) |         |    |          |     |
|    |   |     | placebo in   |        |         |    |          |     |
|    |   |     | Study 2390   |        |         |    |          |     |
+----+---+-----+--------------+--------+---------+----+----------+-----+
| P  | 2 |     | Efficacy,    | P      | SC      | 6  | Moderate | 12  |
| ha | 6 |     | safety, and  | lacebo |         | 85 | to       | We  |
| se | 0 |     | tolerability | ‑contr |         | ^  | severe   | eks |
| I  | 0 |     | of 1.0 mg/kg | olled, |         | b^ | plaque   |     |
| II |   |     |              | d      |         |    | p        |     |
|    |   |     |              | ouble‑ |         |    | soriasis |     |
|    |   |     |              | blind, |         |    |          |     |
|    |   |     |              | rand   |         |    |          |     |
|    |   |     |              | omized |         |    |          |     |
+----+---+-----+--------------+--------+---------+----+----------+-----+
| ^  |   |     |              |        |         |    |          |     |
| a^ |   |     |              |        |         |    |          |     |
| In |   |     |              |        |         |    |          |     |
| cl |   |     |              |        |         |    |          |     |
| ud |   |     |              |        |         |    |          |     |
| es |   |     |              |        |         |    |          |     |
| a  |   |     |              |        |         |    |          |     |
| ll |   |     |              |        |         |    |          |     |
| s  |   |     |              |        |         |    |          |     |
| tu |   |     |              |        |         |    |          |     |
| dy |   |     |              |        |         |    |          |     |
| pa |   |     |              |        |         |    |          |     |
| rt |   |     |              |        |         |    |          |     |
| ic |   |     |              |        |         |    |          |     |
| ip |   |     |              |        |         |    |          |     |
| an |   |     |              |        |         |    |          |     |
| ts |   |     |              |        |         |    |          |     |
| t  |   |     |              |        |         |    |          |     |
| re |   |     |              |        |         |    |          |     |
| at |   |     |              |        |         |    |          |     |
| ed |   |     |              |        |         |    |          |     |
| wi |   |     |              |        |         |    |          |     |
| th |   |     |              |        |         |    |          |     |
| R  |   |     |              |        |         |    |          |     |
| ap |   |     |              |        |         |    |          |     |
| ti |   |     |              |        |         |    |          |     |
| va |   |     |              |        |         |    |          |     |
| or |   |     |              |        |         |    |          |     |
| pl |   |     |              |        |         |    |          |     |
| ac |   |     |              |        |         |    |          |     |
| eb |   |     |              |        |         |    |          |     |
| o. |   |     |              |        |         |    |          |     |
| So |   |     |              |        |         |    |          |     |
| me |   |     |              |        |         |    |          |     |
| su |   |     |              |        |         |    |          |     |
| bj |   |     |              |        |         |    |          |     |
| ec |   |     |              |        |         |    |          |     |
| ts |   |     |              |        |         |    |          |     |
| pa |   |     |              |        |         |    |          |     |
| rt |   |     |              |        |         |    |          |     |
| ic |   |     |              |        |         |    |          |     |
| ip |   |     |              |        |         |    |          |     |
| at |   |     |              |        |         |    |          |     |
| ed |   |     |              |        |         |    |          |     |
| in |   |     |              |        |         |    |          |     |
| mo |   |     |              |        |         |    |          |     |
| re |   |     |              |        |         |    |          |     |
| th |   |     |              |        |         |    |          |     |
| an |   |     |              |        |         |    |          |     |
| o  |   |     |              |        |         |    |          |     |
| ne |   |     |              |        |         |    |          |     |
| st |   |     |              |        |         |    |          |     |
| ud |   |     |              |        |         |    |          |     |
| y. |   |     |              |        |         |    |          |     |
|    |   |     |              |        |         |    |          |     |
| ^  |   |     |              |        |         |    |          |     |
| b^ |   |     |              |        |         |    |          |     |
| An |   |     |              |        |         |    |          |     |
| ad |   |     |              |        |         |    |          |     |
| di |   |     |              |        |         |    |          |     |
| ti |   |     |              |        |         |    |          |     |
| on |   |     |              |        |         |    |          |     |
| al |   |     |              |        |         |    |          |     |
| s  |   |     |              |        |         |    |          |     |
| ub |   |     |              |        |         |    |          |     |
| je |   |     |              |        |         |    |          |     |
| ct |   |     |              |        |         |    |          |     |
| w  |   |     |              |        |         |    |          |     |
| as |   |     |              |        |         |    |          |     |
| r  |   |     |              |        |         |    |          |     |
| an |   |     |              |        |         |    |          |     |
| do |   |     |              |        |         |    |          |     |
| mi |   |     |              |        |         |    |          |     |
| ze |   |     |              |        |         |    |          |     |
| d, |   |     |              |        |         |    |          |     |
| b  |   |     |              |        |         |    |          |     |
| ut |   |     |              |        |         |    |          |     |
| n  |   |     |              |        |         |    |          |     |
| ot |   |     |              |        |         |    |          |     |
| tr |   |     |              |        |         |    |          |     |
| ea |   |     |              |        |         |    |          |     |
| te |   |     |              |        |         |    |          |     |
| d. |   |     |              |        |         |    |          |     |
+----+---+-----+--------------+--------+---------+----+----------+-----+

+-----+-----+--------------+--------+---------+----+----------+-----+
| Ta  |     |              |        |         |    |          |     |
| ble |     |              |        |         |    |          |     |
| 4   |     |              |        |         |    |          |     |
|     |     |              |        |         |    |          |     |
| Cl  |     |              |        |         |    |          |     |
| ini |     |              |        |         |    |          |     |
| cal |     |              |        |         |    |          |     |
| De  |     |              |        |         |    |          |     |
| vel |     |              |        |         |    |          |     |
| opm |     |              |        |         |    |          |     |
| ent |     |              |        |         |    |          |     |
| of  |     |              |        |         |    |          |     |
| Ra  |     |              |        |         |    |          |     |
| pti |     |              |        |         |    |          |     |
| va: |     |              |        |         |    |          |     |
| O   |     |              |        |         |    |          |     |
| ngo |     |              |        |         |    |          |     |
| ing |     |              |        |         |    |          |     |
| Pso |     |              |        |         |    |          |     |
| ria |     |              |        |         |    |          |     |
| sis |     |              |        |         |    |          |     |
| S   |     |              |        |         |    |          |     |
| tud |     |              |        |         |    |          |     |
| ies |     |              |        |         |    |          |     |
+-----+-----+--------------+--------+---------+----+----------+-----+
| T   | Stu | Stud         | St     | R       | Nu | In       | Du  |
| ype | dy\ | y Objectives | udy De | oute(s) | mb | dication | rat |
| of  | Num |              | sign/\ | of\     | er |          | ion |
| St  | ber |              | Type   | Adminis | of |          | of  |
| udy |     |              | of     | tration | Su |          | Tre |
|     |     |              | C      |         | bj |          | atm |
|     |     |              | ontrol |         | ec |          | ent |
|     |     |              |        |         | ts |          |     |
|     |     |              |        |         | ^  |          |     |
|     |     |              |        |         | a^ |          |     |
+-----+-----+--------------+--------+---------+----+----------+-----+
| Ph  | 2   | Safety,      | Open‑  | SC      | 3  | Moderate | 1   |
| ase | 243 | t            | label, |         | 39 | to       | 2-- |
| III |     | olerability, | rand   |         |    | severe   | 132 |
|     |     | and efficacy | omized |         |    | plaque   | We  |
|     |     | of prolonged |        |         |    | p        | eks |
|     |     | maintenance  |        |         |    | soriasis |     |
|     |     | treatment    |        |         |    |          |     |
+-----+-----+--------------+--------+---------+----+----------+-----+
| Ph  | 2   | Immune       | P      | SC      | 60 | Moderate | 12  |
| ase | 244 | response     | lacebo |         |    | p        | We  |
| I   |     | after        | ‑contr |         |    | soriasis | eks |
|     |     | 12 weekly    | olled, |         |    |          |     |
|     |     | doses of 1.0 | s      |         |    |          |     |
|     |     | mg/kg        | ingle‑ |         |    |          |     |
|     |     | Raptiva      | blind, |         |    |          |     |
|     |     |              | rand   |         |    |          |     |
|     |     |              | omized |         |    |          |     |
+-----+-----+--------------+--------+---------+----+----------+-----+
| Ph  | 2   | Safety of    | Open‑  | SC      | 6  | Moderate | 48  |
| ase | 601 | 1.0 mg/kg/wk | label\ |         | 53 | to       | We  |
| III |     | in subjects  | (ext   |         |    | severe   | eks |
|     |     | who were     | ension |         |    | plaque   |     |
|     |     | previously   | of     |         |    | p        |     |
|     |     | treated with | Study  |         |    | soriasis |     |
|     |     | Raptiva or   |  2600) |         |    |          |     |
|     |     | placebo in   |        |         |    |          |     |
|     |     | Study 2600   |        |         |    |          |     |
+-----+-----+--------------+--------+---------+----+----------+-----+
| Ph  | H   | Transition   | Open   | SC      | \  | Moderate | 12  |
| ase | UPS | from SC      | ‑label |         | ~1 | to       | We  |
| I   | 300 | Raptiva      |        |         | 20 | severe   | eks |
| IIb |     | therapy to   |        |         |    | plaque   |     |
|     |     | approved     |        |         |    | p        |     |
|     |     | systemic     |        |         |    | soriasis |     |
|     |     | and/or       |        |         |    |          |     |
|     |     | phototherapy |        |         |    |          |     |
|     |     | for          |        |         |    |          |     |
|     |     | psoriasis    |        |         |    |          |     |
+-----+-----+--------------+--------+---------+----+----------+-----+
| ^a^ |     |              |        |         |    |          |     |
| In  |     |              |        |         |    |          |     |
| clu |     |              |        |         |    |          |     |
| des |     |              |        |         |    |          |     |
| all |     |              |        |         |    |          |     |
| st  |     |              |        |         |    |          |     |
| udy |     |              |        |         |    |          |     |
| par |     |              |        |         |    |          |     |
| tic |     |              |        |         |    |          |     |
| ipa |     |              |        |         |    |          |     |
| nts |     |              |        |         |    |          |     |
| t   |     |              |        |         |    |          |     |
| rea |     |              |        |         |    |          |     |
| ted |     |              |        |         |    |          |     |
| w   |     |              |        |         |    |          |     |
| ith |     |              |        |         |    |          |     |
| R   |     |              |        |         |    |          |     |
| apt |     |              |        |         |    |          |     |
| iva |     |              |        |         |    |          |     |
| or  |     |              |        |         |    |          |     |
| pl  |     |              |        |         |    |          |     |
| ace |     |              |        |         |    |          |     |
| bo. |     |              |        |         |    |          |     |
| S   |     |              |        |         |    |          |     |
| ome |     |              |        |         |    |          |     |
| su  |     |              |        |         |    |          |     |
| bje |     |              |        |         |    |          |     |
| cts |     |              |        |         |    |          |     |
| par |     |              |        |         |    |          |     |
| tic |     |              |        |         |    |          |     |
| ipa |     |              |        |         |    |          |     |
| ted |     |              |        |         |    |          |     |
| in  |     |              |        |         |    |          |     |
| m   |     |              |        |         |    |          |     |
| ore |     |              |        |         |    |          |     |
| t   |     |              |        |         |    |          |     |
| han |     |              |        |         |    |          |     |
| one |     |              |        |         |    |          |     |
| stu |     |              |        |         |    |          |     |
| dy. |     |              |        |         |    |          |     |
+-----+-----+--------------+--------+---------+----+----------+-----+

5\. CLINICAL EFFICACY

5.1 Overview OF STUDY 2390

5.1.1 Study 2390

Study 2390 was a Phase III, randomized, double‑blind, parallel‑group,
placebo‑controlled, multicenter trial designed to evaluate the efficacy
and safety of Raptiva (as the to‑be‑marketed product) in subjects with
moderate to severe plaque psoriasis who were candidates for systemic
therapy.

a\. Study Design and Treatment

Following a 2‑ to 4‑week screening period, eligible subjects were
randomized in a 2:1 ratio to receive SC treatment with either
1.0 mg/kg/wk Raptiva or placebo equivalent for 12 weeks (see Figure 5).
(During the first 12 weeks of treatment, subjects received an initial
dose of 0.7 mg/kg followed by 11 weekly SC doses of 1.0 mg/kg.) Subjects
were to return 1 week after the last SC treatment for Day 84
assessments. Randomization was stratified within study center using the
Day 0 PASI score (≤ 16.0, ≥ 16.1) and prior treatment for psoriasis
(naive to systemic treatment vs. prior systemic treatment).

Figure 5

Study 2390

![](media/image7.wmf)

The only concomitant psoriasis treatments allowed during the study were
emollients, tar or salicylic acid preparations for scalp psoriasis, and
low‑potency (Grade VI or VII) topical corticosteroids if needed for
lesions on the face, hands, feet, axillae, or groin. Oral antihistamines
were allowed if needed for pruritus. Thus, the results are
representative of Raptiva monotherapy.

b\. Study Population

Adults with plaque psoriasis covering ≥ 10% of total BSA and a PASI
score of ≥ 12.0 who were either candidates for systemic psoriasis
therapy or had a history of receiving systemic therapy were randomized
into the study. A total of 556 subjects were enrolled at 29 sites in the
United States and Canada.

c\. Efficacy Outcome Measures

The primary efficacy endpoint was the proportion of subjects with a
≥ 75% improvement in PASI relative to baseline (PASI‑75) at the end of
12 weeks of treatment referred to as PASI responders. PASI is a
physician‑performed assessment of both the extent of psoriasis on the
four body areas (head, trunk, upper limbs, and lower limbs) and the
degree of plaque erythema, scaling, and thickness (Fredriksson et al.
1983). The PASI score accounts for both the extent of BSA affected by
the erythema, scaling, and thickness and the severity of the erythema,
scaling, and thickness. The possible scores range from 0 (no disease) to
72 (maximal disease) (see Appendix B).

Observations on the PASI were corroborated by two Physician's Global
Assessment scales:

-   A static Physicians Global Assessment (PGA) reflecting the
    appearance of the subject on the day of observation, with rankings
    ranging from very severe to clear (see Appendix C)

During the clinical studies this assessment was known as Overall Lesion
Severity (OLS) scale. The principal secondary endpoint was the
proportion of subjects rated as minimal or clear at the end of 12 weeks
of treatment on this scale.

-   A dynamic Physician's Global Assessment (PGA) of Change, ranging
    from worse to cleared (see Appendix D)

This scale reflects a global assessment of the degree of improvement
from baseline. Photographs obtained at baseline, clinic notes, and other
materials were used by the investigator as desired in making this
assessment. The endpoint was the proportion of subjects rated as
excellent or cleared at the end of 12 weeks of treatment.

Other secondary endpoints were mean improvement in the thickness
component of the PASI score, mean improvement in the percentage of BSA
affected by psoriasis, proportion of subjects with ≥ 50% improvement in
PASI score relative to baseline after 12 weeks of treatment (PASI‑50),
and mean percent PASI improvement over time. The following
patient‑reported scales were used: the Itching Scale, Dermatology Life
Quality Index (DLQI), and frequency and severity subscales of the
Psoriasis Symptom Assessment (PSA). Developed for the Raptiva trials,
the PSA rates frequency and severity for eight symptoms of psoriasis and
is similar to the Skindex (Chren et al. 1996). All subject‑reported
outcomes were assessed as change from baseline after 12 weeks of
treatment.

d\. Demographic and Baseline Characteristics

Demographic and baseline characteristics for all randomized subjects are
summarized in Table 5. Overall, the two treatment groups were comparable
with regard to demographic and baseline characteristics, with no
statistically significant differences noted.

+---------------------------+-------------+-------------+-------------+
| Table 5                   |             |             |             |
|                           |             |             |             |
| Demographic and Baseline  |             |             |             |
| Characteristics\          |             |             |             |
| of Randomized Subjects in |             |             |             |
| Study 2390                |             |             |             |
+---------------------------+-------------+-------------+-------------+
| Characteristic            | Placebo\    | Raptiva\    | All         |
|                           | (n = 187)   | (n = 369)   | Subjects\   |
|                           |             |             | (n = 556)   |
+---------------------------+-------------+-------------+-------------+
| Sex, n\                   | 132         | 251         | 383         |
| Male\                     | (70.6%)\    | (68.0%)\    | (68.9%)\    |
| Female                    | 55 (29.4%)  | 118 (32.0%) | 173 (31.1%) |
+---------------------------+-------------+-------------+-------------+
| > Race/ethnicity, n\      | 167         | 331         | 498         |
| > White\                  | (89.3%)\    | (89.7%)\    | (89.6%)\    |
| > Hispanic\               | 7 (3.7%)\   | 17 (4.6%)\  | 24 (4.3%)\  |
| > Other ^a^               | 13 (7.0%)   | 21 (5.7%)   | 34 (6.1%)   |
+---------------------------+-------------+-------------+-------------+
| Age group (yr), n\        | 68 (36.4%)\ | 140         | 208         |
| 18--40\                   | 106         | (37.9%)\    | (37.4%)\    |
| 41--64\                   | (56.7%)\    | 206         | 312         |
| ≥ 65                      | 13 (7.0%)   | (55.8%)\    | (56.1%)\    |
|                           |             | 23 (6.2%)   | 36 (6.5%)   |
+---------------------------+-------------+-------------+-------------+
| Age (yr)\                 | 44.9        | 45.3        | 45.2        |
| Mean (SD)\                | (11.8)\     | (12.8)\     | (12.5)\     |
| Range                     | 20--75      | 18--75      | 18--75      |
+---------------------------+-------------+-------------+-------------+
| Weight (kg)\              | 94.3        | 93.5        | 93.8        |
| Mean (SD)\                | (18.8)\     | (20.6)\     | (20.0)\     |
| Range                     | 50--143     | 45--160     | 45--160     |
+---------------------------+-------------+-------------+-------------+
| Height (cm) ^b^\          | 172.9       | 172.7       | 172.7       |
| Mean (SD)\                | (10.1)\     | (10.4)\     | (10.3)\     |
| Range                     | 147--196    | 123--198    | 123--198    |
+---------------------------+-------------+-------------+-------------+
| BMI (kg/m^2^) ^b^\        | 31.54       | 31.43       | 31.47       |
| Mean (SD)\                | (5.70)\     | (6.78)\     | (6.43)\     |
| Range                     | 20.9--48.4  | 19.0--56.4  | 19.0--56.4  |
+---------------------------+-------------+-------------+-------------+
| Tobacco use, n\           | 61 (32.6%)\ | 117         | 178         |
| Never\                    | 60 (32.1%)\ | (31.7%)\    | (32.0%)\    |
| Previous\                 | 66 (35.3%)  | 113         | 173         |
| Current                   |             | (30.6%)\    | (31.1%)\    |
|                           |             | 139 (37.7%) | 205 (36.9%) |
+---------------------------+-------------+-------------+-------------+
| BMI = body mass index.    |             |             |             |
|                           |             |             |             |
| ^a^ The "Other" group     |             |             |             |
| included individuals who  |             |             |             |
| described their           |             |             |             |
| race/ethnicity as Asian   |             |             |             |
| or Pacific Islander,      |             |             |             |
| Black, American Indian or |             |             |             |
| Alaskan Native, or Other. |             |             |             |
|                           |             |             |             |
| ^b^ Data were available   |             |             |             |
| for 551 subjects: 185 in  |             |             |             |
| the placebo‑treated group |             |             |             |
| and 366 in the            |             |             |             |
| Raptiva‑treated group.    |             |             |             |
+---------------------------+-------------+-------------+-------------+

The two treatment groups were comparable at baseline with regard to the
state of their psoriasis, with no statistically significant differences
noted (see Table 6).

+---------------------------+-------------+-------------+-------------+
| Table 6                   |             |             |             |
|                           |             |             |             |
| Baseline Psoriasis        |             |             |             |
| Characteristics of        |             |             |             |
| Treated Subjects in       |             |             |             |
| Study 2390                |             |             |             |
+---------------------------+-------------+-------------+-------------+
| Characteristic            | Placebo\    | Raptiva\    | All         |
|                           | (n = 187)   | (n = 369)   | Subjects\   |
|                           |             |             | (n = 556)   |
+---------------------------+-------------+-------------+-------------+
| Duration of psoriasis     | n = 187\    | n = 364\    | n = 551\    |
| (yr)\                     | 19.3        | 19.3        | 19.3        |
| Mean (SD)\                | (11.1)\     | (11.9)\     | (11.7)\     |
| Range                     | 1--53       | 1--62       | 1--62       |
+---------------------------+-------------+-------------+-------------+
| Prior systemic therapy,   | 139         | 283         | 422         |
| n\                        | (74.3%)\    | (76.7%)\    | (75.9%)\    |
| Yes\                      | 48 (25.7%)  | 86 (23.3%)  | 134 (24.1%) |
| No                        |             |             |             |
+---------------------------+-------------+-------------+-------------+
| PASI category, n\         | 83 (44.4%)\ | 155         | 238         |
| ≤ 16.0\                   | 88 (47.1%)\ | (42.0%)\    | (42.8%)\    |
| 16.1--30.0\               | 16 (8.6%)   | 181         | 269         |
| \> 30.0                   |             | (49.1%)\    | (48.4%)\    |
|                           |             | 33 (8.9%)   | 49 (8.8%)   |
+---------------------------+-------------+-------------+-------------+
| PASI score\               | 19.36       | 19.41       | 19.40       |
| Mean (SD)\                | (7.41)\     | (7.52)\     | (7.47)\     |
| Range                     | 11.4--50.3  | 10.1--58.7  | 10.1--58.7  |
+---------------------------+-------------+-------------+-------------+
| PASI thickness component\ | 6.18        | 6.19        | 6.19        |
| Mean (SD)\                | (2.33)\     | (2.43)\     | (2.40)\     |
| Range                     | 2.8--14.5   | 2.4--18.8   | 2.4--18.8   |
+---------------------------+-------------+-------------+-------------+
| PGA, n\                   | 1 (0.5%)\   | 1 (0.3%)\   | 2 (0.4%)\   |
| Minimal\                  | 12 (6.4%)\  | 23 (6.2%)\  | 35 (6.3%)\  |
| Mild\                     | 96 (51.3%)\ | 206         | 302         |
| Moderate\                 | 69 (36.9%)\ | (55.8%)\    | (54.3%)\    |
| Severe\                   | 9 (4.8%)    | 121         | 190         |
| Very severe               |             | (32.8%)\    | (34.2%)\    |
|                           |             | 18 (4.9%)   | 27 (4.9%)   |
+---------------------------+-------------+-------------+-------------+
| DLQI\                     | n = 183\    | n = 363\    | n = 546\    |
| Mean (SD)\                | 11.80       | 11.97       | 11.91       |
| Range                     | (6.87)\     | (6.42)\     | (6.57)\     |
|                           | 0.0--30.0   | 0.0--30.0   | 0.0--30.0   |
+---------------------------+-------------+-------------+-------------+
| Itching Scale\            | n = 187\    | n = 368\    | n = 555\    |
| Mean (SD)\                | 6.2 (2.5)\  | 6.4 (2.5)\  | 6.4 (2.5)\  |
| Range                     | 0--10       | 0--10       | 0--10       |
+---------------------------+-------------+-------------+-------------+
| PSA frequency\            | n = 185\    | n = 361\    | n = 546\    |
| Mean (SD)\                | 14.12       | 14.34       | 14.27       |
| Range                     | (5.27)\     | (5.30)\     | (5.29)\     |
|                           | 2.0--24.0   | 2.0--24.0   | 2.0--24.0   |
+---------------------------+-------------+-------------+-------------+
| PSA severity\             | n = 185\    | n = 362\    | n = 547\    |
| Mean (SD)\                | 14.97       | 14.83       | 14.88       |
| Range                     | (5.43)\     | (5.65)\     | (5.57)\     |
|                           | 2.0--24.0   | 0.0--24.0   | 0.0--24.0   |
+---------------------------+-------------+-------------+-------------+
| > Percent BSA of          | 27.33       | 28.29       | 27.97       |
| > psoriasis\              | (16.22)     | (17.04)\    | (16.76)\    |
| > Mean (SD)\              | 10.0--90.0  | 10.0--95.0  | 10.0--95.0  |
| > Range                   |             |             |             |
+---------------------------+-------------+-------------+-------------+

e\. Subject Disposition

A total of 556 subjects were enrolled and randomized into the study:
187 subjects in the placebo‑treated group and 369 subjects in the
1.0 mg/kg/wk Raptiva‑treated group.

A total of 36 subjects (6.5%) discontinued treatment (see Table 7).

+-----------------------------+-------------+-------------+------------+
| Table 7                     |             |             |            |
|                             |             |             |            |
| Subject Disposition and     |             |             |            |
| Reasons for                 |             |             |            |
| Discontinuation\            |             |             |            |
| of Treatment in Study 2390  |             |             |            |
+-----------------------------+-------------+-------------+------------+
| Subject Status              | Placebo\    | Raptiva\    | All        |
|                             | (n = 187)   | (n = 369)   | Subjects\  |
|                             |             |             | (n = 556)  |
+-----------------------------+-------------+-------------+------------+
| Completed treatment         | 175 (93.6%) | 345 (93.5%) | 520        |
|                             |             |             | (93.5%)    |
+-----------------------------+-------------+-------------+------------+
| Discontinued treatment      | 12 (6.4%)   | 24 (6.5%)   | 36 (6.5%)  |
+-----------------------------+-------------+-------------+------------+
| Reason for discontinuation  |             |             |            |
+-----------------------------+-------------+-------------+------------+
| Subject's decision          | 3 (1.6%)    | 7 (1.9%)    | 10 (1.8%)  |
+-----------------------------+-------------+-------------+------------+
| Adverse event               | 2 (1.1%)    | 7 (1.9%)    | 9 (1.6%)   |
+-----------------------------+-------------+-------------+------------+
| Lost to follow‑up           | 5 (2.7%)    | 4 (1.1%)    | 9 (1.6%)   |
+-----------------------------+-------------+-------------+------------+
| Use of excluded medication  | 0           | 5 (1.4%)    | 5 (0.9%)   |
+-----------------------------+-------------+-------------+------------+
| Investigator's decision     | 2 (1.1%)    | 1 (0.3%)    | 3 (0.5%)   |
+-----------------------------+-------------+-------------+------------+

The primary reason cited for discontinuation was subject's decision,
followed by adverse events. The proportion of subjects who chose to
discontinue was similar in the placebo‑treated and Raptiva‑treated
groups.

f\. Efficacy Results

**PASI‑75.** The proportion of PASI‑75 responders was statistically
significantly greater in the Raptiva‑treated group than in the
placebo‑treated group (p \< 0.001; see Table 8). A 22.3% treatment
effect (i.e., the difference in the proportion of responders between the
Raptiva‑treated group and the placebo‑treated group) was observed, with
a 95% confidence interval (CI) of 15.8%--29.5%.

+--------------------------------------+---------------+---------------+
| Table 8                              |               |               |
|                                      |               |               |
| PASI‑75 Response to Treatment at 12  |               |               |
| Weeks for\                           |               |               |
| Randomized Subjects in Study 2390    |               |               |
+--------------------------------------+---------------+---------------+
| PASI Response                        | Placebo\      | Raptiva\      |
|                                      | (n = 187)     | (n = 369)     |
+--------------------------------------+---------------+---------------+
| PASI‑75                              | 8 (4.3%)      | 98 (26.6%)    |
+--------------------------------------+---------------+---------------+
| Fisher's exact p‑value\              | ---           | \< 0.001      |
| Raptiva vs. placebo                  |               |               |
+--------------------------------------+---------------+---------------+
| Treatment effect                     | 22.3%         |               |
+--------------------------------------+---------------+---------------+
| 95% CI for treatment effect          | 15.8%, 29.5%  |               |
+--------------------------------------+---------------+---------------+
| Note: Subjects whose Day 84          |               |               |
| (Week 12) PASI score was missing     |               |               |
| were considered PASI‑75              |               |               |
| non‑responders.                      |               |               |
+--------------------------------------+---------------+---------------+

A more detailed examination of the distribution of percent improvement
in PASI achieved at Day 84 demonstrates a general shift toward
improvement in the Raptiva‑treated group compared with a minimal change
in the placebo‑treated group. There was a greater proportion of subjects
who experienced a PASI worsening at Day 84 compared with baseline (i.e.,
\< 0% improvement from baseline) in the placebo‑treated group (21.4%)
than in the Raptiva‑treated group (6.5%) (see Table 9).

+---+--------------------------------+---------------+---------------+
| T |                                |               |               |
| a |                                |               |               |
| b |                                |               |               |
| l |                                |               |               |
| e |                                |               |               |
| 9 |                                |               |               |
|   |                                |               |               |
| P |                                |               |               |
| A |                                |               |               |
| S |                                |               |               |
| I |                                |               |               |
| R |                                |               |               |
| e |                                |               |               |
| s |                                |               |               |
| p |                                |               |               |
| o |                                |               |               |
| n |                                |               |               |
| s |                                |               |               |
| e |                                |               |               |
| a |                                |               |               |
| t |                                |               |               |
| 1 |                                |               |               |
| 2 |                                |               |               |
| W |                                |               |               |
| e |                                |               |               |
| e |                                |               |               |
| k |                                |               |               |
| s |                                |               |               |
| a |                                |               |               |
| s |                                |               |               |
| P |                                |               |               |
| e |                                |               |               |
| r |                                |               |               |
| c |                                |               |               |
| e |                                |               |               |
| n |                                |               |               |
| t |                                |               |               |
| \ |                                |               |               |
| I |                                |               |               |
| m |                                |               |               |
| p |                                |               |               |
| r |                                |               |               |
| o |                                |               |               |
| v |                                |               |               |
| e |                                |               |               |
| m |                                |               |               |
| e |                                |               |               |
| n |                                |               |               |
| t |                                |               |               |
| f |                                |               |               |
| r |                                |               |               |
| o |                                |               |               |
| m |                                |               |               |
| B |                                |               |               |
| a |                                |               |               |
| s |                                |               |               |
| e |                                |               |               |
| l |                                |               |               |
| i |                                |               |               |
| n |                                |               |               |
| e |                                |               |               |
| i |                                |               |               |
| n |                                |               |               |
| S |                                |               |               |
| t |                                |               |               |
| u |                                |               |               |
| d |                                |               |               |
| y |                                |               |               |
|   |                                |               |               |
| 2 |                                |               |               |
| 3 |                                |               |               |
| 9 |                                |               |               |
| 0 |                                |               |               |
+---+--------------------------------+---------------+---------------+
|   | Percent Improvement\           | Placebo\      | Raptiva\      |
|   | from Baseline                  | (n = 187)     | (n = 369)     |
+---+--------------------------------+---------------+---------------+
| I | ≥ 90%                          | 1 (0.5%)      | 19 (5.1%)     |
| m |                                |               |               |
| p |                                |               |               |
| r |                                |               |               |
| o |                                |               |               |
| v |                                |               |               |
| e |                                |               |               |
| m |                                |               |               |
| e |                                |               |               |
| n |                                |               |               |
| t |                                |               |               |
+---+--------------------------------+---------------+---------------+
|   | ≥ 75% to \< 90%                | 7 (3.7%)      | 79 (21.4%)    |
+---+--------------------------------+---------------+---------------+
|   | ≥ 50% to \< 75%                | 18 (9.6%)     | 118 (32.0%)   |
+---+--------------------------------+---------------+---------------+
|   | ≥ 25% to \< 50%                | 39 (20.9%)    | 59 (16.0%)    |
+---+--------------------------------+---------------+---------------+
|   | ≥ 0% to \< 25%                 | 70 (37.4%)    | 48 (13.0%)    |
+---+--------------------------------+---------------+---------------+
| W | ≥ --25% to \< 0%               | 32 (17.1%)    | 15 (4.1%)     |
| o |                                |               |               |
| r |                                |               |               |
| s |                                |               |               |
| e |                                |               |               |
| n |                                |               |               |
| i |                                |               |               |
| n |                                |               |               |
| g |                                |               |               |
+---+--------------------------------+---------------+---------------+
|   | ≥ --50% to \< --25%            | 5 (2.7%)      | 6 (1.6%)      |
+---+--------------------------------+---------------+---------------+
|   | \< --50%                       | 3 (1.6%)      | 3 (0.8%)      |
+---+--------------------------------+---------------+---------------+
|   | Missing ^a^                    | 12 (6.4%)     | 22 (6.0%)     |
+---+--------------------------------+---------------+---------------+
| ^ |                                |               |               |
| a |                                |               |               |
| ^ |                                |               |               |
| S |                                |               |               |
| u |                                |               |               |
| b |                                |               |               |
| j |                                |               |               |
| e |                                |               |               |
| c |                                |               |               |
| t |                                |               |               |
| s |                                |               |               |
| w |                                |               |               |
| i |                                |               |               |
| t |                                |               |               |
| h |                                |               |               |
| m |                                |               |               |
| i |                                |               |               |
| s |                                |               |               |
| s |                                |               |               |
| i |                                |               |               |
| n |                                |               |               |
| g |                                |               |               |
| D |                                |               |               |
| a |                                |               |               |
| y |                                |               |               |
|   |                                |               |               |
| 8 |                                |               |               |
| 4 |                                |               |               |
| ( |                                |               |               |
| W |                                |               |               |
| e |                                |               |               |
| e |                                |               |               |
| k |                                |               |               |
| 1 |                                |               |               |
| 2 |                                |               |               |
| ) |                                |               |               |
| P |                                |               |               |
| A |                                |               |               |
| S |                                |               |               |
| I |                                |               |               |
| s |                                |               |               |
| c |                                |               |               |
| o |                                |               |               |
| r |                                |               |               |
| e |                                |               |               |
| s |                                |               |               |
| w |                                |               |               |
| e |                                |               |               |
| r |                                |               |               |
| e |                                |               |               |
| c |                                |               |               |
| l |                                |               |               |
| a |                                |               |               |
| s |                                |               |               |
| s |                                |               |               |
| i |                                |               |               |
| f |                                |               |               |
| i |                                |               |               |
| e |                                |               |               |
| d |                                |               |               |
| a |                                |               |               |
| s |                                |               |               |
| n |                                |               |               |
| o |                                |               |               |
| n |                                |               |               |
| ‑ |                                |               |               |
| r |                                |               |               |
| e |                                |               |               |
| s |                                |               |               |
| p |                                |               |               |
| o |                                |               |               |
| n |                                |               |               |
| d |                                |               |               |
| e |                                |               |               |
| r |                                |               |               |
| s |                                |               |               |
| . |                                |               |               |
+---+--------------------------------+---------------+---------------+

The majority of subjects receiving Raptiva (58.5%) experienced
≥ 50% improvement from baseline in PASI score compared with 13.9% of
subjects receiving placebo.

Improvement occurred in each of the three key morphologic
characteristics of psoriasis lesions (thickness, erythema, and scaling)
as measured by improvement in the corresponding components of the PASI
score. The mean improvement in the PASI thickness component at Day 84
relative to Day 0 was statistically significantly greater for subjects
in the Raptiva‑treated group compared with subjects in the
placebo‑treated group (p \< 0.001). The mean improvement (decrease) from
baseline for the Raptiva‑treated group was at least three times that
observed for the placebo‑treated group. Although they were not formal
endpoints of the study, the mean percent improvement in erythema and
scaling corresponded closely to the mean percent improvement in
thickness.

In addition, mean psoriatic BSA declined from 28% to 17% in subjects
receiving Raptiva compared with a decline from 27% to 25% in those
receiving placebo (p \< 0.001). Thus, Raptiva improves all of the
cardinal features of psoriasis that contribute to the overall PASI
score.

Subjects in the Raptiva‑treated group showed a significant mean percent
improvement in PASI score versus the placebo‑treated group as early as
28 days following initial treatment (p \< 0.001). The mean percent
improvement in PASI score is presented over time for each treatment
group in Figure 6.

Figure 6

Mean ± SEM Percent Improvement in PASI Score over Time in Study 2390

![](media/image8.png){width="5.659722222222222in" height="4.15in"}

SEM = standard error of mean.

**PGA.** The proportion of subjects with a PGA rating of minimal or
clear in the Raptiva‑treated group (95 of the 369 subjects; 25.7%) was
statistically significantly higher than that in the placebo‑treated
group (6 of the 187 subjects; 3.2%) (p \< 0.001; see Table 10).

+-----------------------------------+----------------+----------------+
| Table 10                          |                |                |
|                                   |                |                |
| PGA Response at 12 Weeks for      |                |                |
| Subjects in Study 2390            |                |                |
+-----------------------------------+----------------+----------------+
| PGA Response                      | Placebo\       | Raptiva\       |
|                                   | (n = 187)      | (n = 369)      |
+-----------------------------------+----------------+----------------+
| Minimal or clear                  | 6 (3.2%)       | 95 (25.7%)     |
+-----------------------------------+----------------+----------------+
| Mild to very severe ^a^           | 181 (96.8%)    | 274 (74.3%)    |
+-----------------------------------+----------------+----------------+
| Fisher's exact p‑value\           | ---            | \< 0.001       |
| Raptiva vs. placebo               |                |                |
+-----------------------------------+----------------+----------------+
| ^a^ Included subjects who were    |                |                |
| classified as mild, moderate,     |                |                |
| severe, and very severe and those |                |                |
| whose Day 84 (Week 12) PGA rating |                |                |
| was missing.                      |                |                |
+-----------------------------------+----------------+----------------+

**DLQI.** A comparison of improvement from baseline in the DLQI overall
scores at Day 84 for the Raptiva‑treated group with the placebo‑treated
group was performed using the Wilcoxon rank‑sum test. A decrease in DLQI
overall scores represents improvement in dermatologic‑related
functionality and subject well‑being. The improvement in mean DLQI
overall scores was statistically significant in favor of the
Raptiva‑treated group compared with the placebo‑treated group
(p \< 0.001; see Table 11). The improvement in the DLQI overall scores
for the Raptiva‑treated group was at least three times that observed for
the placebo‑treated group.

+-------------------------------------+---------------+---------------+
| Table 11                            |               |               |
|                                     |               |               |
| Improvement from Baseline in        |               |               |
| Overall DLQI Score at Week 12 in    |               |               |
| Study 2390                          |               |               |
+-------------------------------------+---------------+---------------+
| DLQI                                | Placebo\      | Raptiva\      |
|                                     | (n = 187)     | (n = 369)     |
+-------------------------------------+---------------+---------------+
| Day 0\                              | 183\          | 363\          |
| n\                                  | 11.8 (6.9)\   | 12.0 (6.4)\   |
| Mean (SD)\                          | 11.0\         | 11.0\         |
| Median\                             | 0 to 30       | 0 to 30       |
| Range                               |               |               |
+-------------------------------------+---------------+---------------+
| Day 84 (Week 12) ^a^\               | 187\          | 368\          |
| n\                                  | 10.2 (7.1)\   | 6.4 (6.7)\    |
| Mean (SD)\                          | 9.0\          | 4.0\          |
| Median\                             | 0 to 30       | 0 to 30       |
| Range                               |               |               |
+-------------------------------------+---------------+---------------+
| Improvement from baseline ^b^\      | 183\          | 363\          |
| n\                                  | 1.6 (5.7)\    | 5.6 (6.6)\    |
| Mean (SD)\                          | 1.0\          | 5.0\          |
| Median\                             | --13 to 25    | --22 to 25    |
| Range                               |               |               |
+-------------------------------------+---------------+---------------+
| Wilcoxon rank‑sum test p‑value\     | ---           | \< 0.001      |
| Raptiva vs. placebo                 |               |               |
+-------------------------------------+---------------+---------------+
| ^a^ The last observation carried    |               |               |
| forward was used to impute missing  |               |               |
| Day 84 (Week 12) DLQI values.       |               |               |
|                                     |               |               |
| ^b^ Improvement was reflected by a  |               |               |
| decrease in overall DLQI score.     |               |               |
+-------------------------------------+---------------+---------------+

There was a consistent trend toward a treatment effect across all DLQI
subscales (symptoms and feelings, daily activities, leisure, work and
school, personal relationships, treatment).

Subjects in the Raptiva‑treated group showed a clear improvement in DLQI
scores versus the placebo‑treated group at the first post‑baseline
assessment 28 days following initial treatment (p \< 0.001; see Figure
7). In addition, for the Raptiva‑treated subjects, the mean improvement
in DLQI scores at Day 28 was 70% of the mean improvement at Day 84,
indicating an early quality‑of‑life benefit.

Comparison of the pattern of improvement over time in DLQI in Figure 7
versus that for PASI in Figure 6 suggests that subjects perceive a
quality‑of‑life benefit earlier than the physical improvement assessed
by the physician through the PASI.

Figure 7

Mean ± SEM Improvement in DLQI over Time in Study 2390

![](media/image9.png){width="5.334722222222222in" height="3.85in"}

SEM = standard error of mean.

**Itching Scale.** The mean improvement in the Itching Scale at Day 84
relative to Day 0 was statistically significant in favor of the
Raptiva‑treated group relative to the placebo‑treated group (p \< 0.001;
see Table 12).

+-----------------------------------+----------------+----------------+
| Table 12                          |                |                |
|                                   |                |                |
| Mean (SD) Improvement from        |                |                |
| Baseline in the Itching Scale at  |                |                |
| Week 12 in Study 2390             |                |                |
+-----------------------------------+----------------+----------------+
| Change in Itching Score           | Placebo\       | Raptiva\       |
|                                   | (n = 187)      | (n = 369)      |
+-----------------------------------+----------------+----------------+
| Day 0                             | 6.2 (2.5)      | 6.4 (2.5)      |
+-----------------------------------+----------------+----------------+
| Day 84 (Week 12) ^a^              | 5.6 (2.7)      | 3.6 (2.9)      |
+-----------------------------------+----------------+----------------+
| Improvement ^b^                   | 0.7 (2.8)      | 2.8 (3.3)      |
+-----------------------------------+----------------+----------------+
| Two‑sample t‑test p‑value\        | ---            | \< 0.001       |
| Raptiva vs. placebo               |                |                |
+-----------------------------------+----------------+----------------+
| ^a^ The last observation carried  |                |                |
| forward was used to impute        |                |                |
| missing Day 84 (Week 12) Itching  |                |                |
| Scale values.                     |                |                |
|                                   |                |                |
| ^b^ Improvement was reflected by  |                |                |
| a decrease in the score on the    |                |                |
| 10‑point Itching Scale.           |                |                |
+-----------------------------------+----------------+----------------+

As observed for the PASI and DLQI, subjects in the Raptiva‑treated group
showed a clear improvement in mean Itching Scale scores versus the
placebo‑treated group at the first post‑baseline assessment 28 days
following initial treatment (p \< 0.001).

**PSA.** A comparison of improvement from baseline in the frequency and
severity of the psoriasis‑specific symptom scores at Day 84 for the
Raptiva‑treated group versus the placebo‑treated group was performed
using the Wilcoxon rank‑sum test. A decrease in PSA score represents
improvement. Comparisons of the improvement from baseline in the
Raptiva‑treated group versus the placebo‑treated group were
statistically significant for both frequency of symptoms (p \< 0.001)
and severity of symptoms (p \< 0.001), implying an improvement in
psoriasis‑specific symptoms for the Raptiva‑treated group relative to
placebo. The mean improvements in symptom frequency and severity in the
Raptiva‑treated group were more than two times those observed in the
placebo‑treated group.

Subjects in the Raptiva‑treated group showed a clear improvement in both
mean PSA frequency and mean PSA severity scores versus the
placebo‑treated group at the first post‑baseline assessment 28 days
following initial treatment (p \< 0.001).

5.2 Supportive Studies Providing Additional Efficacy Data

5.2.1 Study 2600

a\. Study Design and Treatment

Study 2600 was a Phase III, randomized, double‑blind, parallel‑group,
placebo‑controlled, multicenter study designed to evaluate the safety of
Raptiva (as the to‑be‑marketed product) administered at weekly SC doses
of 1.0 mg/kg in subjects with moderate to severe plaque psoriasis who
were candidates for systemic therapy. Subjects were required to have a
psoriatic BSA of ≥ 10% and PASI ≥ 12.0 to be eligible for study
enrollment.

Following a screening period, eligible subjects were randomized in a 2:1
ratio to receive SC treatment with 0.7 mg/kg for 1 week followed by 11
weeks of either 1.0 mg/kg/wk Raptiva or placebo equivalent. Subjects
were to return 1 week after the last SC treatment for Day 84
assessments.

A total of 686 subjects were randomized in an approximate 2:1 ratio to
receive either 12 weeks of 1.0 mg/kg/wk SC Raptiva or placebo equivalent
at 58 sites in the United States and Canada. Of these subjects,
236 subjects were in the placebo‑treated group and 450 subjects were in
the Raptiva‑treated group.

b\. Efficacy Results

Efficacy endpoints were considered of secondary importance in this
safety study. Efficacy was assessed by determining the proportion of
subjects achieving PASI‑75, PASI‑50, and PGA ratings of clear or minimal
(see Table 13). The treatment effect for the PASI‑75 endpoint (i.e., the
difference in the proportion of PASI‑75 responders between the two
groups) was 20.6%, with a 95% CI of 15.3%--26.6%.

+-----------------+---------------+---------------+------------------+
| Table 13        |               |               |                  |
|                 |               |               |                  |
| Efficacy        |               |               |                  |
| Results at      |               |               |                  |
| 12 Weeks for    |               |               |                  |
| Randomized      |               |               |                  |
| Subjects in     |               |               |                  |
| Study 2600      |               |               |                  |
+-----------------+---------------+---------------+------------------+
| Response        | Placebo\      | Raptiva\      | p‑value ^a^\     |
|                 | (n = 236)     | 1.0 mg/kg/wk\ | Raptiva 1.0      |
|                 |               | (n = 450)     | mg/kg/wk vs.     |
|                 |               |               | Placebo          |
+-----------------+---------------+---------------+------------------+
| PASI‑75         | 7 (3.0%)      | 106 (23.6%)   | \< 0.001         |
+-----------------+---------------+---------------+------------------+
| PASI‑50         | 33 (14.0%)    | 234 (52.0%)   | \< 0.001         |
+-----------------+---------------+---------------+------------------+
| PGA clear or    | 10 (4.2%)     | 91 (20.3%)    | \< 0.001         |
| minimal         |               |               |                  |
+-----------------+---------------+---------------+------------------+
| ^a^ Statistical |               |               |                  |
| comparisons     |               |               |                  |
| were made       |               |               |                  |
| between         |               |               |                  |
| placebo‑treated |               |               |                  |
| subjects and    |               |               |                  |
| all             |               |               |                  |
| Raptiva‑treated |               |               |                  |
| subjects using  |               |               |                  |
| Fisher's exact  |               |               |                  |
| test.           |               |               |                  |
+-----------------+---------------+---------------+------------------+

Raptiva treatment also resulted in a statistically significant
improvement in subject‑reported symptoms of psoriasis as measured by the
PSA. The mean improvements in symptom frequency and severity in the
Raptiva‑treated group were at least three times those observed in the
placebo‑treated group (p \< 0.001 for separate comparisons of PSA
frequency, PSA severity, and both itching components of the PSA).

5.2.2 Study 2058

a\. Study Design and Treatment

The first 12 weeks of Study 2058 were almost identical in design to the
first 12 weeks of Study 2390. The study consisted of first treatment,
observation, retreatment, and extended treatment periods, as well as a
follow‑up period (see Figure 8). The study was performed with a version
of the product that will not be marketed.

Figure 8

Study 2058

![](media/image10.wmf)

During the first 12 weeks of treatment, subjects received a conditioning
dose of 0.7 mg/kg followed by 11 weekly SC doses of 1.0 mg/kg (low‑dose)
Raptiva (n = 162), 2.0 mg/kg (high‑dose) Raptiva (n = 166), or placebo
equivalent to low‑dose or high‑dose Raptiva (n = 170 combined).

b\. Efficacy Results for the First 12 Weeks of Treatment

The primary efficacy endpoint was the proportion of subjects with a
PASI‑75 response at the end of the first 12 weeks of treatment. The
principal secondary endpoint was the proportion of subjects with a PGA
rating of minimal or clear at the end of 12 weeks of treatment. Other
secondary efficacy endpoints were percentage of subjects with a PGA of
Change of cleared or excellent, time to relapse after the Day 84 visit
for the FT period for subjects who achieved PASI‑75 at the Day 84 visit,
mean improvement in the thickness component of the PASI, mean
improvement in the Itching Scale, and mean improvement in the BSA
affected by psoriasis.

At Day 84, statistically significantly more subjects in the 1.0 mg/kg/wk
group (38.9%) and the 2.0 mg/kg/wk group (26.5%) exhibited a PASI‑75
response compared with the placebo‑treated group (2.4%; p \< 0.001). The
proportion of subjects with a PGA rating of minimal or clear in the
1.0 mg/kg/wk group (32.1%) and the 2.0 mg/kg/wk group (22.3%) was
statistically significantly higher than that in the placebo‑treated
group (2.9%; p \< 0.001). Similar statistically significant differences
in favor of each Raptiva‑treated group over placebo (p ≤ 0.001) were
observed for all secondary efficacy endpoints tested. For subjects with
a PASI‑75 response, the median time to relapse (loss of ≥ 50% of the
improvement in the PASI score achieved between Day 0 and Day 84) was
67 days after the last Raptiva dose.

Results for treatment periods beyond the initial 12 weeks of treatment
are presented in Section 5.4.

5.2.3 Study 2059

a\. Study Design and Treatment

The first 12 weeks of Study 2059 were also almost identical in design to
the first 12 weeks of Study 2390. Following a screening period, eligible
subjects were randomized in a 2:1 ratio to a conditioning dose of 0.7
mg/kg followed by 11 weekly SC doses of 1.0 mg/kg Raptiva (n = 232),
2.0 mg/kg Raptiva (n = 243), or to placebo (n = 122). The study
consisted of first treatment (12 weeks) and extended treatment
(12 weeks) periods, as well as a follow‑up period (see Figure 9). The
study was performed primarily with a version of the product that will
not be marketed.

Figure 9

Study 2059

![](media/image11.wmf)

b\. Efficacy Results for the First 12 Weeks of Treatment

The primary efficacy endpoint was the proportion of subjects with a
PASI‑75 response at the end of 12 weeks of treatment. The principal
secondary endpoint was the proportion of subjects with a PGA rating of
minimal or clear at the end of 12 weeks of treatment. Other secondary
efficacy endpoints were percentage of subjects with a PGA of Change of
cleared or excellent, mean improvement in the thickness component of the
PASI, mean improvement in the Itching Scale, and mean improvement in the
BSA affected by psoriasis.

At Day 84, statistically significantly more subjects in the 1.0 mg/kg/wk
group (22.4%) and the 2.0 mg/kg/wk group (28.4%) had a PASI‑75 response
compared with the placebo‑treated group (4.9%; p \< 0.001). The
proportion of subjects with a PGA rating of minimal or clear in the
1.0 mg/kg/wk group (19.4%) and the 2.0 mg/kg/wk group (22.6%) was
statistically significantly higher than that in the placebo‑treated
group (3.3%; p \< 0.001). Similar statistically significant differences
in favor of each Raptiva‑treated group over placebo (p \< 0.001) were
observed for all secondary efficacy endpoints.

Results for treatment periods beyond the initial 12 weeks of treatment
are presented in Section 5.4.

5.3 Comparison of Results in Subpopulations

The difference between the Raptiva and placebo PASI rates at Day 84 was
summarized by subpopulations using pooled data from the first 12 weeks
of treatment in the four placebo‑controlled, Phase III trials (2058,
2059, 2390, and 2600).

Treatment effect for subgroups defined using demographic factors of age,
sex, and race is displayed in Figure 10. As an example of what is
plotted in the figure, the pooled placebo PASI‑75 rate was 4% and the
pooled Raptiva rate was 27%. The difference, 23%, is plotted as the
circle in the top row. The 95% confidence interval in this case is
approximately 20%--26%, which is plotted as the squares in the first
row. Across the subgroups, the estimated treatment effect is similar,
and the 95% confidence intervals are all to the right of the vertical
line at zero, demonstrating the efficacy of Raptiva in each subgroup.

Figure 10

Raptiva Minus Placebo PASI‑75 Rates at Day 84 by Demographic Subgroups\
(95% CI)

![](media/image12.wmf)

For each subgroup, the solid circle is plotted at the difference between
the Raptiva and placebo PASI‑75 rates, and the squares span the 95%
confidence interval.

Treatment effect for subgroups defined using disease‑related factors of
baseline PASI, history of systemic therapy, and duration of disease is
displayed in Figure 11. Again, estimated treatment effect is similar
across each of the subgroups, and the 95% confidence intervals are all
to the right of zero, demonstrating the efficacy of Raptiva in each
subgroup. Importantly, Raptiva is equally effective in patients with
moderate, severe, and very severe disease.

Figure 11

Raptiva Minus Placebo PASI‑75 Rates at Day 84 by Disease‑Related
Subgroups\
(95% CI)

![](media/image13.wmf)

For each subgroup, the solid circle is plotted at the difference between
the Raptiva and placebo PASI‑75 rates, and the squares span the 95%
confidence interval.

In addition, the difference between the Raptiva and placebo PASI‑75
response rate was also consistent across patient subgroups based on
season of treatment, subject weight, and subject body mass index.

5.4 Treatment beyond 12 Weeks

a\. Extended Treatment: Weeks 12--24

**Study 2391.** The efficacy of continuous treatment with 1.0 mg/kg/wk
Raptiva beyond 12 weeks is demonstrated by combined data from Study 2390
and an uncontrolled, open‑label study, 2391, which allowed subjects who
completed the Phase III, randomized, placebo‑controlled Study 2390 to
continue Raptiva treatment beyond the initial 12 weeks (see Table 14).
Efficacy was examined in an intent‑to‑treat (ITT) analysis of the cohort
of subjects randomized to Raptiva in Study 2390. The PASI‑75 response
rate at the end of this second 12 weeks of treatment reached 44% from
27% at the end of the first 12 weeks of treatment in Study 2390.

+-------------------------------------+--------------------------------+
| Table 14                            |                                |
|                                     |                                |
| PASI‑75 and PASI‑50 Responses after |                                |
| 24 Weeks of Continuous Treatment    |                                |
| for Subjects: Study 2391            |                                |
+-------------------------------------+--------------------------------+
| PASI Response ^a^                   | Group 2390‑A (n = 369) ^b^     |
+-------------------------------------+--------------------------------+
| PASI‑75                             | 161 (43.6%)                    |
+-------------------------------------+--------------------------------+
| > 95% Cl of response rate           | 38.5%, 49.0%                   |
+-------------------------------------+--------------------------------+
| PASI‑50                             | 245 (66.4%)                    |
+-------------------------------------+--------------------------------+
| > 95% Cl of response rate           | 61.3%, 71.2%                   |
+-------------------------------------+--------------------------------+
| ^a^ Subject who discontinued early  |                                |
| from Study 2390 or 2391 were        |                                |
| classified as non‑responders.       |                                |
|                                     |                                |
| ^b^ This group consisted of         |                                |
| subjects who were randomized to     |                                |
| receive Raptiva in Study 2390.      |                                |
+-------------------------------------+--------------------------------+

**Studies 2058 and 2059.** In Studies 2058 and 2059, many subjects who
had received Raptiva for the first 12‑week treatment period entered the
Extended Treatment period and received a second course of 12 weekly SC
doses of Raptiva or placebo (see Figures 8 and 9). The results from this
second 12 weeks of treatment in Studies 2058 and 2059 were consistent
with those seen in the data from Study 2391. In both studies, continued
treatment with Raptiva was demonstrated to be superior to
discontinuation.

b\. Treatment beyond 24 Weeks

Long‑term response to treatment with Raptiva is being evaluated in the
ongoing, open‑label study, 2243. Subjects were treated with 2.0 mg/kg/wk
Raptiva for the first 12 weeks. The design of this study stipulated that
only subjects achieving a PASI‑50 response or a PGA rating of mild or
better were allowed to continue treatment beyond the initial 12 weeks of
treatment. Dosing in these subjects is decreased to 1.0 mg/kg/wk at the
beginning of the subsequent Maintenance Treatment period; if a subject
experiences relapse, the Raptiva dose is escalated to 2.0 mg/kg/wk for
the remaining treatment period. Of the 339 subjects who started the
study, 289 achieved a level of response that allowed them to receive
continuous treatment past 12 weeks.

Response rates for cohorts of subjects entering sequential 12‑week
treatment courses are presented in Table 15.

+----------------+------------+------------+------------+-----------+
| Table 15       |            |            |            |           |
|                |            |            |            |           |
| Treatment      |            |            |            |           |
| beyond 24      |            |            |            |           |
| Weeks,         |            |            |            |           |
| Overview of    |            |            |            |           |
| Efficacy by    |            |            |            |           |
| PASI Response  |            |            |            |           |
| in Study 2243: |            |            |            |           |
| PASI Response  |            |            |            |           |
| from Baseline  |            |            |            |           |
| during First   |            |            |            |           |
| and Extended   |            |            |            |           |
| Treatment      |            |            |            |           |
| (\> 12 Weeks)  |            |            |            |           |
| with Raptiva   |            |            |            |           |
+----------------+------------+------------+------------+-----------+
| Study          | Week 12    | Week 24    | Week 36    | Week 48   |
+----------------+------------+------------+------------+-----------+
| 2243           |            |            |            |           |
+----------------+------------+------------+------------+-----------+
| > n ^a^        | 339        | 289        | 269        | 243       |
+----------------+------------+------------+------------+-----------+
| > PASI‑75      | 140        | 149        | 159        | 152       |
|                | (41.3%)    | (51.6%)    | (59.1%)    | (62.6%)   |
+----------------+------------+------------+------------+-----------+
| ITT analysis   |            |            |            |           |
| of PASI        |            |            |            |           |
| response data  |            |            |            |           |
| ^b^            |            |            |            |           |
+----------------+------------+------------+------------+-----------+
| > n            | 339        | 339        | 339        | 339       |
+----------------+------------+------------+------------+-----------+
| > PASI‑75      | 140        | 149        | 158        | 152       |
|                | (41.3%)    | (44.0%)    | (46.6%)    | (44.8%)   |
+----------------+------------+------------+------------+-----------+
| ITT = intent   |            |            |            |           |
| to treat.      |            |            |            |           |
|                |            |            |            |           |
| ^a^ The        |            |            |            |           |
| population     |            |            |            |           |
| comprises all  |            |            |            |           |
| enrolled       |            |            |            |           |
| subjects for   |            |            |            |           |
| the first 12   |            |            |            |           |
| weeks. After   |            |            |            |           |
| 12 weeks, the  |            |            |            |           |
| population     |            |            |            |           |
| includes only  |            |            |            |           |
| original       |            |            |            |           |
| enrollees who  |            |            |            |           |
| achieved       |            |            |            |           |
| PASI‑50 or PGA |            |            |            |           |
| ratings of     |            |            |            |           |
| mild, minimal, |            |            |            |           |
| or clear at    |            |            |            |           |
| Week 12.       |            |            |            |           |
| Population     |            |            |            |           |
| changes        |            |            |            |           |
| between Week   |            |            |            |           |
| 24 and         |            |            |            |           |
| subsequent     |            |            |            |           |
| 12‑week        |            |            |            |           |
| segments are   |            |            |            |           |
| due to subject |            |            |            |           |
| dis            |            |            |            |           |
| continuations. |            |            |            |           |
|                |            |            |            |           |
| ^b^ This ITT   |            |            |            |           |
| analysis       |            |            |            |           |
| assumes that   |            |            |            |           |
| all subjects   |            |            |            |           |
| who            |            |            |            |           |
| discontinued   |            |            |            |           |
| from the study |            |            |            |           |
| would remain   |            |            |            |           |
| \< PASI‑75 for |            |            |            |           |
| each           |            |            |            |           |
| subsequent     |            |            |            |           |
| 12‑week        |            |            |            |           |
| treatment      |            |            |            |           |
| period.        |            |            |            |           |
+----------------+------------+------------+------------+-----------+

In assessing the long‑term results presented in Table 15, it is
recognized that all subjects with continuous dosing beyond 12 weeks did
so as subsets of the original psoriatic population at baseline. In
Study 2243, only subjects who achieved a PASI‑50 response or a PGA
rating of mild or better at the end of first 12‑week treatment period
were provided an opportunity for further continuous dosing to Week 48.
In addition to the response rates by 12‑week treatment segment presented
in Table 15, a conservative ITT analysis was performed by assuming that
all subjects who did not continue beyond the 12‑week treatment period
and all post--first treatment dropouts remained \< PASI‑75. The Week 24
to Week 48 response rates by this conservative method were higher than
the Week 12 value of 41.3% (ranging from 44.0% to 46.6%).

c\. Retreatment during Active Relapse

In Study 2058, subjects who achieved a PASI‑75 response at the end of
the initial 12‑week treatment period then entered an untreated
observation period. These subjects were followed until they experienced
a protocol‑defined relapse of disease, defined as a loss of ≥ 50% of the
Week 12 improvement in PASI score. The median time to relapse was 67
days from the last Raptiva dose.

At the time of relapse, subjects were randomized to double‑blind placebo
or Raptiva during a 12‑week retreatment period. At the end of the
retreatment period, 30.9% of Raptiva‑treated subjects re‑achieved a
PASI‑75 versus none of the placebo‑treated subjects (p \< 0.001),
demonstrating the efficacy of Raptiva in the treatment of patients with
active relapse of their disease.

Because all the subjects given Raptiva retreatment had been PASI‑75
responders to the first 12 weeks of treatment with Raptiva, the
re‑treatment PASI‑75 rate of 30.9% suggests a possible attenuation of
the original response. However, the psoriatic state of subjects at the
beginning of retreatment was very different from that of subjects at the
beginning the first treatment period.

Subjects beginning retreatment were in active relapse, in contrast to
the stability of subjects beginning first treatment after observation
during screening. The worsening PASI scores of patients entering
retreatment did not stabilize, on average, until after 14 days of
retreatment, with improvements seen subsequently. After first treatment
in subjects with stable disease, PASI scores improved, on average, after
the first 14 days of treatment (see Figure 6).

This suggests that an intervening recurrence of disease did not
appreciably attenuate the subsequent response to treatment, but that
retreatment during a phase of rapid worsening is expected to require
additional time to demonstrate a stable efficacy response of the
magnitude observed after first treatment.

Further support that the efficacy of Raptiva on retreatment is similar
to that of first treatment is provided by data from Study 2062, as
described in the next section.

d\. Other Retreatment Experience

In Study 2062, subjects who had participated in prior studies of Raptiva
were allowed to receive retreatment with Raptiva. Prior exposure to
Raptiva ranged from a single IV dose to 12 weeks of SC Raptiva. Entry
into the Study 2062 was not restricted based on PASI or percent BSA of
psoriasis at baseline.

In the 364 subjects retreated with Raptiva in Study 2062, 25.3% achieved
a PASI‑75 response and 56.9% achieved a PASI‑50 response, indicating
that response to retreatment is similar to response to initial Raptiva
treatment, as seen in the Phase III placebo‑controlled studies.

A further analysis of Study 2062 data was performed in order to mimic
the analysis of the Study 2058 retreatment period, but remove the effect
of relapse on the results. For this analysis, subjects who met the
following two criteria were selected:

-   Subjects were PASI‑75 responders to Raptiva treatment for 12 weeks
    in their previous study

-   Subjects were enrolled in Study 2062 with \> 67 days between their
    first dose of Raptiva in Study 2062 and their last dose in the
    previous study. The cutoff of 67 days was chosen because this was
    the median time to relapse prior to the retreatment period in Study
    2058

PASI‑75 and PASI‑50 responses were then determined at the end of
Study 2062 relative to the PASI baseline of the first 12‑week treatment
period in the previous study.

There were 86 subjects who met the two criteria above. The PASI‑75 rate
was 61.6%, and the PASI‑50 rate was 84.9%. These rates are substantially
larger than those observed in the retreatment period of Study 2058 and
demonstrate the maintenance of efficacy of Raptiva upon retreatment.

5.5 clinical efficacy conclusions

During the first 12 weeks of treatment, statistically significant
results favoring Raptiva over placebo were achieved for the primary
efficacy endpoint and all secondary endpoints (p \< 0.001 for each
comparison). Significant improvement was also seen in all
physician‑assessed (PGA of Change, PASI thickness, and psoriatic BSA)
and patient‑reported (DLQI, Itching Scale, PSA frequency and severity)
outcome measures.

Improvement in PASI was rapid. Significant improvement in PASI was noted
in Raptiva‑treated subjects compared with placebo‑treated subjects 4
weeks after initiation of treatment in Study 2390 (p \< 0.001). In
addition, subjects in the Raptiva‑treated group showed a clear
improvement in mean DLQI scores, mean Itching Scale scores, mean PSA
frequency, and mean PSA severity scores compared with the
placebo‑treated group at the first post‑baseline assessment 4 weeks
following initial treatment (p \< 0.001).

Efficacy was consistent across subgroups. Similar efficacy was seen in
subject groups defined by age, sex, body habitus, history of systemic
therapy, duration of disease, season, region, and baseline PASI score.

Continued treatment with Raptiva maintained the improvements achieved
during the initial 12 weeks of Raptiva treatment and was associated with
further improvement as indicated by a PASI‑75 response rate of
approximately 44% after 24 weeks of continued treatment in Study 2390
and its extension, Study 2391.

6\. CLINICAL SAFETY

6.1 Overview

A total of 2,762 subjects have been treated with Raptiva in the
psoriasis clinical program. Of these, 1,620 subjects received Raptiva
during the 12‑week, placebo‑controlled portion of the four Phase III
studies (2390, 2600, 2058, and 2059). The nearly identical entry
criteria and design of the first 12‑week, placebo‑controlled period
support an analysis of the pooled data from the first 12 weeks of these
studies. Comparisons between placebo and Raptiva patients are based
primarily on this 12‑week period.

Long‑term safety is supported by data from 1,115 subjects who received
more than 12 weeks of Raptiva treatment. Two hundred and twenty‑eight of
these subjects received weekly injections for 1 year.

The adverse events that occurred at low frequency are examined using
data combined from all of the subcutaneous Raptiva studies. Incidence
rates for these events are presented by subject‑years of observation. In
the current safety database, there are 186 subject‑years of observation
for subjects who received placebo and 1,791 subject‑years of observation
for subjects who received Raptiva. Because these observation periods
were not concurrent and the average observation time per subject
differed between treatment groups, results of the incidence rate
analyses should be interpreted with caution.

The majority of the subjects in the Raptiva database received either 1.0
mg/kg/wk or 2.0 mg/kg/wk. In a few subjects, the dose was as high as 4.0
mg/kg/wk.

Given the 1620 subjects exposed to Raptiva in the placebo‑controlled
period of the Phase III trials, the likelihood of observing an adverse
event during a 12‑week treatment period with a true incidence of 1% is
almost 100% and the likelihood of observing an event with a true
incidence of 0.1% is \~80%. Over all studies of Raptiva with
subcutaneous exposure of 8--12 weeks, the likelihood of observing an
adverse event with a true incidence of 1% or 0.1% during the treatment
period for the 2,556 Raptiva‑treated subjects is approximately 100% and
92%, respectively.

6.2 CLINICAL Results

6.2.1 Demographics and Baseline Characteristics

The baseline demographics for subjects treated with Raptiva or placebo
during the first 12 weeks in the Phase III studies were comparable (see
Table 16). The high body mass index (BMI) of subjects was consistent
with observations that obesity is a frequent co‑morbidity with psoriasis
(Stern 1995; Camisa 1998). Other common co‑morbid conditions were also
represented in the study cohort. Overall, 33.1% of subjects had
pre‑existing arthritis, 24.5% had hypertension, 10.2% had
hypercholesterolemia, and 9.8% had diabetes.

+------------+----------+----------+----------+----------+---+----------+
| Table 16   |          |          |          |          |   |          |
|            |          |          |          |          |   |          |
| Baseline   |          |          |          |          |   |          |
| De         |          |          |          |          |   |          |
| mographics |          |          |          |          |   |          |
| for        |          |          |          |          |   |          |
| Subjects   |          |          |          |          |   |          |
| in the     |          |          |          |          |   |          |
| Phase III, |          |          |          |          |   |          |
| Placebo‑   |          |          |          |          |   |          |
| Controlled |          |          |          |          |   |          |
| Stu        |          |          |          |          |   |          |
| dies 2390, |          |          |          |          |   |          |
| 2600,      |          |          |          |          |   |          |
| 2058, and  |          |          |          |          |   |          |
| 2059       |          |          |          |          |   |          |
+------------+----------+----------+----------+----------+---+----------+
|            |          | Raptiva  |          |          |   |          |
+------------+----------+----------+----------+----------+---+----------+
| Char       | Placebo\ | 1.0      | 2.0      | All      |   | All      |
| acteristic | (n=715)  | m        | m        | S        |   | S        |
|            |          | g/kg/wk\ | g/kg/wk\ | ubjects\ |   | ubjects\ |
|            |          | (        | (n=407)  | (        |   | (        |
|            |          | n=1,213) |          | n=1,620) |   | n=2,335) |
+------------+----------+----------+----------+----------+---+----------+
| Age (yr)   |          |          |          |          |   |          |
+------------+----------+----------+----------+----------+---+----------+
| > Mean     | 44.7     | 45.6     | 45.1     | 45.5     |   | 45.2     |
| > (SD)     | (120)    | (12.4)   | (13.0)   | (12.5)   |   | (12.4)   |
+------------+----------+----------+----------+----------+---+----------+
| > Median   | 45       | 45       | 44       | 45       |   | 45       |
+------------+----------+----------+----------+----------+---+----------+
| > Range    | 18--75   | 18--75   | 18--74   | 18--75   |   | 18--75   |
+------------+----------+----------+----------+----------+---+----------+
| Age group  |          |          |          |          |   |          |
| (yr)       |          |          |          |          |   |          |
+------------+----------+----------+----------+----------+---+----------+
| > 18--40   | 260      | 428      | 161      | 589      |   | 849      |
|            | (36.4%)  | (35.3%)  | (39.6%)  | (36.4%)  |   | (36.4%)  |
+------------+----------+----------+----------+----------+---+----------+
| > 41--64   | 417      | 694      | 209      | 903      |   | 1,320    |
|            | (58.3%)  | (57.2%)  | (51.4%)  | (55.7%)  |   | (56.5%)  |
+------------+----------+----------+----------+----------+---+----------+
| > ≥ 65     | 38       | 91       | 37       | 128      |   | 166      |
|            | (5.3%)   | (7.5%)   | (9.1%)   | (7.9%)   |   | (7.1%)   |
+------------+----------+----------+----------+----------+---+----------+
| Sex        |          |          |          |          |   |          |
+------------+----------+----------+----------+----------+---+----------+
| > Male     | 465      | 824      | 273      | 1,097    |   | 1,572    |
|            | (66.4%)  | (67.9%)  | (67.1%)  | (67.7%)  |   | (67.3%)  |
+------------+----------+----------+----------+----------+---+----------+
| > Female   | 240      | 389      | 134      | 523      |   | 763      |
|            | (33.6%)  | (32.1%)  | (32.9%)  | (32.3%)  |   | (32.7%)  |
+------------+----------+----------+----------+----------+---+----------+
| Race       |          |          |          |          |   |          |
| /ethnicity |          |          |          |          |   |          |
+------------+----------+----------+----------+----------+---+----------+
| > White    | 645      | 1,087    | 354      | 1,411    |   | 2,086    |
|            | (90.2%)  | (89.6%)  | (87.0%)  | (89.0%)  |   | (89.3%)  |
+------------+----------+----------+----------+----------+---+----------+
| > Black    | 18       | 28       | 8 (2.0%) | 36       |   | 54       |
|            | (2.5%)   | (2.3%)   |          | (2.2%)   |   | (2.3%)   |
+------------+----------+----------+----------+----------+---+----------+
| > Asian or | 18       | 31       | 10       | 41       |   | 59       |
| > Pacific  | (2.5%)   | (2.6%)   | (2.5%)   | (2.5%)   |   | (2.5%)   |
| > Islander |          |          |          |          |   |          |
+------------+----------+----------+----------+----------+---+----------+
| > Hispanic | 26       | 53       | 30       | 83       |   | 109      |
|            | (3.6%)   | (4.4%)   | (7.4%)   | (5.1%)   |   | (4.7%)   |
+------------+----------+----------+----------+----------+---+----------+
| > American | 1 (0.1%) | 5 (0.4%) | 1 (0.2%) | 6 (0.4%) |   | 7 (0.3%) |
| > Indian   |          |          |          |          |   |          |
| > or       |          |          |          |          |   |          |
| > Alaskan  |          |          |          |          |   |          |
| > Native   |          |          |          |          |   |          |
+------------+----------+----------+----------+----------+---+----------+
| > Other    | 7 (1.0%) | 9 (0.7%) | 4 (1.0%) | 13       |   | 20       |
|            |          |          |          | (0.8%)   |   | (0.9%)   |
+------------+----------+----------+----------+----------+---+----------+
| Weight     |          |          |          |          |   |          |
| (kg)       |          |          |          |          |   |          |
+------------+----------+----------+----------+----------+---+----------+
| > Mean     | 93.2     | 92.8     | 93.6     | 93.0     |   | 93.0     |
| > (SD)     | (20.4)   | (20.1)   | (20.5)   | (20.2)   |   | (20.3)   |
+------------+----------+----------+----------+----------+---+----------+
| > Median   | 91       | 91       | 92       | 92       |   | 91       |
+------------+----------+----------+----------+----------+---+----------+
| > Range    | 45--159  | 45--160  | 43--144  | 43--160  |   | 43--160  |
+------------+----------+----------+----------+----------+---+----------+
| BMI        |          |          |          |          |   |          |
| (kg/m^2^), |          |          |          |          |   |          |
| n          |          |          |          |          |   |          |
+------------+----------+----------+----------+----------+---+----------+
| > Mean     | 31.35    | 31.25    | 31.43    | 31.29    |   | 31.31    |
| > (SD)     | (6.56)   | (6.45)   | (6.65)   | (6.50)   |   | (6.52)   |
+------------+----------+----------+----------+----------+---+----------+
| > Median   | 30.3     | 30.5     | 30.8     | 30.5     |   | 30.4     |
+------------+----------+----------+----------+----------+---+----------+
| > Range    | 14       | 17       | 18       | 17       |   | 14       |
|            | .8--60.2 | .9--58.9 | .5--53.6 | .9--58.9 |   | .8--60.2 |
+------------+----------+----------+----------+----------+---+----------+

For baseline psoriasis characteristics, the Raptiva and placebo‑treated
groups were comparable (see Table 17).

+-----------+----------+----------+----------+-------------+----------+
| Table 17  |          |          |          |             |          |
|           |          |          |          |             |          |
| Baseline  |          |          |          |             |          |
| Psoriasis |          |          |          |             |          |
| Charac    |          |          |          |             |          |
| teristics |          |          |          |             |          |
| for       |          |          |          |             |          |
| Subjects  |          |          |          |             |          |
| in the    |          |          |          |             |          |
| Phase     |          |          |          |             |          |
| III,      |          |          |          |             |          |
| Placebo‑C |          |          |          |             |          |
| ontrolled |          |          |          |             |          |
| Studies   |          |          |          |             |          |
| 2390,     |          |          |          |             |          |
| 2600,     |          |          |          |             |          |
| 2058, and |          |          |          |             |          |
| 2059      |          |          |          |             |          |
+-----------+----------+----------+----------+-------------+----------+
|           |          | Raptiva  |          |             |          |
+-----------+----------+----------+----------+-------------+----------+
| Chara     | Placebo\ | 1.0      | 2.0      | All Raptiva | All      |
| cteristic | (n=715)  | m        | m        | Subjects    | S        |
|           |          | g/kg/wk\ | g/kg/wk\ | (n=1,620)   | ubjects\ |
|           |          | (        | (n=407)  |             | (        |
|           |          | n=1,213) |          |             | n=2,335) |
+-----------+----------+----------+----------+-------------+----------+
| PASI      |          |          |          |             |          |
| score     |          |          |          |             |          |
+-----------+----------+----------+----------+-------------+----------+
| > Mean    | 19.2     | 19.3     | 19.4     | 19.4 (7.6)  | 19.3     |
| > (SD)    | (7.6)    | (7.5)    | (7.9)    |             | (7.6)    |
+-----------+----------+----------+----------+-------------+----------+
| > Median  | 17       | 17       | 17       | 17          | 17       |
+-----------+----------+----------+----------+-------------+----------+
| > Range   | 10--58   | 10--59   | 6--56    | 6--59       | 6--59    |
+-----------+----------+----------+----------+-------------+----------+
| PASI      |          |          |          |             |          |
| category, |          |          |          |             |          |
| n         |          |          |          |             |          |
+-----------+----------+----------+----------+-------------+----------+
| > ≤ 16    | 326      | 524      | 174      | 698 (43.1%) | 1,024    |
|           | (45.6%)  | (43.2%)  | (42.8%)  |             | (43.9%)  |
+-----------+----------+----------+----------+-------------+----------+
| > 1       | 325      | 576      | 197      | 773 (47.7%) | 1,098    |
| 6.1--30.0 | (45.5%)  | (47.3%)  | (48.4%)  |             | (47.0%)  |
+-----------+----------+----------+----------+-------------+----------+
| > \> 30.0 | 64       | 113      | 36       | 149 (9.2%)  | 213      |
|           | (9.0%)   | (9.3%)   | (8.8%)   |             | (9.1%)   |
+-----------+----------+----------+----------+-------------+----------+
| Prior     |          |          |          |             |          |
| systemic  |          |          |          |             |          |
| t         |          |          |          |             |          |
| reatment, |          |          |          |             |          |
| n         |          |          |          |             |          |
+-----------+----------+----------+----------+-------------+----------+
| > Yes     | 490      | 861      | 234      | 1,104       | 1,594    |
|           | (68.5%)  | (71.0%)  | (59.7%)  | (68.1%)     | (68.3%)  |
+-----------+----------+----------+----------+-------------+----------+
| > No      | 225      | 352      | 164      | 516 (31.9%) | 741      |
|           | (31.5%)  | (29.0%)  | (40.3%)  |             | (31.7%)  |
+-----------+----------+----------+----------+-------------+----------+
| Percent   |          |          |          |             |          |
| BSA of    |          |          |          |             |          |
| psoriasis |          |          |          |             |          |
+-----------+----------+----------+----------+-------------+----------+
| > Mean    | 28.3     | 29.0     | 30.2     | 29.3 (17)   | 29.0     |
| > (SD)    | (17)     | (17)     | (17)     |             | (17)     |
+-----------+----------+----------+----------+-------------+----------+
| > Median  | 23       | 24       | 25       | 24          | 24       |
+-----------+----------+----------+----------+-------------+----------+
| > Range   | 10--90   | 10--98   | 7--94    | 7--94       | 7--98    |
+-----------+----------+----------+----------+-------------+----------+
| Duration  | (        | (n       | (        | (n = 1,589) | (n       |
| of        | n = 701) | = 1,194) | n = 395) |             | = 2,290) |
| psoriasis |          |          |          |             |          |
| (yr)      |          |          |          |             |          |
+-----------+----------+----------+----------+-------------+----------+
| > Mean    | 18.6     | 18.9     | 17.6     | 18.6 (12)   | 18.6     |
| > (SD)    | (11)     | (12)     | (12)     |             | (12)     |
+-----------+----------+----------+----------+-------------+----------+
| > Median  | 17       | 17       | 15       | 16          | 17       |
+-----------+----------+----------+----------+-------------+----------+
| > Range   | 0--62    | 0--68    | 1--70    | 0--70       | 0--70    |
+-----------+----------+----------+----------+-------------+----------+

6.2.2 Subject Disposition (Phase III Studies)

Rates of treatment discontinuation during the first 12 weeks of exposure
in the placebo‑controlled Phase III studies were low. Approximately 8%
of subjects discontinued treatment during the placebo‑controlled phase
of the four Phase III studies, with similar discontinuation rates in the
placebo‑treated and Raptiva‑treated groups (see Table 18).

The most common adverse events leading to discontinuation for subjects
receiving Raptiva during this period were headache (9 subjects; 0.6%),
psoriasis (9 subjects; 0.6%), pain (6 subjects; 0.4%), arthritis
(6 subjects; 0.4%), and arthralgia (0.3%).

+---------------+-------+----------+-----------+---------+----------+
| Table 18      |       |          |           |         |          |
|               |       |          |           |         |          |
| Subject       |       |          |           |         |          |
| Disposition   |       |          |           |         |          |
| and Reasons   |       |          |           |         |          |
| for Premature |       |          |           |         |          |
| Di            |       |          |           |         |          |
| scontinuation |       |          |           |         |          |
| for Subjects\ |       |          |           |         |          |
| during the    |       |          |           |         |          |
| First         |       |          |           |         |          |
| 12 Weeks of   |       |          |           |         |          |
| Treatment in  |       |          |           |         |          |
| the Phase     |       |          |           |         |          |
| III,          |       |          |           |         |          |
| Place         |       |          |           |         |          |
| bo‑Controlled |       |          |           |         |          |
| Studies 2390, |       |          |           |         |          |
| 2600, 2058,   |       |          |           |         |          |
| and 2059      |       |          |           |         |          |
+---------------+-------+----------+-----------+---------+----------+
| Subject       |       | Raptiva  |           |         |          |
| Status        |       |          |           |         |          |
+---------------+-------+----------+-----------+---------+----------+
|               | Pla   | 1.0      | 2.0       | All     | All      |
|               | cebo\ | mg/kg/wk | mg/kg/wk  | Raptiva | S        |
|               | (n =  | (n       | (n = 407) | (n =    | ubjects\ |
|               |  715) | = 1,213) |           |  1,620) | (n       |
|               |       |          |           |         | = 2,335) |
+---------------+-------+----------+-----------+---------+----------+
| Discontinued  | 60    | 85       | 37 (9.1%) | 122     | 182      |
| FT period     | (     | (7.0%)   |           | (7.5%)  | (7.8%)   |
|               | 8.4%) |          |           |         |          |
+---------------+-------+----------+-----------+---------+----------+
| Reason for FT |       |          |           |         |          |
| dis           |       |          |           |         |          |
| continuation, |       |          |           |         |          |
| n             |       |          |           |         |          |
+---------------+-------+----------+-----------+---------+----------+
| > Adverse     | 14    | 30       | 14 (3.4%) | 44      | 58       |
| > event       | (     | (2.5%)   |           | (2.7%)  | (2.5%)   |
|               | 2.0%) |          |           |         |          |
+---------------+-------+----------+-----------+---------+----------+
| > Subject's   | 21    | 25       | 10 (2.5%) | 35      | 56       |
| > decision    | (     | (2.1%)   |           | (2.2%)  | (2.4%)   |
|               | 2.9%) |          |           |         |          |
+---------------+-------+----------+-----------+---------+----------+
| > Lost to     | 13    | 12       | 7 (1.7%)  | 19      | 32       |
| > follow‑up   | (     | (1.0%)   |           | (1.2%)  | (1.4%)   |
|               | 1.8%) |          |           |         |          |
+---------------+-------+----------+-----------+---------+----------+
| > I           | 8     | 9 (0.7%) | 2 (0.5%)  | 11      | 19       |
| nvestigator's | (     |          |           | (0.7%)  | (0.8%)   |
| > decision    | 1.1%) |          |           |         |          |
+---------------+-------+----------+-----------+---------+----------+
| > Use of      | 3     | 8 (0.7%) | 4 (1.0%)  | 12      | 15       |
| > excluded    | (     |          |           | (0.7%)  | (0.6%)   |
| > treatment   | 0.4%) |          |           |         |          |
+---------------+-------+----------+-----------+---------+----------+
| > Death       | 1     | 0        | 0         | 0       | 1        |
|               | (     |          |           |         | (        |
|               | 0.1%) |          |           |         | \< 0.1%) |
+---------------+-------+----------+-----------+---------+----------+
| > Pregnancy   | 0     | 1 (0.1%) | 0         | 1       | 1        |
|               |       |          |           | (0.1%)  | (        |
|               |       |          |           |         | \< 0.1%) |
+---------------+-------+----------+-----------+---------+----------+
| FT = first    |       |          |           |         |          |
| 12‑week       |       |          |           |         |          |
| treatment.    |       |          |           |         |          |
+---------------+-------+----------+-----------+---------+----------+

6.2.3 Drug Exposure (Phase III Studies)

During the first 12 weeks of treatment in the Phase III studies, more
than 70% of the subjects received all doses of study drug, with no
discernible differences between the placebo and active treatment groups
(see Table 19).

+------------+----------+--------------+--------------+---------------+
| Table 19   |          |              |              |               |
|            |          |              |              |               |
| Extent of  |          |              |              |               |
| Exposure   |          |              |              |               |
| to Study   |          |              |              |               |
| Drug for   |          |              |              |               |
| Subjects   |          |              |              |               |
| during the |          |              |              |               |
| First      |          |              |              |               |
| 12 Weeks   |          |              |              |               |
| of         |          |              |              |               |
| Treatment  |          |              |              |               |
| in the     |          |              |              |               |
| Placebo‑   |          |              |              |               |
| Controlled |          |              |              |               |
| Studies    |          |              |              |               |
| 2390,      |          |              |              |               |
| 2600,      |          |              |              |               |
| 2058, and  |          |              |              |               |
| 2059       |          |              |              |               |
+------------+----------+--------------+--------------+---------------+
|            |          | Raptiva      |              |               |
+------------+----------+--------------+--------------+---------------+
|            | Placebo\ | 1.0          | 2.0          | All Raptiva   |
|            | (        | mg/kg/wk\    | mg/kg/wk\    | Subjects      |
|            | n = 715) | (n = 1,213)  | (n = 407)    | (n = 1,620)   |
+------------+----------+--------------+--------------+---------------+
| Number of  |          |              |              |               |
| doses      |          |              |              |               |
| received   |          |              |              |               |
+------------+----------+--------------+--------------+---------------+
| > Mean     | 11.1     | 11.3 (1.9)   | 11.1 (2.2)   | 11.2 (2.0)    |
| > (SD)     | (2.3)    |              |              |               |
+------------+----------+--------------+--------------+---------------+
| > Median   | 12       | 12           | 12           | 12            |
+------------+----------+--------------+--------------+---------------+
| Subjects   |          |              |              |               |
| who        |          |              |              |               |
| received   |          |              |              |               |
| all 12     |          |              |              |               |
| doses      |          |              |              |               |
+------------+----------+--------------+--------------+---------------+
| > n        | 523      | 902 (74.4%)  | 293 (72.0%)  | 1,195 (73.8%) |
|            | (73.1%)  |              |              |               |
+------------+----------+--------------+--------------+---------------+
| Total      |          |              |              |               |
| cumulative |          |              |              |               |
| dose (mg)  |          |              |              |               |
+------------+----------+--------------+--------------+---------------+
| > Mean     | 0        | 1,020.92     | 1,954.50     | 1,225.47      |
| > (SD)     |          | (285.74)     | (612.79)     | (565.11)      |
+------------+----------+--------------+--------------+---------------+
| > Median   | 0        | 1,015.2      | 1,993.1      | 1,123.2       |
+------------+----------+--------------+--------------+---------------+

6.2.4 Common Adverse Events (Phase III Studies)

Overall, 81% of all subjects had at least one adverse event during their
first 12 weeks of treatment. The percentage of subjects experiencing
adverse events was approximately 9% greater for the 1.0 mg/kg/wk
Raptiva‑treated group and 13% greater for the 2.0 mg/kg/wk
Raptiva‑treated group than for the placebo‑treated group. All adverse
events that occurred in ≥ 5% of subjects in the 1.0 mg/kg/wk group, 2.0
mg/kg/wk group, or placebo‑treated group are presented in Table 20.

+------------------+---------+-----------+-----------+---------------+
| Table 20         |         |           |           |               |
|                  |         |           |           |               |
| Adverse Events   |         |           |           |               |
| That Occurred in |         |           |           |               |
| ≥ 5% of Subjects |         |           |           |               |
| in Any Raptiva   |         |           |           |               |
| or               |         |           |           |               |
| Placebo‑Treated  |         |           |           |               |
| group during the |         |           |           |               |
| First 12 Weeks   |         |           |           |               |
| of Treatment in  |         |           |           |               |
| the              |         |           |           |               |
| Pl               |         |           |           |               |
| acebo‑Controlled |         |           |           |               |
| Studies          |         |           |           |               |
+------------------+---------+-----------+-----------+---------------+
|                  |         | Raptiva   |           |               |
+------------------+---------+-----------+-----------+---------------+
| COSTART Body     | P       | 1.0       | 2.0       | All Raptiva   |
| System/\         | lacebo\ | mg/kg/wk\ | mg/kg/wk\ | Subjects\     |
| Preferred Term   | (n      | (n        | (n = 407) | (n = 1,620)   |
|                  |  = 715) |  = 1,213) |           |               |
+------------------+---------+-----------+-----------+---------------+
| Total ^a^        | 526     | 1,000     | 354       | 1,354 (83.6%) |
|                  | (73.6%) | (82.4%)   | (87.0%)   |               |
+------------------+---------+-----------+-----------+---------------+
| Body as a whole  |         |           |           |               |
+------------------+---------+-----------+-----------+---------------+
| > **Headache**   | **159   | **391     | **151     | **542         |
|                  | (2      | (32.2%)** | (37.1%)** | (33.5%)**     |
|                  | 2.2%)** |           |           |               |
+------------------+---------+-----------+-----------+---------------+
| > *Infection     | *110    | *166      | *59       | *225 (13.9%)* |
| > NOS*           | (       | (13.7%)*  | (14.5%)*  |               |
|                  | 15.4%)* |           |           |               |
+------------------+---------+-----------+-----------+---------------+
| > **Chills**     | **32    | **154     | **53      | **207         |
|                  | (       | (12.7%)** | (13.0%)** | (12.8%)**     |
|                  | 4.5%)** |           |           |               |
+------------------+---------+-----------+-----------+---------------+
| > **Pain**       | **38    | **122     | **45      | **167         |
|                  | (       | (10.1%)** | (11.1%)** | (10.3%)**     |
|                  | 5.3%)** |           |           |               |
+------------------+---------+-----------+-----------+---------------+
| > **Fever**      | **24    | **80      | **46      | **126         |
|                  | (       | (6.6%)**  | (11.3%)** | (7.8%)**      |
|                  | 3.4%)** |           |           |               |
+------------------+---------+-----------+-----------+---------------+
| > **Asthenia**   | **37    | **81      | **38      | **119         |
|                  | (       | (6.7%)**  | (9.3%)**  | (7.3%)**      |
|                  | 5.2%)** |           |           |               |
+------------------+---------+-----------+-----------+---------------+
| > **Flu          | **29    | **83      | **19      | **102         |
| > syndrome**     | (       | (6.8%)**  | (4.7%)**  | (6.3%)**      |
|                  | 4.1%)** |           |           |               |
+------------------+---------+-----------+-----------+---------------+
| > Accidental     | 45      | 68 (5.6%) | 27 (6.6%) | 95 (5.9%)     |
| > injury         | (6.3%)  |           |           |               |
+------------------+---------+-----------+-----------+---------------+
| > **Back pain**  | **14    | **50      | **25      | **75 (4.6%)** |
|                  | (       | (4.1%)**  | (6.1%)**  |               |
|                  | 2.0%)** |           |           |               |
+------------------+---------+-----------+-----------+---------------+
| Digestive        |         |           |           |               |
+------------------+---------+-----------+-----------+---------------+
| > **Nausea**     | **51    | **128     | **56      | **184         |
|                  | (       | (10.6%)** | (13.8%)** | (11.4%)**     |
|                  | 7.1%)** |           |           |               |
+------------------+---------+-----------+-----------+---------------+
| > Diarrhea       | 48      | 72 (5.9%) | 30 (7.4%) | 102 (6.3%)    |
|                  | (6.7%)  |           |           |               |
+------------------+---------+-----------+-----------+---------------+
| Musculoskeletal  |         |           |           |               |
+------------------+---------+-----------+-----------+---------------+
| > **Myalgia**    | **35    | **102     | **32      | **134         |
|                  | (       | (8.4%)**  | (7.9%)**  | (8.3%)**      |
|                  | 4.9%)** |           |           |               |
+------------------+---------+-----------+-----------+---------------+
| Respiratory      |         |           |           |               |
+------------------+---------+-----------+-----------+---------------+
| > Pharyngitis    | 47      | 88 (7.3%) | 31 (7.6%) | 119 (7.3%)    |
|                  | (6.6%)  |           |           |               |
+------------------+---------+-----------+-----------+---------------+
| > Rhinitis       | 46      | 81 (6.7%) | 17 (4.2%) | 98 (6.0%)     |
|                  | (6.4%)  |           |           |               |
+------------------+---------+-----------+-----------+---------------+
| > Sinusitis      | 34      | 63 (5.2%) | 14 (3.4%) | 77 (4.8%)     |
|                  | (4.8%)  |           |           |               |
+------------------+---------+-----------+-----------+---------------+
| Skin/appendages  |         |           |           |               |
+------------------+---------+-----------+-----------+---------------+
| > Herpes simplex | 24      | 49 (4.0%) | 25 (6.1%) | 74 (4.6%)     |
|                  | (3.4%)  |           |           |               |
+------------------+---------+-----------+-----------+---------------+
| NOS=Not          |         |           |           |               |
| otherwise        |         |           |           |               |
| specified; this  |         |           |           |               |
| includes mostly  |         |           |           |               |
| reports of upper |         |           |           |               |
| respiratory      |         |           |           |               |
| tract infection, |         |           |           |               |
| with some        |         |           |           |               |
| additional       |         |           |           |               |
| events of        |         |           |           |               |
| infected         |         |           |           |               |
| psoriatic        |         |           |           |               |
| lesions, leg     |         |           |           |               |
| wound infection, |         |           |           |               |
| and dental       |         |           |           |               |
| infection.       |         |           |           |               |
|                  |         |           |           |               |
| Note: Adverse    |         |           |           |               |
| events that      |         |           |           |               |
| occurred at      |         |           |           |               |
| rates ≥ 1%       |         |           |           |               |
| higher in the    |         |           |           |               |
| 1.0 mg/kg/wk     |         |           |           |               |
| Raptiva‑treated  |         |           |           |               |
| group than in    |         |           |           |               |
| the              |         |           |           |               |
| placebo‑treated  |         |           |           |               |
| group are        |         |           |           |               |
| indicated in     |         |           |           |               |
| bold font.       |         |           |           |               |
| Adverse events   |         |           |           |               |
| that occurred at |         |           |           |               |
| rates ≥ 1%       |         |           |           |               |
| higher in the    |         |           |           |               |
| placebo‑treated  |         |           |           |               |
| group than in    |         |           |           |               |
| the 1.0 mg/kg/wk |         |           |           |               |
| Raptiva‑treated  |         |           |           |               |
| group are in     |         |           |           |               |
| italics.         |         |           |           |               |
|                  |         |           |           |               |
| ^a^ Represents   |         |           |           |               |
| the number of    |         |           |           |               |
| subjects with at |         |           |           |               |
| least one        |         |           |           |               |
| adverse event.   |         |           |           |               |
+------------------+---------+-----------+-----------+---------------+

Headache, chills, fever, nausea, vomiting, and myalgia occurring within
48 hours of any dose of study drug were pre‑specified as acute adverse
reactions. These tended to be mild and self‑limited, and are discussed
in greater detail in Section 6.2.6.

Pain was reported for nearly twice as many subjects in the 1.0 mg/kg/wk
Raptiva‑treated group as in the placebo‑treated group. Frequent
descriptions of the pain were generalized body aches or pain, pain in
the lower extremities (knees, ankles, feet) and dental pain. Most
reports of pain were mild to moderate in intensity, with \< 1% reported
as severe. None were serious. Only 0.4% of patients discontinued
treatment because of an adverse event of pain. In addition to the 1,620
subjects who were first exposed to Raptiva in a placebo‑controlled
study, 954 were first exposed in an uncontrolled setting. The overall
percentage of subjects with at least one adverse event and the types and
rates of adverse events reported were similar in these two groups of
subjects.

Common adverse events during prolonged treatment, retreatment, and drug
withdrawal are presented in Sections 6.4, 6.5, and 6.6, respectively.

6.2.5 Drug‑Related Adverse Events (Phase III Studies)

During the first 12 weeks of treatment in the placebo‑controlled
studies, investigators reported more adverse events as drug‑related in
subjects receiving Raptiva than in those receiving placebo. The most
common types of adverse events judged to be study drug--related were
headache, chills, fever, flu syndrome, nausea, and myalgia. Each of
these were reported for 2%--12% more Raptiva‑treated subjects than
placebo‑treated subjects (see Table 21). Of note, headache, chills,
fever, nausea, vomiting, and myalgia were pre‑specified in the protocols
as potential mild to moderate adverse events associated with initial
injections of Raptiva (acute adverse reactions, see Section 6.2.6).

+-----------------+---------+------------+-----------+---------------+
| Table 21        |         |            |           |               |
|                 |         |            |           |               |
| Study           |         |            |           |               |
| Drug--Related   |         |            |           |               |
| Adverse Events  |         |            |           |               |
| That Occurred   |         |            |           |               |
| in ≥ 5% of      |         |            |           |               |
| Subjects in Any |         |            |           |               |
| Raptiva or      |         |            |           |               |
| Placebo‑Treated |         |            |           |               |
| group during    |         |            |           |               |
| the First 12    |         |            |           |               |
| Weeks of        |         |            |           |               |
| Treatment in    |         |            |           |               |
| the             |         |            |           |               |
| Pla             |         |            |           |               |
| cebo‑Controlled |         |            |           |               |
| Studies         |         |            |           |               |
+-----------------+---------+------------+-----------+---------------+
|                 |         | Raptiva    |           |               |
+-----------------+---------+------------+-----------+---------------+
| Preferred Term  | P       | 1.0        | 2.0       | All Raptiva   |
|                 | lacebo\ | mg/kg/wk\  | mg/kg/wk\ | Subjects      |
|                 | (n      | (          | (n = 407) | (n = 1,620)   |
|                 |  = 715) | n = 1,213) |           |               |
+-----------------+---------+------------+-----------+---------------+
| Total ^a^       | 217     | 554        | 222       | 776 (47.9%)   |
|                 | (30.3%) | (45.7%)    | (54.5%)   |               |
+-----------------+---------+------------+-----------+---------------+
| Headache        | 96      | 262        | 105       | 367 (22.7%)   |
|                 | (13.4%) | (21.6%)    | (25.8%)   |               |
+-----------------+---------+------------+-----------+---------------+
| Chills          | 19      | 136        | 47        | 183 (11.3%)   |
|                 | (2.7%)  | (11.2%)    | (11.5%)   |               |
+-----------------+---------+------------+-----------+---------------+
| Nausea          | 34      | 89 (7.3%)  | 43        | 132 (8.1%)    |
|                 | (4.8%)  |            | (10.6%)   |               |
+-----------------+---------+------------+-----------+---------------+
| Fever           | 11      | 54 (4.5%)  | 32 (7.9%) | 86 (5.3%)     |
|                 | (1.5%)  |            |           |               |
+-----------------+---------+------------+-----------+---------------+
| Myalgia         | 24      | 70 (5.8%)  | 25 (6.1%) | 95 (5.9%)     |
|                 | (3.4%)  |            |           |               |
+-----------------+---------+------------+-----------+---------------+
| Asthenia        | 29      | 48 (4.0%)  | 31 (7.6%) | 79 (4.9%)     |
|                 | (4.1%)  |            |           |               |
+-----------------+---------+------------+-----------+---------------+
| ^a^ Represents  |         |            |           |               |
| the number of   |         |            |           |               |
| subjects with   |         |            |           |               |
| at least one    |         |            |           |               |
| adverse event   |         |            |           |               |
| reported by the |         |            |           |               |
| investigator as |         |            |           |               |
| drug related.   |         |            |           |               |
+-----------------+---------+------------+-----------+---------------+

6.2.6 Acute Adverse Reactions (Phase III Studies)

Acute adverse reactions were pre‑defined as headache, fever, chills,
nausea, vomiting, or myalgia starting within 48 hours (day of or two
days following) of an injection of study drug. Acute reactions such as
these are not uncommon with biologic agents, especially monoclonal
antibodies, and generally tend to occur after the initial doses and to
be mild and self‑limited.

During the first 12 weeks of the placebo‑controlled studies, the
percentage of subjects experiencing at least one acute adverse reaction
was approximately twice as great for Raptiva‑treated subjects than for
placebo‑treated subjects. Headache was the most prevalent type of acute
adverse reaction (see Table 22). The incidence of vomiting was
comparable in the placebo‑treated and 1.0 mg/kg/wk Raptiva‑treated
groups.

These events were mostly mild to moderate in intensity, and none were
serious. The rate of study discontinuation due to an acute adverse
reaction was less than 1%. The median duration of the events were 1--2
days, and most events were self‑limited or resolved with Tylenol or
NSAIDS.

+---------------+------------+------------+-----------+---------------+
| Table 22      |            |            |           |               |
|               |            |            |           |               |
| Acute Adverse |            |            |           |               |
| Reactions     |            |            |           |               |
| Experienced   |            |            |           |               |
| by Subjects\  |            |            |           |               |
| during the    |            |            |           |               |
| First 12      |            |            |           |               |
| Weeks of      |            |            |           |               |
| Treatment in  |            |            |           |               |
| the           |            |            |           |               |
| Place         |            |            |           |               |
| bo‑Controlled |            |            |           |               |
| Studies       |            |            |           |               |
+---------------+------------+------------+-----------+---------------+
|               |            | Raptiva    |           |               |
+---------------+------------+------------+-----------+---------------+
| Adverse Event | Placebo\   | 1.0        | 2.0       | All Raptiva\  |
|               | (n = 715)  | mg/kg/wk   | mg/kg/wk  | Subjects      |
|               |            | (          | (n = 407) | (n = 1,620)   |
|               |            | n = 1,213) |           |               |
+---------------+------------+------------+-----------+---------------+
| Total ^a^     | 173        | 485        | 187       | 672 (41.5%)   |
|               | (24.2%)    | (40.0%)    | (45.9%)   |               |
+---------------+------------+------------+-----------+---------------+
| Headache      | 121        | 341        | 130       | 471 (29.1%)   |
|               | (16.9%)    | (28.1%)    | (31.9%)   |               |
+---------------+------------+------------+-----------+---------------+
| Chills        | 25 (3.5%)  | 142        | 47        | 189 (11.7%)   |
|               |            | (11.7%)    | (11.5%)   |               |
+---------------+------------+------------+-----------+---------------+
| Nausea        | 42 (5.9%)  | 105 (8.7%) | 49        | 154 (9.5%)    |
|               |            |            | (12.0%)   |               |
+---------------+------------+------------+-----------+---------------+
| Fever ^b^     | 12 (1.7%)  | 61 (5.0%)  | 39 (9.6%) | 100 (6.2%)    |
+---------------+------------+------------+-----------+---------------+
| Myalgia       | 28 (3.9%)  | 86 (7.1%)  | 29 (7.1%) | 115 (7.1%)    |
+---------------+------------+------------+-----------+---------------+
| Vomiting      | 5 (0.7%)   | 13 (1.1%)  | 11 (2.7%) | 24 (1.5%)     |
+---------------+------------+------------+-----------+---------------+
| ^a^           |            |            |           |               |
| Represents    |            |            |           |               |
| the number of |            |            |           |               |
| subjects with |            |            |           |               |
| at least one  |            |            |           |               |
| acute adverse |            |            |           |               |
| reaction.     |            |            |           |               |
|               |            |            |           |               |
| ^b^ Included  |            |            |           |               |
| subjective    |            |            |           |               |
| sensations of |            |            |           |               |
| feverishness  |            |            |           |               |
| or warmth,    |            |            |           |               |
| rather than   |            |            |           |               |
| objectively   |            |            |           |               |
| measured      |            |            |           |               |
| temperature   |            |            |           |               |
| elevations.   |            |            |           |               |
+---------------+------------+------------+-----------+---------------+

The percentage of Raptiva‑treated subjects with at least one acute
adverse reaction was greatest with the first dose, decreased to less
than half the rate with the second dose, and diminished to a percentage
comparable to that for subjects treated with placebo following the third
and subsequent doses (see Figure 12).

Figure 12

Acute Adverse Reactions Experienced by Subjects during the First 12
Weeks of Treatment in the Placebo‑Controlled Studies

![](media/image14.wmf)

6.2.7 Deaths and Other Serious Adverse Events

a\. Deaths (All Studies)

In the total psoriasis safety database, death was an infrequent and was
reported for 7 of the 2762 Raptiva‑treated subjects (0.3%) and 3 of the
715 placebo‑treated subjects (0.4%). Two subjects died while receiving
Raptiva, and 5 died after completing treatment. No deaths were
attributed to study drug by the investigators. Table 23 summarizes these
events.

+------+------+--------+--------+--------+-----------+---------------+
| T    |      |        |        |        |           |               |
| able |      |        |        |        |           |               |
| 23   |      |        |        |        |           |               |
|      |      |        |        |        |           |               |
| De   |      |        |        |        |           |               |
| aths |      |        |        |        |           |               |
+------+------+--------+--------+--------+-----------+---------------+
| S    | Age  | Most   | Du     | Time   | Cause of  | Clinically    |
| ubje | (    | Recent | ration | since  | Death     | Relevant      |
| ct/\ | yr)/ | Dose   | of     | Last   |           | Medical       |
| S    | Sex  |        | Study  | Dose   |           | History       |
| tudy |      |        | Drug   |        |           |               |
|      |      |        | Ex     |        |           |               |
|      |      |        | posure |        |           |               |
+------+------+--------+--------+--------+-----------+---------------+
| 115  | 60/M | 1.0    | 12     | 26.9   | M         | None          |
| 20/\ |      | mg/kg  | Weeks  | Weeks  | etastatic |               |
| 2058 |      |        |        |        | rectal    |               |
|      |      |        |        |        | cancer    |               |
+------+------+--------+--------+--------+-----------+---------------+
| 68   | 56/M | 1.0    | 12     | \~72   | A         | None          |
| 812/ |      | mg/kg  | Weeks  | Weeks  | ccidental |               |
| ^c^\ |      |        |        |        | death     |               |
| 2059 |      |        |        |        | (plane    |               |
|      |      |        |        |        | crash)    |               |
+------+------+--------+--------+--------+-----------+---------------+
| 812  | 70/M | P      | 0      | 9.3    | A         | Hypertension  |
| 35/\ |      | lacebo |        | Weeks  | ccidental |               |
| 2059 |      |        |        |        | death     |               |
|      |      |        |        |        | (         |               |
|      |      |        |        |        | drowning) |               |
+------+------+--------+--------+--------+-----------+---------------+
| 816  | 58/M | 4.0    | 9      | 5 Days | Arterio   | Type 2        |
| 01/\ |      | mg/kg  | Weeks  |        | sclerosis | diabetes      |
| 2059 |      |        |        |        |           | mellitus,     |
|      |      |        |        |        |           | hypertension, |
|      |      |        |        |        |           | hypercho      |
|      |      |        |        |        |           | lesterolemia, |
|      |      |        |        |        |           | double        |
|      |      |        |        |        |           | coronary      |
|      |      |        |        |        |           | bypass (two   |
|      |      |        |        |        |           | procedures),  |
|      |      |        |        |        |           | intermittent  |
|      |      |        |        |        |           | bilateral leg |
|      |      |        |        |        |           | swelling,     |
|      |      |        |        |        |           | anemia        |
+------+------+--------+--------+--------+-----------+---------------+
| 120  | 68/F | 1.0    | 20     | \~38   | Unknown   | Hypertension, |
| 62/\ |      | mg/kg  | Weeks  | Weeks  |           | hypercho      |
| 2062 |      |        |        |        |           | lesterolemia, |
|      |      |        |        |        |           | diabetes,     |
|      |      |        |        |        |           | stroke,       |
|      |      |        |        |        |           | congestive    |
|      |      |        |        |        |           | heart         |
|      |      |        |        |        |           | failure,      |
|      |      |        |        |        |           | pleural       |
|      |      |        |        |        |           | disorder      |
+------+------+--------+--------+--------+-----------+---------------+
| 179  | 68/F | 1.0    | 12     | \~41   | Athero    | Dyspnea,      |
| 07/\ |      | mg/kg  | Weeks  | Weeks  | sclerotic | palpitations, |
| 2062 |      |        |        |        | cardi     | angina,       |
|      |      |        |        |        | ovascular | diabetes,     |
|      |      |        |        |        | disease   | hypertension, |
|      |      |        |        |        |           | claudication  |
|      |      |        |        |        |           | right calf,   |
|      |      |        |        |        |           | chronic       |
|      |      |        |        |        |           | anemia        |
+------+------+--------+--------+--------+-----------+---------------+
| 289  | 68/M | 2.0    | 11     | \~27   | Micr      | Migraines,    |
| 13/\ |      | mg/kg  | Weeks  | Weeks  | onodular\ | hypertension, |
| 2243 |      |        |        |        | cirrhosis | hy            |
|      |      |        |        |        |           | perlipidemia, |
|      |      |        |        |        |           | triple        |
|      |      |        |        |        |           | coronary      |
|      |      |        |        |        |           | bypass (two   |
|      |      |        |        |        |           | events), and  |
|      |      |        |        |        |           | elevated SGOT |
|      |      |        |        |        |           | and total and |
|      |      |        |        |        |           | direct        |
|      |      |        |        |        |           | bilirubin     |
+------+------+--------+--------+--------+-----------+---------------+
| 410  | 53/F | P      | 7 Days | 25     | Sudden    | COPD          |
| 11/\ |      | lacebo |        | Days   | cardiac   |               |
| 2600 |      |        |        |        | death     |               |
+------+------+--------+--------+--------+-----------+---------------+
| 422  | 47/F | P      | 7 Days | 4 Days | Seizure   | Seizures and  |
| 08/\ |      | lacebo |        |        |           | bipolar       |
| 2600 |      |        |        |        |           | disorder      |
+------+------+--------+--------+--------+-----------+---------------+
| 330  | 52/M | 1.0    | 161    | 48     | M         | Hypertension  |
| 07/\ |      | mg/kg  | Days   | Days   | yocardial | and smoking   |
| 2391 |      |        |        |        | i         |               |
|      |      |        |        |        | nfarction |               |
+------+------+--------+--------+--------+-----------+---------------+
| CO   |      |        |        |        |           |               |
| PD = |      |        |        |        |           |               |
|  chr |      |        |        |        |           |               |
| onic |      |        |        |        |           |               |
| obs  |      |        |        |        |           |               |
| truc |      |        |        |        |           |               |
| tive |      |        |        |        |           |               |
| p    |      |        |        |        |           |               |
| ulmo |      |        |        |        |           |               |
| nary |      |        |        |        |           |               |
| dise |      |        |        |        |           |               |
| ase; |      |        |        |        |           |               |
| F =  |      |        |        |        |           |               |
|  fem |      |        |        |        |           |               |
| ale; |      |        |        |        |           |               |
| M    |      |        |        |        |           |               |
|  = m |      |        |        |        |           |               |
| ale. |      |        |        |        |           |               |
+------+------+--------+--------+--------+-----------+---------------+

b\. Serious Adverse Events

**First Treatment Period of the Phase III, Placebo‑Controlled Studies**

In the first 12‑week treatment period of the placebo‑controlled studies,
the percentage of subjects reporting at least one serious adverse event
was low in all treatment groups. Most types of serious adverse events
were reported for a single subject, and no pattern suggestive of
particular toxicity was apparent. All serious adverse events reported
during this period are presented in Table 24.

+-------------------+--------+-------------+----------+--------------+---+
| Table 24          |        |             |          |              |   |
|                   |        |             |          |              |   |
| Serious Adverse   |        |             |          |              |   |
| Events That       |        |             |          |              |   |
| Occurred during   |        |             |          |              |   |
| the First 12      |        |             |          |              |   |
| Weeks of          |        |             |          |              |   |
| Treatment in the  |        |             |          |              |   |
| P                 |        |             |          |              |   |
| lacebo‑Controlled |        |             |          |              |   |
| Studies           |        |             |          |              |   |
+-------------------+--------+-------------+----------+--------------+---+
|                   |        | Raptiva     |          |              |   |
+-------------------+--------+-------------+----------+--------------+---+
| Preferred Term    | Pl     | 1.0         | 2.0      | All Raptiva  |   |
|                   | acebo\ | mg/kg/wk\   | m        | Subjects     |   |
|                   | (      | (n=1,213)   | g/kg/wk\ | (n=1,620)    |   |
|                   | n=715) |             | (n=407)  |              |   |
+-------------------+--------+-------------+----------+--------------+---+
| Total ^a^         | 12     | 24 (2.0%)   | 12       | 36 (2.2%)    |   |
|                   | (1.7%) |             | (2.9%)   |              |   |
+-------------------+--------+-------------+----------+--------------+---+
| Cellulitis        | 0      | 1 (\< 0.1%) | 2 (0.5%) | 3 (0.2%)     |   |
+-------------------+--------+-------------+----------+--------------+---+
| Kidney calculus   | 0      | 2 (0.2%)    | 1 (0.2%) | 3 (0.2%)     |   |
+-------------------+--------+-------------+----------+--------------+---+
| Accidental injury | 0      | 1 (\< 0.1%) | 1 (0.2%) | 2 (0.1%)     |   |
+-------------------+--------+-------------+----------+--------------+---+
| Atrial            | 0      | 1 (\< 0.1%) | 1 (0.2%) | 2 (0.1%)     |   |
| fibrillation      |        |             |          |              |   |
+-------------------+--------+-------------+----------+--------------+---+
| Coronary artery   | 0      | 1 (\< 0.1%) | 1 (0.2%) | 2 (0.1%)     |   |
| disorder          |        |             |          |              |   |
+-------------------+--------+-------------+----------+--------------+---+
| Gastroenteritis   | 1      | 1 (\< 0.1%) | 1 (0.2%) | 2 (0.1%)     |   |
|                   | (0.1%) |             |          |              |   |
+-------------------+--------+-------------+----------+--------------+---+
| Pneumonia         | 0      | 2 (0.2%)    | 0        | 2 (0.1%)     |   |
+-------------------+--------+-------------+----------+--------------+---+
| Skin carcinoma    | 1      | 2 (0.2%)    | 0        | 2 (0.1%)     |   |
|                   | (0.1%) |             |          |              |   |
+-------------------+--------+-------------+----------+--------------+---+
| Chest pain        | 1      | 0           | 1 (0.2%) | 1 (\< 0.1%)  |   |
|                   | (0.1%) |             |          |              |   |
+-------------------+--------+-------------+----------+--------------+---+
| Fever             | 0      | 1 (\< 0.1%) | 0        | 1 (\< 0.1%)  |   |
+-------------------+--------+-------------+----------+--------------+---+
| Headache          | 0      | 1 (\< 0.1%) | 0        | 1 (\< 0.1%)  |   |
+-------------------+--------+-------------+----------+--------------+---+
| Sarcoidosis       | 0      | 1 (\< 0.1%) | 0        | 1 (\< 0.1%)  |   |
+-------------------+--------+-------------+----------+--------------+---+
| Sepsis            | 0      | 1 (\< 0.1%) | 0        | 1 (\< 0.1%)  |   |
+-------------------+--------+-------------+----------+--------------+---+
| Arteriospasm      | 0      | 1 (\< 0.1%) | 0        | 1 (\< 0.1%)  |   |
+-------------------+--------+-------------+----------+--------------+---+
| Congestive heart  | 0      | 1 (\< 0.1%) | 0        | 1 (\< 0.1%)  |   |
| failure           |        |             |          |              |   |
+-------------------+--------+-------------+----------+--------------+---+
| ^a^ Represents    |        |             |          |              |   |
| the number of     |        |             |          |              |   |
| subjects with at  |        |             |          |              |   |
| least one serious |        |             |          |              |   |
| adverse event.    |        |             |          |              |   |
+-------------------+--------+-------------+----------+--------------+---+

+-----------------+-----------+-----------+----------+----------------+
| Table 24        |           |           |          |                |
| (cont'd)        |           |           |          |                |
|                 |           |           |          |                |
| Serious Adverse |           |           |          |                |
| Events That     |           |           |          |                |
| Occurred during |           |           |          |                |
| the First 12    |           |           |          |                |
| Weeks of        |           |           |          |                |
| Treatment in    |           |           |          |                |
| the             |           |           |          |                |
| Pla             |           |           |          |                |
| cebo‑Controlled |           |           |          |                |
| Studies         |           |           |          |                |
+-----------------+-----------+-----------+----------+----------------+
|                 |           | Raptiva   |          |                |
+-----------------+-----------+-----------+----------+----------------+
| Preferred Term  | Placebo\  | 1.0       | 2.0      | All Raptiva    |
|                 | (n=715)   | mg/kg/wk\ | m        | Subjects       |
|                 |           | (n=1,213) | g/kg/wk\ | (n=1,620)      |
|                 |           |           | (n=407)  |                |
+-----------------+-----------+-----------+----------+----------------+
| Myocardial      | 1 (0.1%)  | 1         | 0        | 1 (\< 0.1%)    |
| infarct         |           | (\< 0.1%) |          |                |
+-----------------+-----------+-----------+----------+----------------+
| Cholecystitis   | 0         | 1         | 0        | 1 (\< 0.1%)    |
|                 |           | (\< 0.1%) |          |                |
+-----------------+-----------+-----------+----------+----------------+
| Sialadenitis    | 0         | 0         | 1 (0.2%) | 1 (\< 0.1%)    |
+-----------------+-----------+-----------+----------+----------------+
| Diabetes        | 0         | 1         | 0        | 1 (\< 0.1%)    |
| mellitus        |           | (\< 0.1%) |          |                |
+-----------------+-----------+-----------+----------+----------------+
| Lymphadenopathy | 0         | 1         | 0        | 1 (\< 0.1%)    |
|                 |           | (\< 0.1%) |          |                |
+-----------------+-----------+-----------+----------+----------------+
| Bone disorder   | 1 (0.1%)  | 0         | 1 (0.2%) | 1 (\< 0.1%)    |
+-----------------+-----------+-----------+----------+----------------+
| Convulsion      | 0         | 0         | 1 (0.2%) | 1 (\< 0.1%)    |
+-----------------+-----------+-----------+----------+----------------+
| Depression      | 2 (0.3%)  | 1         | 0        | 1 (\< 0.1%)    |
|                 |           | (\< 0.1%) |          |                |
+-----------------+-----------+-----------+----------+----------------+
| Myelitis        | 0         | 1         | 0        | 1 (\< 0.1%)    |
|                 |           | (\< 0.1%) |          |                |
+-----------------+-----------+-----------+----------+----------------+
| Asthma          | 1 (0.1%)  | 0         | 1 (0.2%) | 1 (\< 0.1%)    |
+-----------------+-----------+-----------+----------+----------------+
| Bronchiolitis   | 0         | 1         | 0        | 1 (\< 0.1%)    |
|                 |           | (\< 0.1%) |          |                |
+-----------------+-----------+-----------+----------+----------------+
| Laryngismus     | 0         | 0         | 1 (0.2%) | 1 (\< 0.1%)    |
+-----------------+-----------+-----------+----------+----------------+
| Abortion        | 0         | 1         | 0        | 1 (\< 0.1%)    |
|                 |           | (\< 0.1%) |          |                |
+-----------------+-----------+-----------+----------+----------------+
| Cholelithiasis  | 1 (0.1%)  | 0         | 0        | 0              |
+-----------------+-----------+-----------+----------+----------------+
| G               | 1 (0.1%)  | 0         | 0        | 0              |
| astrointestinal |           |           |          |                |
| carcinoma       |           |           |          |                |
+-----------------+-----------+-----------+----------+----------------+
| Grand mal       | 1 (0.1%)  | 0         | 0        | 0              |
| convulsion      |           |           |          |                |
+-----------------+-----------+-----------+----------+----------------+
| Lung disorder   | 1 (0.1%)  | 0         | 0        | 0              |
+-----------------+-----------+-----------+----------+----------------+
| ^a^ Represents  |           |           |          |                |
| the number of   |           |           |          |                |
| subjects with   |           |           |          |                |
| at least one    |           |           |          |                |
| serious adverse |           |           |          |                |
| event.          |           |           |          |                |
+-----------------+-----------+-----------+----------+----------------+

Serious adverse events occurring during more prolonged treatment, the
second course of treatment, or washout are discussed in Sections 6.4,
6.5, and 6.6, respectively.

6.2.8 Malignancies (All Psoriasis Studies)

Because increased rate of malignancies have been seen with other
immunosuppressive agents used to treat psoriasis, malignancy data from
the Raptiva clinical program was closely examined.

During the initial 12‑week treatment period of the randomized,
placebo‑controlled, Phase III studies, malignancies were reported for
2 subjects receiving placebo (0.3%; one event each of gastrointestinal
carcinoma and non‑melanomatous skin cancer \[NMSC\]) and 4 subjects
receiving Raptiva (0.2%; four events of NMSC). Across all clinical
studies of Raptiva in psoriasis, the observed incidence rate of
malignancy in Raptiva‑treated subjects was similar to that observed in
placebo‑treated subjects (see Table 25).

+----------+----------+----------+----------+-----------+----------+
| Table 25 |          |          |          |           |          |
|          |          |          |          |           |          |
| I        |          |          |          |           |          |
| ncidence |          |          |          |           |          |
| Rates    |          |          |          |           |          |
| for      |          |          |          |           |          |
| Mali     |          |          |          |           |          |
| gnancies |          |          |          |           |          |
| in the   |          |          |          |           |          |
| P        |          |          |          |           |          |
| soriasis |          |          |          |           |          |
| Clinical |          |          |          |           |          |
| Trials   |          |          |          |           |          |
+----------+----------+----------+----------+-----------+----------+
| Type of  | T        | Observed | Observed | Rate/\    | 95% CI   |
| Ma       | reatment | No. of   | S        | 100       | for Rate |
| lignancy |          | Subjects | ubject‑\ | Subj      |          |
|          |          |          | Years    | ect‑Years |          |
+----------+----------+----------+----------+-----------+----------+
| All      | Placebo\ | 3\       | 185.44\  | 1.62\     | 0.33,    |
|          | Raptiva  | 30       | 1,782.43 | 1.68      | 4.73\    |
|          |          |          |          |           | 1.14,    |
|          |          |          |          |           | 2.40     |
+----------+----------+----------+----------+-----------+----------+
| Solid    | Placebo\ | 1\       | 185.69\  | 0.54\     | 0.01,    |
| tumor    | Raptiva  | 8        | 1,790.06 | 0.45      | 3.00\    |
|          |          |          |          |           | 0.19,    |
|          |          |          |          |           | 0.88     |
+----------+----------+----------+----------+-----------+----------+
| NMSC     | Placebo\ | 2\       | 185.51\  | 1.08\     | 0.13,    |
|          | Raptiva  | 20       | 1,784.15 | 1.12      | 3.89\    |
|          |          |          |          |           | 0.68,    |
|          |          |          |          |           | 1.73     |
+----------+----------+----------+----------+-----------+----------+
| Lymphoma | Placebo\ | 0\       | 185.69\  | 0\        | 0, 1.99\ |
| ^a^      | Raptiva  | 1        | 1,790.90 | 0.06      | 0.00,    |
|          |          |          |          |           | 0.31     |
+----------+----------+----------+----------+-----------+----------+
| M        | Placebo\ | 0\       | 185.69\  | 0\        | 0, 1.99\ |
| alignant | Raptiva  | 1        | 1,790.82 | 0.06      | 0.00,    |
| melanoma |          |          |          |           | 0.31     |
+----------+----------+----------+----------+-----------+----------+
| NMSC =   |          |          |          |           |          |
| non‑mela |          |          |          |           |          |
| nomatous |          |          |          |           |          |
| skin     |          |          |          |           |          |
| cancer.  |          |          |          |           |          |
|          |          |          |          |           |          |
| Note:    |          |          |          |           |          |
| Includes |          |          |          |           |          |
| data     |          |          |          |           |          |
| from     |          |          |          |           |          |
| p        |          |          |          |           |          |
| soriasis |          |          |          |           |          |
| studies  |          |          |          |           |          |
| HU9602,  |          |          |          |           |          |
| HUPS249, |          |          |          |           |          |
| HUPS252, |          |          |          |           |          |
| HUPS254, |          |          |          |           |          |
| HUPS256, |          |          |          |           |          |
| 2058,    |          |          |          |           |          |
| 2059,    |          |          |          |           |          |
| 2062,    |          |          |          |           |          |
| 2142,    |          |          |          |           |          |
| 2243,    |          |          |          |           |          |
| 2390,    |          |          |          |           |          |
| 2391,    |          |          |          |           |          |
| and      |          |          |          |           |          |
| 2600.    |          |          |          |           |          |
|          |          |          |          |           |          |
| The      |          |          |          |           |          |
| in       |          |          |          |           |          |
| dividual |          |          |          |           |          |
| numbers  |          |          |          |           |          |
| may not  |          |          |          |           |          |
| add up   |          |          |          |           |          |
| to the   |          |          |          |           |          |
| total    |          |          |          |           |          |
| because  |          |          |          |           |          |
| some     |          |          |          |           |          |
| patients |          |          |          |           |          |
| had more |          |          |          |           |          |
| than one |          |          |          |           |          |
| mal      |          |          |          |           |          |
| ignancy. |          |          |          |           |          |
| The      |          |          |          |           |          |
| subje    |          |          |          |           |          |
| ct‑years |          |          |          |           |          |
| vary     |          |          |          |           |          |
| slightly |          |          |          |           |          |
| due to   |          |          |          |           |          |
| c        |          |          |          |           |          |
| ensoring |          |          |          |           |          |
| of the   |          |          |          |           |          |
| subjects |          |          |          |           |          |
| after    |          |          |          |           |          |
| their    |          |          |          |           |          |
| mal      |          |          |          |           |          |
| ignancy. |          |          |          |           |          |
|          |          |          |          |           |          |
| ^a^ No   |          |          |          |           |          |
| case of  |          |          |          |           |          |
| lym      |          |          |          |           |          |
| phoproli |          |          |          |           |          |
| ferative |          |          |          |           |          |
| disease  |          |          |          |           |          |
| was      |          |          |          |           |          |
| seen;    |          |          |          |           |          |
| one case |          |          |          |           |          |
| of       |          |          |          |           |          |
| H        |          |          |          |           |          |
| odgkin's |          |          |          |           |          |
| lymphoma |          |          |          |           |          |
| was      |          |          |          |           |          |
| seen.    |          |          |          |           |          |
+----------+----------+----------+----------+-----------+----------+

The eight solid tumors in Raptiva‑treated patients consisted of four
cases of gastrointestinal carcinoma, two of prostatic carcinoma, and one
each of breast carcinoma and lung carcinoma.

NMSC includes both squamous cell and basal cell skin cancers. For
20 Raptiva‑treated subjects, there were 13 reports of basal cell and
13 reports of squamous cell cancer. For 2 placebo‑treated subjects,
there were two reports each of basal cell and squamous cell cancers.
Thus, for both Raptiva‑treated and placebo‑treated subjects, the ratio
of basal cell to squamous cell lesions was 1:1.

At the time of the submission of the Safety Update, there was one
reported case of Hodgkin's lymphoma, which is generally not associated
with immunosuppression (see Table 25). There had been no reported cases
of lymphoproliferative disease during the formal study follow‑up period,
although one case of cutaneous T‑cell lymphoma, which occurred 28 weeks
after the last dose of Raptiva, had been reported. Since this
submission, a B‑cell lymphoma case was reported in a subject
participating in an ongoing study. This additional case of lymphoma,
along with an updated estimate for subject‑years of observation (2203.16
subject‑years), yields an incidence rate of 0.09 per 100 subject‑years
and a 95% confidence interval of 0.01 and 0.33, which is consistent with
the expected background rate.

Because of the disparity in observation time for subjects receiving
Raptiva or placebo, and given the low incidence of malignancies, the
comparison between placebo and Raptiva must be made with caution.
Therefore, the observed frequency of malignancy in Raptiva‑treated
subjects was also compared with expected frequencies derived from up to
three external reference cohorts. These external cohorts were the U.S.
general population (age‑ and sex‑adjusted rates from the Surveillance,
Epidemiology and End Results \[SEER\] database, the national tumor
registry) and two moderate to severe psoriasis cohorts identified from
insurance claims databases: UnitedHealthcare and Saskatchewan Health.

At the time of the submission of the Safety Update, the observed numbers
of Raptiva‑treated subjects with lymphoma, solid tumors, or malignant
melanomas were consistent with the number of expected cases estimated
from the reference cohort data (see Table 26). With the additional
B‑cell lymphomas, the observed two cases of lymphoma (one Hodgkin's
lymphoma and one non‑Hodgkin's lymphoma) in Raptiva‑treated subjects
remained within the expected range based on data from two external
cohorts (Saskatchewan Health: 3.7 and UnitedHealthcare: 2.9) using
updated subject‑years of observation. The published literature indicates
that moderate to severe plaque psoriasis patients are at an increased
risk of lymphoproliferative disorder compared with the general
population (Margolis et al. 2001).

The observed number of cases of NMSCs in Raptiva‑treated subjects was
greater than the expected number based on the Saskatchewan and
UnitedHealthcare cohorts. This difference between the observed and
expected cases may represent ascertainment bias, since subjects in the
Raptiva clinical trials were subject to more intensive surveillance,
particularly of dermatologic lesions, than patients receiving standard
clinical care. Ascertainment bias for skin cancer among in psoriasis
study cohorts has been reported in the literature (Marcil and Stern
2001).

+-------------+-------+---------+--------+------+----------+---------+
| Table 26    |       |         |        |      |          |         |
|             |       |         |        |      |          |         |
| Observed    |       |         |        |      |          |         |
| versus      |       |         |        |      |          |         |
| Expected    |       |         |        |      |          |         |
| Rates of    |       |         |        |      |          |         |
| Ma          |       |         |        |      |          |         |
| lignancies: |       |         |        |      |          |         |
| Rapt        |       |         |        |      |          |         |
| iva‑Treated |       |         |        |      |          |         |
| Subjects    |       |         |        |      |          |         |
+-------------+-------+---------+--------+------+----------+---------+
|             | Rapti |         |        | Exte |          |         |
|             | va‑Tr |         |        | rnal |          |         |
|             | eated |         |        | R    |          |         |
|             | Sub   |         |        | efer |          |         |
|             | jects |         |        | ence |          |         |
|             |       |         |        | Coh  |          |         |
|             |       |         |        | orts |          |         |
+-------------+-------+---------+--------+------+----------+---------+
| Malignancy  | Obs   | 95%     | Ob     | Co   | Expected | 95%\    |
| Category    | erved | Con     | served | hort | No. of   | Con     |
|             | No.   | fidence | Sub    |      | Patients | fidence |
|             | of    | I       | ject‑\ |      | ^a^      | I       |
|             | Sub   | nterval | Years  |      |          | nterval |
|             | jects |         |        |      |          |         |
+-------------+-------+---------+--------+------+----------+---------+
| Solid tumor | 8     | 3.45,   | 1,     | SH   | 7.3      | 4.3,    |
|             |       | 15.76   | 790.06 |      |          | 11.6    |
+-------------+-------+---------+--------+------+----------+---------+
|             |       |         |        | UHC  | 4.7      | 2.3,    |
|             |       |         |        |      |          | 8.1     |
+-------------+-------+---------+--------+------+----------+---------+
|             |       |         |        | SEER | 7.8      | NA      |
+-------------+-------+---------+--------+------+----------+---------+
| NMSC ^b^    | 20    | 12.22,  | 1,     | SH   | 7.0      | 3.9,    |
|             |       | 30.89   | 784.15 |      |          | 11.2    |
+-------------+-------+---------+--------+------+----------+---------+
|             |       |         |        | UHC  | 7.0      | 4.1,    |
|             |       |         |        |      |          | 11.1    |
+-------------+-------+---------+--------+------+----------+---------+
| Lymphoma    | 1     | 0.03,   | 1,     | SH   | 3.0      | 1.3,    |
|             |       | 5.57    | 790.90 |      |          | 6.3     |
+-------------+-------+---------+--------+------+----------+---------+
|             |       |         |        | UHC  | 2.3      | 0.9,    |
|             |       |         |        |      |          | 5.0     |
+-------------+-------+---------+--------+------+----------+---------+
|             |       |         |        | SEER | 0.6      | NA      |
+-------------+-------+---------+--------+------+----------+---------+
| Malignant   | 1     | 0.03,   | 1,     | SH   | 0.4      | 0.0,    |
| melanoma    |       | 5.57    | 790.82 |      |          | 2.3     |
| ^c^         |       |         |        |      |          |         |
+-------------+-------+---------+--------+------+----------+---------+
|             |       |         |        | SEER | 0.4      | NA      |
+-------------+-------+---------+--------+------+----------+---------+
| NA = not    |       |         |        |      |          |         |
| available;  |       |         |        |      |          |         |
| N           |       |         |        |      |          |         |
| MSC = non‑m |       |         |        |      |          |         |
| elanomatous |       |         |        |      |          |         |
| skin        |       |         |        |      |          |         |
| cancer;     |       |         |        |      |          |         |
| SEER = Su   |       |         |        |      |          |         |
| rveillance, |       |         |        |      |          |         |
| E           |       |         |        |      |          |         |
| pidemiology |       |         |        |      |          |         |
| and End     |       |         |        |      |          |         |
| Results;    |       |         |        |      |          |         |
| SH = S      |       |         |        |      |          |         |
| askatchewan |       |         |        |      |          |         |
| Health;     |       |         |        |      |          |         |
| U           |       |         |        |      |          |         |
| HC = United |       |         |        |      |          |         |
| Healthcare. |       |         |        |      |          |         |
|             |       |         |        |      |          |         |
| ^a^         |       |         |        |      |          |         |
| Calculation |       |         |        |      |          |         |
| of the      |       |         |        |      |          |         |
| expected    |       |         |        |      |          |         |
| number of   |       |         |        |      |          |         |
| events was  |       |         |        |      |          |         |
| based on    |       |         |        |      |          |         |
| the         |       |         |        |      |          |         |
| expected    |       |         |        |      |          |         |
| rate of     |       |         |        |      |          |         |
| events per  |       |         |        |      |          |         |
| 100 pa      |       |         |        |      |          |         |
| tient‑years |       |         |        |      |          |         |
| multiplied  |       |         |        |      |          |         |
| by the      |       |         |        |      |          |         |
| observed    |       |         |        |      |          |         |
| number of   |       |         |        |      |          |         |
| su          |       |         |        |      |          |         |
| bject‑years |       |         |        |      |          |         |
| in the      |       |         |        |      |          |         |
| psoriasis   |       |         |        |      |          |         |
| Raptiva     |       |         |        |      |          |         |
| trials      |       |         |        |      |          |         |
| divided by  |       |         |        |      |          |         |
| 100. The    |       |         |        |      |          |         |
| unadjusted  |       |         |        |      |          |         |
| expected    |       |         |        |      |          |         |
| incidence   |       |         |        |      |          |         |
| rates and   |       |         |        |      |          |         |
| number of   |       |         |        |      |          |         |
| events were |       |         |        |      |          |         |
| given for   |       |         |        |      |          |         |
| the SH and  |       |         |        |      |          |         |
| UHC         |       |         |        |      |          |         |
| databases,  |       |         |        |      |          |         |
| whereas     |       |         |        |      |          |         |
| those       |       |         |        |      |          |         |
| derived     |       |         |        |      |          |         |
| from the    |       |         |        |      |          |         |
| SEER        |       |         |        |      |          |         |
| database    |       |         |        |      |          |         |
| were age    |       |         |        |      |          |         |
| and         |       |         |        |      |          |         |
| se          |       |         |        |      |          |         |
| x adjusted. |       |         |        |      |          |         |
|             |       |         |        |      |          |         |
| ^b^ SEER    |       |         |        |      |          |         |
| does not    |       |         |        |      |          |         |
| compile     |       |         |        |      |          |         |
| incidence   |       |         |        |      |          |         |
| rates for   |       |         |        |      |          |         |
| NMSC.       |       |         |        |      |          |         |
|             |       |         |        |      |          |         |
| ^c^ UHC did |       |         |        |      |          |         |
| not provide |       |         |        |      |          |         |
| estimates   |       |         |        |      |          |         |
| for         |       |         |        |      |          |         |
| malignant   |       |         |        |      |          |         |
| melanoma.   |       |         |        |      |          |         |
+-------------+-------+---------+--------+------+----------+---------+

6.2.9 Infection‑Related Adverse Events (Phase III Studies)

Infections can also be increased with immunosuppressive agents, and the
infection data from the Raptiva program was also examined very closely.

During the 12‑week treatment period of the placebo‑controlled studies,
the occurrence of diagnosed infections was comparable between Raptiva‑
and placebo‑treated subjects (see Table 27). Seven subjects who received
Raptiva experienced eight serious adverse events of infection. The
events were cellulitis (three events reported), pneumonia (two events),
gastroenteritis (two events), and sepsis (one event). One
placebo‑treated subject experienced a serious adverse event of
gastroenteritis.

During the first exposure to Raptiva in the open‑label studies, the
percentage of subjects with at least one diagnosed infection and the
types of infections were similar to those for subjects receiving Raptiva
in the placebo‑controlled studies.

+------------------+-----------+-----------+-----------+--------------+
| Table 27         |           |           |           |              |
|                  |           |           |           |              |
| Adverse Events   |           |           |           |              |
| Diagnostic of    |           |           |           |              |
| Infection That   |           |           |           |              |
| Occurred\        |           |           |           |              |
| during the First |           |           |           |              |
| 12 Weeks of      |           |           |           |              |
| Treatment in the |           |           |           |              |
| Pl               |           |           |           |              |
| acebo‑Controlled |           |           |           |              |
| Studies          |           |           |           |              |
+------------------+-----------+-----------+-----------+--------------+
|                  |           | Raptiva   |           |              |
+------------------+-----------+-----------+-----------+--------------+
| Preferred Term   | Placebo\  | 1.0       | 2.0       | All Raptiva  |
|                  | (n = 715) | mg/kg/wk  | mg/kg/wk  | Subjects     |
|                  |           | (n        | (n = 407) | (n = 1,620)  |
|                  |           |  = 1,213) |           |              |
+------------------+-----------+-----------+-----------+--------------+
| Total ^a^        | 188       | 350       | 114       | 464 (28.6%)  |
|                  | (26.3%)   | (28.9%)   | (28.0%)   |              |
+------------------+-----------+-----------+-----------+--------------+
| Infection NOS    | 110       | 166       | 59        | 225 (13.9%)  |
|                  | (15.4%)   | (13.7%)   | (14.5%)   |              |
+------------------+-----------+-----------+-----------+--------------+
| Herpes simplex   | 24 (3.4%) | 49 (4.0%) | 25 (6.1%) | 74 (4.6%)    |
| ^b^              |           |           |           |              |
+------------------+-----------+-----------+-----------+--------------+
| Gastroenteritis  | 24 (3.4%) | 29 (2.4%) | 5 (1.2%)  | 34 (2.1%)    |
+------------------+-----------+-----------+-----------+--------------+
| Bronchitis       | 9 (1.3%)  | 27 (2.2%) | 4 (1.0%)  | 31 (1.9%)    |
+------------------+-----------+-----------+-----------+--------------+
| Viral infection  | 8 (1.1%)  | 27 (2.2%) | 3 (0.7%)  | 30 (1.9%)    |
+------------------+-----------+-----------+-----------+--------------+
| Urinary tract    | 9 (1.3%)  | 19 (1.6%) | 8 (2.0%)  | 27 (1.7%)    |
| infection        |           |           |           |              |
+------------------+-----------+-----------+-----------+--------------+
| Otitis media     | 9 (1.3%)  | 18 (1.5%) | 5 (1.2%)  | 23 (1.4%)    |
+------------------+-----------+-----------+-----------+--------------+
| Infection,       | 4 (0.6%)  | 15 (1.2%) | 4 (1.0%)  | 19 (1.2%)    |
| bacterial        |           |           |           |              |
+------------------+-----------+-----------+-----------+--------------+
| Fungal           | 1 (0.1%)  | 5 (0.4%)  | 9 (2.2%)  | 14 (0.9%)    |
| dermatitis       |           |           |           |              |
+------------------+-----------+-----------+-----------+--------------+
| Cellulitis       | 3 (0.4%)  | 9 (0.7%)  | 4 (1.0%)  | 13 (0.8%)    |
+------------------+-----------+-----------+-----------+--------------+
| Periodontal      | 2 (0.3%)  | 8 (0.7%)  | 1 (0.2%)  | 9 (0.6%)     |
| abscess          |           |           |           |              |
+------------------+-----------+-----------+-----------+--------------+
| Infection,       | 0         | 6 (0.5%)  | 1 (0.2%)  | 7 (0.4%)     |
| fungal           |           |           |           |              |
+------------------+-----------+-----------+-----------+--------------+
| Pneumonia        | 2 (0.3%)  | 7 (0.6%)  | 0         | 7 (0.4%)     |
+------------------+-----------+-----------+-----------+--------------+
| Furunculosis     | 3 (0.4%)  | 4 (0.3%)  | 3 (0.7%)  | 7 (0.4%)     |
+------------------+-----------+-----------+-----------+--------------+
| Herpes zoster    | 0         | 4 (0.3%)  | 0         | 4 (0.2%)     |
| ^b^              |           |           |           |              |
+------------------+-----------+-----------+-----------+--------------+
| Abscess          | 0         | 3 (0.2%)  | 0         | 3 (0.2%)     |
+------------------+-----------+-----------+-----------+--------------+
| Vaginal          | 1 (0.1%)  | 3 (0.2%)  | 0         | 3 (0.2%)     |
| moniliasis       |           |           |           |              |
+------------------+-----------+-----------+-----------+--------------+
| Infection,       | 0         | 1         | 1 (0.2%)  | 2 (0.1%)     |
| parasitic        |           | (\< 0.1%) |           |              |
+------------------+-----------+-----------+-----------+--------------+
| Oral moniliasis  | 0         | 2 (0.2%)  | 0         | 2 (0.1%)     |
+------------------+-----------+-----------+-----------+--------------+
| Axillary         | 0         | 1         | 0         | 1 (\< 0.1%)  |
| moniliasis       |           | (\< 0.1%) |           |              |
+------------------+-----------+-----------+-----------+--------------+
| Sepsis           | 0         | 1         | 0         | 1 (\< 0.1%)  |
|                  |           | (\< 0.1%) |           |              |
+------------------+-----------+-----------+-----------+--------------+
| Hepatitis        | 0         | 0         | 1 (0.2%)  | 1 (\< 0.1%)  |
+------------------+-----------+-----------+-----------+--------------+
| Meningitis       | 0         | 0         | 1 (0.2%)  | 1 (\< 0.1%)  |
+------------------+-----------+-----------+-----------+--------------+
| Moniliasis       | 1 (0.1%)  | 0         | 0         | 0            |
+------------------+-----------+-----------+-----------+--------------+
| NOS = not        |           |           |           |              |
| otherwise        |           |           |           |              |
| specified;       |           |           |           |              |
| includes mostly  |           |           |           |              |
| reports of upper |           |           |           |              |
| respiratory      |           |           |           |              |
| tract infection, |           |           |           |              |
| with some        |           |           |           |              |
| additional       |           |           |           |              |
| events of        |           |           |           |              |
| infected         |           |           |           |              |
| psoriatic        |           |           |           |              |
| lesions, leg     |           |           |           |              |
| wound infection, |           |           |           |              |
| and dental       |           |           |           |              |
| infection.       |           |           |           |              |
|                  |           |           |           |              |
| ^a^ Represents   |           |           |           |              |
| the number of    |           |           |           |              |
| subjects with at |           |           |           |              |
| least adverse    |           |           |           |              |
| event diagnostic |           |           |           |              |
| of infection.    |           |           |           |              |
|                  |           |           |           |              |
| ^b^ No events of |           |           |           |              |
| systemic herpes  |           |           |           |              |
| simplex or       |           |           |           |              |
| zoster were      |           |           |           |              |
| reported.        |           |           |           |              |
+------------------+-----------+-----------+-----------+--------------+

a\. Integrated Analysis of Serious Infections Requiring Hospitalization
(All SC Psoriasis Studies Conducted by Genentech)

The rate of infections leading to hospital admission was slightly higher
in the subjects receiving Raptiva compared with the subjects receiving
placebo. However, the difference was small, and the confidence intervals
overlapped. Given the low frequency, and given that the placebo rate is
based on two incidents, the rates must be interpreted with caution. The
rates seen in both groups are comparable to the expected number based on
a Saskatchewan Health (SH) claims database for patients with psoriasis
(see Table 28).

+--------+---------+----------+---------+--------+---------+--------+
| Table  |         |          |         |        |         |        |
| 28     |         |          |         |        |         |        |
|        |         |          |         |        |         |        |
| Ob     |         |          |         |        |         |        |
| served |         |          |         |        |         |        |
| versus |         |          |         |        |         |        |
| Ex     |         |          |         |        |         |        |
| pected |         |          |         |        |         |        |
| Infe   |         |          |         |        |         |        |
| ctions |         |          |         |        |         |        |
| Req    |         |          |         |        |         |        |
| uiring |         |          |         |        |         |        |
| Hos    |         |          |         |        |         |        |
| pitali |         |          |         |        |         |        |
| zation |         |          |         |        |         |        |
+--------+---------+----------+---------+--------+---------+--------+
| Tre    | Ob      | Observed | O       | 95%    | E       | 95%    |
| atment | served\ | Subje    | bserved | Conf   | xpected | Conf   |
|        | No. of  | ct‑Years | In      | idence | No. of  | idence |
|        | S       |          | cidence | In     | P       | In     |
|        | ubjects |          | R       | terval | atients | terval |
|        | with    |          | ate/100 |        | with    |        |
|        | Events  |          | Patien  |        | Events  |        |
|        |         |          | t‑Years |        | ^a^     |        |
+--------+---------+----------+---------+--------+---------+--------+
| P      | 2       | 169.48   | 1.18    | 0.14,  | 3.1     | 2.4,   |
| lacebo |         |          |         | 4.26   |         | 3.8    |
+--------+---------+----------+---------+--------+---------+--------+
| R      | 27      | 1,680.67 | 1.61    | 1.06,  | 30.3    | 23.7,  |
| aptiva |         |          |         | 2.34   |         | 38.2   |
+--------+---------+----------+---------+--------+---------+--------+
| ^a^    |         |          |         |        |         |        |
| The    |         |          |         |        |         |        |
| ex     |         |          |         |        |         |        |
| pected |         |          |         |        |         |        |
| number |         |          |         |        |         |        |
| of     |         |          |         |        |         |        |
| events |         |          |         |        |         |        |
| was    |         |          |         |        |         |        |
| calc   |         |          |         |        |         |        |
| ulated |         |          |         |        |         |        |
| as the |         |          |         |        |         |        |
| ex     |         |          |         |        |         |        |
| pected |         |          |         |        |         |        |
| rate   |         |          |         |        |         |        |
| of     |         |          |         |        |         |        |
| events |         |          |         |        |         |        |
| per    |         |          |         |        |         |        |
| 100    |         |          |         |        |         |        |
| p      |         |          |         |        |         |        |
| atient |         |          |         |        |         |        |
| ‑years |         |          |         |        |         |        |
| in the |         |          |         |        |         |        |
| Saskat |         |          |         |        |         |        |
| chewan |         |          |         |        |         |        |
| Health |         |          |         |        |         |        |
| cohort |         |          |         |        |         |        |
| mult   |         |          |         |        |         |        |
| iplied |         |          |         |        |         |        |
| by the |         |          |         |        |         |        |
| ob     |         |          |         |        |         |        |
| served |         |          |         |        |         |        |
| number |         |          |         |        |         |        |
| of     |         |          |         |        |         |        |
| s      |         |          |         |        |         |        |
| ubject |         |          |         |        |         |        |
| ‑years |         |          |         |        |         |        |
| in the |         |          |         |        |         |        |
| pso    |         |          |         |        |         |        |
| riasis |         |          |         |        |         |        |
| R      |         |          |         |        |         |        |
| aptiva |         |          |         |        |         |        |
| trials |         |          |         |        |         |        |
| d      |         |          |         |        |         |        |
| ivided |         |          |         |        |         |        |
| by     |         |          |         |        |         |        |
| 100.   |         |          |         |        |         |        |
+--------+---------+----------+---------+--------+---------+--------+

b\. Opportunistic Infections

An examination of the entire safety database for Raptiva revealed only
one infection potentially representative of an opportunistic infection.
One subject developed *Legionella* pneumonia 6 weeks after the last dose
of Raptiva. Of note, *Legionella* was diagnosed contemporaneously in at
least 2 other individuals (not taking Raptiva) within the same
geographic area as the study subject. The Raptiva subject was not the
index case. There were no cases of tuberculosis, toxoplasmosis,
histoplasmosis, or other opportunistic infections observed during the
Raptiva program.

6.2.10 Thrombocytopenia (All Psoriasis Studies)

To date, eight occurrences of NCI‑CTC Grade 3 TCP (platelet count
\< 50 K/mm^3^), Grade 4 TCP (platelet count \< 10 K/mm^3^), or TCP that
was classified as "serious" by investigators have been reported over all
completed and ongoing Raptiva psoriasis studies.

An independent medical platelet expert reviewed the eight cases to
assess the likelihood of a causal or contributory relationship to
Raptiva exposure. One occurrence of NCI‑CTC Grade 3 TCP was considered
to be related to prostate cancer (Subject No. 23512), and a second case
was in a subject who had been previously diagnosed with idiopathic
thrombocytopenic purpura (Subject No. 2523900259). The remaining six
cases were judged to have characteristics consistent with possible
drug‑induced TCP. These cases are summarized in Table 29.

+----------+--------+----------+------------+------------+----------+
| Table 29 |        |          |            |            |          |
|          |        |          |            |            |          |
| NCI‑CTC  |        |          |            |            |          |
| Grade 3  |        |          |            |            |          |
| or 4     |        |          |            |            |          |
| Thromboc |        |          |            |            |          |
| ytopenia |        |          |            |            |          |
| Events   |        |          |            |            |          |
| or       |        |          |            |            |          |
| Thromboc |        |          |            |            |          |
| ytopenia |        |          |            |            |          |
| Occ      |        |          |            |            |          |
| urrences |        |          |            |            |          |
| Cl       |        |          |            |            |          |
| assified |        |          |            |            |          |
| by the   |        |          |            |            |          |
| Inves    |        |          |            |            |          |
| tigators |        |          |            |            |          |
| as       |        |          |            |            |          |
| Serious  |        |          |            |            |          |
+----------+--------+----------+------------+------------+----------+
| S        | Study  | Raptiva  | Platelet   | Weeks from | Clinic   |
| ubject/\ |        | Dose(s)  | Nadir      | First      | al Signs |
| Demo     |        | (m       | Count ×    | Raptiva    | and\     |
| graphics |        | g/kg/wk) | 1          | Dose to    | Symptoms |
|          |        |          | 0^3^/mm^3^ | Platelet   |          |
|          |        |          |            | Nadir      |          |
+----------+--------+----------+------------+------------+----------+
| 10501/\  | 2058   | 2.0      | 52         | 18         | None     |
| 6        |        |          |            |            |          |
| 1‑yr‑old |        |          |            |            |          |
| White    |        |          |            |            |          |
| male     |        |          |            |            |          |
+----------+--------+----------+------------+------------+----------+
| 27103/\  | 2243   | 1.0--2.0 | 28         | 71         | None     |
| 2        |        |          |            |            |          |
| 9‑yr‑old |        |          |            |            |          |
| White    |        |          |            |            |          |
| male     |        |          |            |            |          |
+----------+--------+----------+------------+------------+----------+
| 33203/\  | 2391   | 1.0      | 10         | 13         | Vaginal  |
| 4        |        |          |            |            | b        |
| 1‑yr‑old |        |          |            |            | leeding, |
| White    |        |          |            |            | a        |
| female   |        |          |            |            | bdominal |
|          |        |          |            |            | ec       |
|          |        |          |            |            | chymosis |
+----------+--------+----------+------------+------------+----------+
| 37204/\  | 2601   | 1.0      | 27         | 14         | None     |
| 7        |        |          |            |            |          |
| 8‑yr‑old |        |          |            |            |          |
| White    |        |          |            |            |          |
| female   |        |          |            |            |          |
+----------+--------+----------+------------+------------+----------+
| 41232/\  | 2601   | 1.0      | 16         | 24         | Blood in |
| 3        |        |          |            |            | stool    |
| 9‑yr‑old |        |          |            |            |          |
| White    |        |          |            |            |          |
| male     |        |          |            |            |          |
+----------+--------+----------+------------+------------+----------+
| 44202/\  | 2601   | 1.0      | 3          | 20         | Bleeding |
| 7        |        |          |            |            | with     |
| 3‑yr‑old |        |          |            |            | scr      |
| White    |        |          |            |            | atching: |
| female   |        |          |            |            | p        |
|          |        |          |            |            | etechiae |
+----------+--------+----------+------------+------------+----------+
| Note:    |        |          |            |            |          |
| The two  |        |          |            |            |          |
| cases of |        |          |            |            |          |
| Grade 3  |        |          |            |            |          |
| TCP that |        |          |            |            |          |
| were     |        |          |            |            |          |
| judged   |        |          |            |            |          |
| to be    |        |          |            |            |          |
| related  |        |          |            |            |          |
| to       |        |          |            |            |          |
| prostate |        |          |            |            |          |
| cancer   |        |          |            |            |          |
| and ITP  |        |          |            |            |          |
| are not  |        |          |            |            |          |
| included |        |          |            |            |          |
| in this  |        |          |            |            |          |
| table.   |        |          |            |            |          |
| Some     |        |          |            |            |          |
| cases of |        |          |            |            |          |
| TCP were |        |          |            |            |          |
| reported |        |          |            |            |          |
| after    |        |          |            |            |          |
| the BLA  |        |          |            |            |          |
| sub      |        |          |            |            |          |
| mission. |        |          |            |            |          |
+----------+--------+----------+------------+------------+----------+

In 5 subjects, the platelet nadir occurred between 13 and 24 weeks after
the first dose of Raptiva. Based on available platelet count
measurements, the onset of the platelet decline appeared to occur
between 8 and 12 weeks after the first dose of Raptiva. All 6 subjects
discontinued Raptiva and their platelet counts recovered rapidly. Five
subjects were treated with systemic corticosteroids, and 1 also received
Rh immune globulin and a platelet transfusion. Bone marrow aspirates and
biopsies in 2 subjects showed no evidence of bone marrow suppression.
The 6 subjects have not tested positive for anti‑Raptiva antibodies. The
clinical course and rapid response to corticosteroids are consistent
with immune‑mediated TCP. No subject had evidence of disseminated
intravascular coagulation or thrombotic events.

Four subjects who developed NCI‑CTC Grade 3 or 4 TCP during Raptiva
treatment had received other medications or had concurrent medical
conditions that could have contributed or predisposed the subject to the
onset of TCP. One subject each had been started on valproic acid and
cephalexin just prior to the onset of TCP. According to the Package
Inserts, these two drugs have been associated with TCP. Other potential
contributing conditions were viral illnesses in 3 subjects and Grave's
disease in 2 others.

The incidence of TCP during the first 12 weeks of treatment in the four
placebo‑controlled studies (2058, 2059, 2390, and 2600) is summarized in
Table 30. TCP was conservatively defined as any platelet count below
130 K/mm^3^ (the lower limit of laboratory normal range) during the
first 12 weeks of treatment regardless of baseline count. Overall,
21 Raptiva‑treated subjects (1.3%) and 2 placebo‑treated subjects (0.3%)
experienced platelet counts below 130 K/mm^3^ during the FT period.
Because 9 of the 21 Raptiva‑treated subjects had baseline platelet
counts \< 130 K/mm^3^, only 12 Raptiva‑treated subjects (0.7%)
experienced treatment‑emergent platelet counts \< 130 K/mm^3^ during the
FT period, compared with 2 (0.3%) placebo‑treated subjects.

+-------------+----------+------------+------------+-----------------+
| Table 30    |          |            |            |                 |
|             |          |            |            |                 |
| Throm       |          |            |            |                 |
| bocytopenia |          |            |            |                 |
| during the  |          |            |            |                 |
| First 12    |          |            |            |                 |
| Weeks of    |          |            |            |                 |
| Treatment   |          |            |            |                 |
| in the      |          |            |            |                 |
| Placebo     |          |            |            |                 |
| ‑Controlled |          |            |            |                 |
| Studies     |          |            |            |                 |
+-------------+----------+------------+------------+-----------------+
| Lowest      | Placebo\ | Raptiva    |            |                 |
| Platelet    | (n=715)  |            |            |                 |
| Count\      |          |            |            |                 |
| (×1         |          |            |            |                 |
| 0^3^/mm^3^) |          |            |            |                 |
+-------------+----------+------------+------------+-----------------+
|             |          | 1.0        | 2.0        | All Raptiva     |
|             |          | mg/kg/wk\  | mg/kg/wk\  | Subjects        |
|             |          | (n=1,213)  | (n=407)    | (n=1,620)       |
+-------------+----------+------------+------------+-----------------+
| Any count   | 2 (0.3%) | 13 (1.1%)  | 8 (2.0%)   | 21 (1.3%)       |
| \           |          |            |            |                 |
| < 130/mm^3^ |          |            |            |                 |
+-------------+----------+------------+------------+-----------------+
| 100 to      | 1 (0.1%) | 11 (0.9%)  | 4 (1.0 %)  | 15 (0.9%)       |
| \           |          |            |            |                 |
| < 130/mm^3^ |          |            |            |                 |
+-------------+----------+------------+------------+-----------------+
| 75 to       | 1 (0.1%) | 2 (0.2%)   | 3 (0.7%)   | 5 (0.3%)        |
| \           |          |            |            |                 |
| < 100/mm^3^ |          |            |            |                 |
+-------------+----------+------------+------------+-----------------+
| 50 to       | 0        | 0          | 0          | 0               |
| \< 75/mm^3^ |          |            |            |                 |
+-------------+----------+------------+------------+-----------------+
| 25 to       | 0        | 0          | 1 (0.2%)   | 1 (0.1%)        |
| \< 50/mm^3^ |          |            |            |                 |
+-------------+----------+------------+------------+-----------------+
| \< 25/mm^3^ | 0        | 0          | 0          | 0               |
+-------------+----------+------------+------------+-----------------+

Analyses of the incidence of platelet counts of \< 130 K/mm^3^ during
first exposure and extended exposure periods (through 72 weeks) from all
completed studies showed no evidence for an increasing risk of TCP with
extended Raptiva exposure beyond 24 weeks.

The incidence of treatment‑emergent TCP was summarized for all completed
and ongoing Raptiva studies based on the data used for the Safety Update
to the original BLA. (Note: This excludes three cases in Table 34 from
ongoing Study 2601). Treatment‑emergent TCP was defined as a shift in
platelet counts from normal or high values at baseline (≥ 130 K/mm^3^)
to below 130 K/mm^3^ or shift from low at baseline (\< 130 K/mm^3^) to
\< 75% of baseline count. Among subjects receiving Raptiva or who were
previously treated with Raptiva, there were 44 cases of
treatment‑emergent TCP reported over 1,668 subject‑years of observation,
giving an incidence rate of 2.64 events per 100 subject‑years. Among
subjects receiving placebo with no prior Raptiva exposure, there were
two cases of treatment‑emergent TCP reported over 169 subject‑years of
observation, giving an incidence rate of 1.18 events per 100
subject‑years. The ratio of incidence rates (Raptiva to placebo) for
treatment‑emergent TCP was 2.24.

6.2.11 Adverse Events of Psoriasis (Phase III Studies)

a\. Psoriasis Adverse Events during Treatment (Phase III Studies)

No subject experienced a serious adverse event of psoriasis during the
first 12‑week treatment period of the placebo‑controlled studies. The
overall incidence of non‑serious psoriatic adverse events was low (3.2%
in each dose group) in subjects receiving Raptiva; the rate was 1.4% in
the placebo‑treated group. Guttate psoriasis was the predominant type of
psoriatic adverse event. The incidence of severe psoriasis adverse
events was also low: 0.7% in the Raptiva‑treated group and 0% in the
placebo‑treated group. The rates of study drug discontinuation because
of an adverse event of psoriasis were 0.6% and 0.1% in the Raptiva and
placebo‑treated groups, respectively.

b\. Adverse Events of Psoriasis during Washout

Use of other psoriasis therapies was restricted after Raptiva
discontinuation in the clinical trials. In the early trials, psoriasis
treatments were discouraged even after relapse (loss of 50% of previous
improvement during Raptiva treatment). Although appropriate in the
setting of a clinical trial, this approach is not consistent with
clinical practice. In later studies, subjects were allowed to transition
to topical treatments or UVB after Raptiva discontinuation and were also
allowed to use systemic therapies or PUVA after relapse.

Across all studies (controlled and open‑label), adverse events of
psoriasis during Washout (the 12‑week period following discontinuation
of Raptiva) were reported by 13.0% of subjects who completed the Adverse
Event Form (see Table 31).

+----------------------------------+-----------------------------------+
| Table 31                         |                                   |
|                                  |                                   |
| Psoriasis Adverse Events         |                                   |
| Experienced by Subjects          |                                   |
| Previously Treated with Raptiva  |                                   |
| during Washout                   |                                   |
+----------------------------------+-----------------------------------+
|                                  |                                   |
+----------------------------------+-----------------------------------+
| Adverse Event                    | Raptiva\                          |
|                                  | (n = 1,201)                       |
+----------------------------------+-----------------------------------+
| Subjects with completed forms    | 1,166                             |
+----------------------------------+-----------------------------------+
| Total ^a^                        | 152 (13.0%)                       |
+----------------------------------+-----------------------------------+
| Recurrence of plaque psoriasis   | 73 (6.3%)                         |
+----------------------------------+-----------------------------------+
| Unusual morphology               | 42 (3.6%)                         |
+----------------------------------+-----------------------------------+
| Guttate psoriasis                | 24 (2.1%)                         |
+----------------------------------+-----------------------------------+
| Psoriatic erythroderma ^c^       | 8 (0.7%)                          |
+----------------------------------+-----------------------------------+
| Pustular psoriasis ^b^           | 7 (0.6%)                          |
+----------------------------------+-----------------------------------+
| Inverse psoriasis                | 2 (0.2%)                          |
+----------------------------------+-----------------------------------+
| ^a^ The total represents the     |                                   |
| number of subjects with          |                                   |
| completed Adverse Event Case     |                                   |
| Report Forms.                    |                                   |
|                                  |                                   |
| ^b^ One case of pustular         |                                   |
| psoriasis of von Zumbusch, five  |                                   |
| localized with pustular lesions  |                                   |
| restricted to the groin, palms,  |                                   |
| or soles.                        |                                   |
|                                  |                                   |
| ^c^ Erythrodermic flare and      |                                   |
| psoriatic erythroderma.          |                                   |
+----------------------------------+-----------------------------------+

Only 6 subjects (0.5% of 1,166 subjects) had adverse events of psoriasis
that were reported as serious: psoriatic erythroderma (3 subjects),
pustular psoriasis (2 subjects), and recurrence of plaque psoriasis (1
subject) (see Table 32). Of note, 3 of the subjects received the 4.0
mg/kg/wk dose and 1 received the 2.0 mg/kg/wk dose. Five of the subjects
were admitted to the hospital for management. At the termination of
Raptiva treatment, 2 of the 6 subjects were responders and 4 were
non‑responders.

Subjects who transitioned to topical therapies or UVB after Raptiva
discontinuation or started systemic therapies after relapse experienced
lower rates of psoriatic adverse events than did untreated patients (see
Table 32). therapeutics.

+---------------------------------------+------------------------------+
| Table 32                              |                              |
|                                       |                              |
| Psoriasis Adverse Events by           |                              |
| Medication Received during Washout\   |                              |
| for Evaluable Subjects from Studies   |                              |
| HUPS254, HUPS256, 2058, 2059, 2142,   |                              |
| 2243, and 2062                        |                              |
+---------------------------------------+------------------------------+
| Subject Group                         | No. of Subjects Experiencing |
|                                       | a Psoriasis Adverse Event    |
|                                       | ^a^                          |
+---------------------------------------+------------------------------+
| Total                                 | 152/1,166 (13.0%)            |
+---------------------------------------+------------------------------+
| No psoriasis therapy                  | 96/458 (21.0%)               |
+---------------------------------------+------------------------------+
| Topical therapies                     | 53/627 (8.5%)                |
+---------------------------------------+------------------------------+
| Phototherapies                        | 7/116 (6.0%)                 |
+---------------------------------------+------------------------------+
| Systemic therapies                    | 9/262 (3.4%)                 |
+---------------------------------------+------------------------------+
| ^a^ Subjects who washed out and had   |                              |
| completed CRFs for both adverse       |                              |
| events and concomitant medications.   |                              |
+---------------------------------------+------------------------------+

Rates of more clinically significant psoriasis adverse events, defined
as psoriasis adverse events excluding mild and guttate‑type lesions,
were reduced to 0.5% in subjects receiving high‑potency topical
corticosteroids and to 0.0% in subjects receiving topical vitamin D
derivatives (see Table 33).

+--------------------------------------+-------------------------------+
| Table 33                             |                               |
|                                      |                               |
| Rate of Adverse Events of Psoriasis, |                               |
| Excluding Mild and Guttate           |                               |
| Psoriasis, by Concomitant Therapy    |                               |
| during Washout                       |                               |
+--------------------------------------+-------------------------------+
| Treatment                            | Rate of Psoriasis Adverse     |
|                                      | Events                        |
+--------------------------------------+-------------------------------+
| No psoriasis medication              | 13.3% (65/489)                |
+--------------------------------------+-------------------------------+
| Medium‑potency corticosteroids       | 3.7% (11/297)                 |
+--------------------------------------+-------------------------------+
| High‑potency corticosteroids         | 0.5% (1/186)                  |
+--------------------------------------+-------------------------------+
| Vitamin D derivatives                | 0 (0/105)                     |
+--------------------------------------+-------------------------------+
| Ultraviolet light B                  | 2.7% (2/74)                   |
+--------------------------------------+-------------------------------+
| Systemic retinoids                   | 0 (0/24)                      |
+--------------------------------------+-------------------------------+
| Methotrexate                         | 1.2% (1/81)                   |
+--------------------------------------+-------------------------------+
| Cyclosporine                         | 0 (0/55)                      |
+--------------------------------------+-------------------------------+
| Note: Includes serious, severe, or   |                               |
| moderate adverse events, excluding   |                               |
| guttate psoriasis, and subjects with |                               |
| at least two PASI evaluations from   |                               |
| Studies 2058, 2059, 2062, and 2142.  |                               |
+--------------------------------------+-------------------------------+

The incidence of psoriatic adverse events following withdrawal of
Raptiva may have been increased by the clinical trial design, which
restricted Raptiva taper, transition to alternate therapies, or use of
concomitant medications. The above data suggest that subjects who
received concomitant psoriasis medications during washout had a lower
incidence of psoriasis adverse events. In clinical practice, it is
anticipated that patients will be transitioned or rotated to other
therapies upon discontinuation of Raptiva and that they will receive
treatment with re‑initiation of Raptiva or initiation of other psoriasis
therapies upon recurrence of psoriasis. Additional trials are in
progress assessing Raptiva taper regimens (Study 2391) and transition to
other psoriasis therapies (Study HUPS300).

6.2.12 Arthritis (Phase III Studies)

During the first 12‑week treatment period of the Phase III,
placebo‑controlled studies, the rate of arthritis in the placebo‑treated
group (2.2%) was similar to the rate in the 1.0 mg/kg/wk Raptiva‑treated
group (2.4%). The rate in the 2.0 mg/kg/wk group was similar but
slightly higher (3.9%). There were no serious adverse events of
arthritis during this period. The majority of subjects who reported
arthritis adverse events had prior history of arthritis. In the overall
database a few (0.6%) subjects experienced a serious adverse event of
arthritis.

Because arthritis is not the same as psoriatic arthritis, a Phase III
study to evaluate the safety and efficacy of Raptiva in psoriatic
arthritis patients is ongoing.

6.2.13 Hypersensitivity‑Related Adverse Events (Phase III Studies)

Hypersensitivity‑related adverse events were defined as an adverse event
that included a symptom such as urticaria or angioedema, which could be
suggestive of a potential hypersensitivity reaction, regardless of
suspected relationship to Raptiva. During the first 12‑week treatment
period of the four Phase III, placebo‑controlled studies, the percentage
of subjects reporting at least one hypersensitivity‑related adverse
event was similar in the placebo and 1.0 mg/kg/wk Raptiva‑treated
groups, and somewhat higher in the 2.0 mg/kg/wk Raptiva‑treated group
(see Table 34). The most frequent events were rash, urticaria, and
allergic reaction. Most events of allergic reaction were described as
seasonal allergy or allergic rhinitis. Although 22 of the 1,620 subjects
(1.4%) receiving Raptiva experienced urticaria; however only 2 subjects
discontinued treatment. Most patients experienced resolution of the
urticaria despite continued treatment and/or rechallenge. Therefore,
many hypersensitivity‑related adverse events did not appear related to
Raptiva.

+-----------------+----------+-----------+-----------+---------------+
| Table 34        |          |           |           |               |
|                 |          |           |           |               |
| H               |          |           |           |               |
| ypersensitivity |          |           |           |               |
| Adverse Events  |          |           |           |               |
| That Occurred   |          |           |           |               |
| during the      |          |           |           |               |
| First 12 Weeks  |          |           |           |               |
| of Treatment in |          |           |           |               |
| the             |          |           |           |               |
| Pla             |          |           |           |               |
| cebo‑Controlled |          |           |           |               |
| Studies         |          |           |           |               |
+-----------------+----------+-----------+-----------+---------------+
| Adverse Event   |          | Raptiva   |           |               |
+-----------------+----------+-----------+-----------+---------------+
|                 | Placebo\ | 1.0       | 2.0       | All Raptiva   |
|                 | (        | mg/kg/wk\ | mg/kg/wk\ | Subjects\     |
|                 | n = 715) | (n        | (n = 407) | (n = 1,620)   |
|                 |          |  = 1,213) |           |               |
+-----------------+----------+-----------+-----------+---------------+
| Total ^a^       | 49       | 95 (7.8%) | 37 (9.1%) | 132 (8.1%)    |
|                 | (6.9%)   |           |           |               |
+-----------------+----------+-----------+-----------+---------------+
| Rash            | 20       | 37 (3.1%) | 11 (2.7%) | 48 (3.0%)     |
|                 | (2.8%)   |           |           |               |
+-----------------+----------+-----------+-----------+---------------+
| Urticaria       | 3 (0.4%) | 16 (1.3%) | 6 (1.5%)  | 22 (1.4%)     |
+-----------------+----------+-----------+-----------+---------------+
| Allergic        | 6 (0.8%) | 14 (1.2%) | 5 (1.2%)  | 19 (1.2%)     |
| reaction        |          |           |           |               |
+-----------------+----------+-----------+-----------+---------------+
| Dyspnea         | 3 (0.4%) | 9 (0.7%)  | 3 (0.7%)  | 12 (0.7%)     |
+-----------------+----------+-----------+-----------+---------------+
| Face edema      | 6 (0.8%) | 6 (0.5%)  | 3 (0.7%)  | 9 (0.6%)      |
+-----------------+----------+-----------+-----------+---------------+
| Maculopapular   | 3 (0.4%) | 8 (0.7%)  | 2 (0.5%)  | 10 (0.6%)     |
| rash            |          |           |           |               |
+-----------------+----------+-----------+-----------+---------------+
| Injection‑site  | 1 (0.1%) | 6 (0.5%)  | 2 (0.5%)  | 8 (0.5%)      |
| h               |          |           |           |               |
| ypersensitivity |          |           |           |               |
+-----------------+----------+-----------+-----------+---------------+
| Asthma          | 6 (0.8%) | 4 (0.3%)  | 3 (0.7%)  | 7 (0.4%)      |
+-----------------+----------+-----------+-----------+---------------+
| Angioedema      | 0        | 1         | 3 (0.7%)  | 4 (0.2%)      |
|                 |          | (\< 0.1%) |           |               |
+-----------------+----------+-----------+-----------+---------------+
| Laryngismus     | 5 (0.7%) | 1         | 1 (0.2%)  | 2 (0.1%)      |
|                 |          | (\< 0.1%) |           |               |
+-----------------+----------+-----------+-----------+---------------+
| Bronchiolitis   | 0        | 1         | 0         | 1 (\< 0.1%)   |
|                 |          | (\< 0.1%) |           |               |
+-----------------+----------+-----------+-----------+---------------+
| Erythema        | 0        | 1         | 0         | 1 (\< 0.1%)   |
| multiforme      |          | (\< 0.1%) |           |               |
+-----------------+----------+-----------+-----------+---------------+
| ^a^ Represents  |          |           |           |               |
| the number of   |          |           |           |               |
| subjects with   |          |           |           |               |
| at least one    |          |           |           |               |
| h               |          |           |           |               |
| ypersensitivity |          |           |           |               |
| adverse event.  |          |           |           |               |
+-----------------+----------+-----------+-----------+---------------+

> The rate of hypersensitivity adverse events was similar between
> patients who were positive for anti‑Raptiva antibodies and those who
> were negative, except during retreatment. During retreatment with
> Raptiva, hypersensitivity related adverse events were reported for
> 18.2% of antibody‑positive subjects (4 of 22 subjects) compared with
> 6.7% of all subjects (23 of 341 subjects).

6.2.14 Injection‑Site Adverse Events (Phase III Studies)

> Less than 1% of subjects in the first 12‑week treatment period of the
> Phase III, placebo‑controlled studies experienced a visible adverse
> reaction at the injection site, with no discernible differences noted
> between the Raptiva and placebo‑treated groups. Injection‑site pain
> was experienced by about 1% of patients, with similar incidence in the
> Raptiva and placebo‑treated groups.

6.2.15 Audiologic Assessments

Audiologic testing was performed in three studies (HUPS254, HUPS256,
2058) after 1 subject in the Phase II study (HUPS252) experienced a
serious adverse event of transient unilateral hearing loss. In all three
studies, audiograms showed improvement and worsening in similar
proportions of subjects. Overall, the observations appeared to be
consistent with test‑retest variability without evidence of
Raptiva‑induced ototoxicity. Two expert audiologists who reviewed
audiograms from Studies HUPS254, HUPS256, and 2058 concluded that there
was no evidence of ototoxicity.

6.3 Laboratory Safety Tests (Phase III Studies)

The pertinent findings from laboratory tests are summarized below:

-   The most common abnormality is an approximate doubling of mean
    lymphocyte count that was present throughout Raptiva treatment and
    resolved after discontinuation; elevations of eosinophil and
    neutrophil counts were seen to a lesser degree.

-   A small excess of treatment‑emergent thrombocytopenia (TCP) events
    was observed among Raptiva‑treated subjects compared with
    placebo‑treated subjects. These events were rare and reversible upon
    discontinuation of Raptiva with or without corticosteroid
    administration (see Section 6.2.10 for additional details).

-   Blood chemistry abnormalities more common in Raptiva‑treated
    subjects versus placebo‑treated subjects were as follows:

1\) Small increases in alkaline phosphatase (mean change \[SD\] of ‑0.68
\[1.82\] U/L in placebo‑treated group versus 5.98 \[17.43\] U/L in
Raptiva‑treated group)

2\) A small increase in the proportion of subjects with a shift to
elevated alkaline phosphatase (0.6% high shifts in placebo‑treated group
vs. 4.1% in Raptiva‑treated group)

3\) A small increase in the proportion of subjects with a shift to
SGPT/ALT (2.6% high shifts in placebo vs. 5.0% in Raptiva‑treated
groups). Fractionation demonstrated the increase in high shifts in
alkaline phosphatase not to be primarily due to increases in liver
isoenzymes.

-   Examination of C‑reactive protein (CRP) and fibrinogen as
    representative acute phase reactants demonstrated increases in some
    Raptiva‑treated subjects. For CRP, 22.5% Raptiva‑treated subjects
    experienced high shifts compared with 13.0% of placebo‑treated
    subjects. Mean (SD) change from baseline was 0.40 (1.83) in Raptiva
    treated subjects compared with 0.09 (0.84) in placebo‑treated
    subjects.

-   Anti‑Raptiva antibodies were detected in 67 of the 1,063 subjects
    (approximately 6.3%), with 0.3% of subjects having titers
    \> 1.0 μg/mL. No apparent differences were noted in safety,
    efficacy, and pharmacodynamic results between subjects who developed
    anti‑Raptiva antibodies and those who did not. In subjects who were
    anti‑Raptiva antibody positive, the PASI 75 response was 20.0% and
    the PASI‑50 response was 53.3% after 12 weeks of treatment.

6.4 Long‑Term CLINICAL RESULTS

Extended exposure is defined as treatment with Raptiva for two or more
periods, each usually of 12 weeks duration, for which the interval
between the last dose of study drug in a previous treatment period and
the first dose of drug in the subsequent treatment period is  ≤35 days.
Extended exposure safety data from all studies were pooled by length of
exposure in 12‑week increments: 0--12 weeks (First Exposure),
12--24 weeks, 24--36 weeks,\
36--48 weeks, and 48--60 weeks.

The data summarized over the first 12 weeks of treatment and used for
comparison with the extended exposure segments were obtained from
subjects who were eligible for extended exposure, in order to make the
most appropriate comparison between the periods. As a result, first
exposure data for any subject who could not have received extended
exposure were not included.

For subjects who received 1.0 mg/kg/wk or 2.0 mg/kg/wk Raptiva, the
percentage of subjects with at least one adverse event was higher during
the first 12 weeks of treatment than in any of the subsequent extended
exposure 12‑week segments. Low discontinuation rates (see Table 18)
preclude the possibility that the reduction in adverse events is due to
preferential discontinuation of subjects experiencing adverse events.

All adverse event types that occurred in at least 5% of subjects during
any 12‑week treatment segment from first exposure through 60 weeks are
presented in Table 35. For most types of adverse events, the percentage
of subjects reporting the event was lower during every extended exposure
segment than during the first 12‑week treatment period. There were no
noteworthy trends toward higher percentages of adverse events with
longer Raptiva exposure.

+----------+---------+---------+--------+--------+--------+--------+
| Table 35 |         |         |        |        |        |        |
|          |         |         |        |        |        |        |
| Adverse  |         |         |        |        |        |        |
| Events   |         |         |        |        |        |        |
| Exp      |         |         |        |        |        |        |
| erienced |         |         |        |        |        |        |
| by ≥ 5%  |         |         |        |        |        |        |
| of       |         |         |        |        |        |        |
| Subjects |         |         |        |        |        |        |
| by       |         |         |        |        |        |        |
| 12‑Week  |         |         |        |        |        |        |
| Course   |         |         |        |        |        |        |
| of\      |         |         |        |        |        |        |
| Raptiva  |         |         |        |        |        |        |
| T        |         |         |        |        |        |        |
| reatment |         |         |        |        |        |        |
+----------+---------+---------+--------+--------+--------+--------+
| Adverse  | Placebo | Raptiva |        |        |        |        |
| Event    | ^a^\    |         |        |        |        |        |
|          | 0--12   |         |        |        |        |        |
|          | Wk\     |         |        |        |        |        |
|          | (n      |         |        |        |        |        |
|          |  = 715) |         |        |        |        |        |
+----------+---------+---------+--------+--------+--------+--------+
|          |         | 0--12   | 12--24 | 24--36 | 36--48 | 48--60 |
|          |         | Wk ^b^\ | Wk\    | Wk\    | Wk\    | Wk\    |
|          |         | (n =    | (n =   | (n     | (n     | (n     |
|          |         |  1,713) | 1,115) | = 318) | = 247) | = 228) |
+----------+---------+---------+--------+--------+--------+--------+
| Total    | 526     | 1,420   | 754    | 196    | 143    | 106    |
|          | (73.6%) | (82.9%) | (      | (      | (      | (      |
|          |         |         | 67.6%) | 61.6%) | 57.9%) | 46.5%) |
+----------+---------+---------+--------+--------+--------+--------+
| Headache | 159     | 585     | 78     | 14     | 6      | 8      |
|          | (22.2%) | (34.2%) | (7.0%) | (4.4%) | (2.4%) | (3.5%) |
+----------+---------+---------+--------+--------+--------+--------+
| I        | 110     | 249     | 167    | 52     | 33     | 25     |
| nfection | (15.4%) | (14.5%) | (      | (      | (      | (      |
|          |         |         | 15.0%) | 16.4%) | 13.4%) | 11.0%) |
+----------+---------+---------+--------+--------+--------+--------+
| Chills   | 32      | 204     | 12     | 3      | 2      | 0      |
|          | (4.5%)  | (11.9%) | (1.1%) | (0.9%) | (0.8%) |        |
+----------+---------+---------+--------+--------+--------+--------+
| Nausea   | 51      | 198     | 31     | 5      | 4      | 1      |
|          | (7.1%)  | (11.6%) | (2.8%) | (1.6%) | (1.6%) | (0.4%) |
+----------+---------+---------+--------+--------+--------+--------+
| Pain     | 38      | 187     | 59     | 18     | 11     | 6      |
|          | (5.3%)  | (10.9%) | (5.3%) | (5.7%) | (4.5%) | (2.6%) |
+----------+---------+---------+--------+--------+--------+--------+
| Fever    | 24      | 149     | 20     | 8      | 4      | 3      |
|          | (3.4%)  | (8.7%)  | (1.8%) | (2.5%) | (1.6%) | (1.3%) |
+----------+---------+---------+--------+--------+--------+--------+
| Asthenia | 37      | 136     | 21     | 3      | 0      | 2      |
|          | (5.2%)  | (7.9%)  | (1.9%) | (0.9%) |        | (0.9%) |
+----------+---------+---------+--------+--------+--------+--------+
| Pha      | 47      | 129     | 36     | 12     | 10     | 2      |
| ryngitis | (6.6%)  | (7.5%)  | (3.2%) | (3.8%) | (4.0%) | (0.9%) |
+----------+---------+---------+--------+--------+--------+--------+
| Myalgia  | 35      | 129     | 22     | 3      | 2      | 2      |
|          | (4.9%)  | (7.5%)  | (2.0%) | (0.9%) | (0.8%) | (0.9%) |
+----------+---------+---------+--------+--------+--------+--------+
| Diarrhea | 48      | 111     | 38     | 5      | 4      | 5      |
|          | (6.7%)  | (6.5%)  | (3.4%) | (1.6%) | (1.6%) | (2.2%) |
+----------+---------+---------+--------+--------+--------+--------+
| Rhinitis | 46      | 103     | 40     | 25     | 14     | 3      |
|          | (6.4%)  | (6.0%)  | (3.6%) | (7.9%) | (5.7%) | (1.3%) |
+----------+---------+---------+--------+--------+--------+--------+
| Ac       | 45      | 100     | 47     | 15     | 7      | 2      |
| cidental | (6.3%)  | (5.8%)  | (4.2%) | (4.7%) | (2.8%) | (0.9%) |
| injury   |         |         |        |        |        |        |
+----------+---------+---------+--------+--------+--------+--------+
| Flu      | 29      | 88      | 32     | 3      | 6      | 1      |
| syndrome | (4.1%)  | (5.1%)  | (2.9%) | (0.9%) | (2.4%) | (0.4%) |
+----------+---------+---------+--------+--------+--------+--------+
| Back     | 14      | 85      | 30     | 8      | 6      | 4      |
| pain     | (2.0%)  | (5.0%)  | (2.7%) | (2.5%) | (2.4%) | (1.8%) |
+----------+---------+---------+--------+--------+--------+--------+
| Cough    | 31      | 80      | 41     | 14     | 15     | 5      |
| i        | (4.3%)  | (4.7%)  | (3.7%) | (4.4%) | (6.1%) | (2.2%) |
| ncreased |         |         |        |        |        |        |
+----------+---------+---------+--------+--------+--------+--------+
| S        | 34      | 76      | 34     | 10     | 21     | 6      |
| inusitis | (4.8%)  | (4.4%)  | (3.0%) | (3.1%) | (8.5%) | (2.6%) |
+----------+---------+---------+--------+--------+--------+--------+
| ^a^      |         |         |        |        |        |        |
| Placebo  |         |         |        |        |        |        |
| data     |         |         |        |        |        |        |
| from the |         |         |        |        |        |        |
| first    |         |         |        |        |        |        |
| 12‑week  |         |         |        |        |        |        |
| t        |         |         |        |        |        |        |
| reatment |         |         |        |        |        |        |
| period   |         |         |        |        |        |        |
| of the   |         |         |        |        |        |        |
| four     |         |         |        |        |        |        |
| Phase    |         |         |        |        |        |        |
| III,     |         |         |        |        |        |        |
| ran      |         |         |        |        |        |        |
| domized, |         |         |        |        |        |        |
| pl       |         |         |        |        |        |        |
| acebo‑co |         |         |        |        |        |        |
| ntrolled |         |         |        |        |        |        |
| studies. |         |         |        |        |        |        |
|          |         |         |        |        |        |        |
| ^b^      |         |         |        |        |        |        |
| Com      |         |         |        |        |        |        |
| parisons |         |         |        |        |        |        |
| were     |         |         |        |        |        |        |
| made     |         |         |        |        |        |        |
| with     |         |         |        |        |        |        |
| subjects |         |         |        |        |        |        |
| treated  |         |         |        |        |        |        |
| with     |         |         |        |        |        |        |
| Raptiva  |         |         |        |        |        |        |
| from the |         |         |        |        |        |        |
| subset   |         |         |        |        |        |        |
| of       |         |         |        |        |        |        |
| subjects |         |         |        |        |        |        |
| eligible |         |         |        |        |        |        |
| for      |         |         |        |        |        |        |
| c        |         |         |        |        |        |        |
| ontinued |         |         |        |        |        |        |
| t        |         |         |        |        |        |        |
| reatment |         |         |        |        |        |        |
| beyond   |         |         |        |        |        |        |
| the      |         |         |        |        |        |        |
| initial  |         |         |        |        |        |        |
| 12       |         |         |        |        |        |        |
| weeks.   |         |         |        |        |        |        |
| The      |         |         |        |        |        |        |
| Raptiva  |         |         |        |        |        |        |
| ‑treated |         |         |        |        |        |        |
| groups   |         |         |        |        |        |        |
| were     |         |         |        |        |        |        |
| c        |         |         |        |        |        |        |
| ombined. |         |         |        |        |        |        |
+----------+---------+---------+--------+--------+--------+--------+

Serious adverse events that occurred during treatment beyond 12 weeks
are presented in Table 36. Based on the available data, the overall
rates of serious adverse events did not increase with increased exposure
to Raptiva, nor was there any evidence of cumulative toxicity over time.

+---------------------+--------+---------+---------+---------+--------+
| Table 36            |        |         |         |         |        |
|                     |        |         |         |         |        |
| Serious Adverse     |        |         |         |         |        |
| Events Reported for |        |         |         |         |        |
| 2 or More Subjects  |        |         |         |         |        |
| Treated with        |        |         |         |         |        |
| Raptiva within Any  |        |         |         |         |        |
| 12‑Week Treatment   |        |         |         |         |        |
| Period of the       |        |         |         |         |        |
| Placebo‑Controlled  |        |         |         |         |        |
| and Open‑Label      |        |         |         |         |        |
| Studies             |        |         |         |         |        |
+---------------------+--------+---------+---------+---------+--------+
|                     | Ex     |         |         |         |        |
|                     | tended |         |         |         |        |
|                     | Ex     |         |         |         |        |
|                     | posure |         |         |         |        |
+---------------------+--------+---------+---------+---------+--------+
| Adverse Event       | FE     | 13--24  | 25--36  | 37--48  | 49--60 |
|                     | ^a^\   | Wk\     | Wk\     | Wk\     | Wk\    |
|                     | (n =   | (n =    | (n      | (n      | (n     |
|                     | 1,713) |  1,115) |  = 318) |  = 247) | = 228) |
+---------------------+--------+---------+---------+---------+--------+
| Total               | 43     | 28      | 6       | 9       | 6      |
|                     | (2.5%) | (2.5%)  | (1.9%)  | (3.6%)  | (2.6%) |
+---------------------+--------+---------+---------+---------+--------+
| Cellulitis          | 5      | 2       | 0       | 0       | 0      |
|                     | (0.3%) | (0.2%)  |         |         |        |
+---------------------+--------+---------+---------+---------+--------+
| Arthritis           | 5      | 1       | 0       | 1       | 0      |
|                     | (0.3%) | (\      |         | (0.4%)  |        |
|                     |        | < 0.1%) |         |         |        |
+---------------------+--------+---------+---------+---------+--------+
| Accidental injury   | 4      | 2       | 0       | 1       | 0      |
|                     | (0.2%) | (0.2%)  |         | (0.4%)  |        |
+---------------------+--------+---------+---------+---------+--------+
| Kidney calculus     | 3      | 0       | 0       | 0       | 0      |
|                     | (0.2%) |         |         |         |        |
+---------------------+--------+---------+---------+---------+--------+
| Skin carcinoma      | 2      | 3       | 0       | 2       | 1      |
|                     | (0.1%) | (0.3%)  |         | (0.8%)  | (0.4%) |
+---------------------+--------+---------+---------+---------+--------+
| Bone disorder       | 2      | 0       | 0       | 0       | 0      |
|                     | (0.1%) |         |         |         |        |
+---------------------+--------+---------+---------+---------+--------+
| Pneumonia           | 1      | 0       | 0       | 0       | 0      |
|                     | (\<    |         |         |         |        |
|                     |  0.1%) |         |         |         |        |
+---------------------+--------+---------+---------+---------+--------+
| Coronary artery     | 2      | 1       | 0       | 0       | 0      |
| disorder            | (0.1)  | (\      |         |         |        |
|                     |        | < 0.1%) |         |         |        |
+---------------------+--------+---------+---------+---------+--------+
| Gastroenteritis     | 2      | 1       | 0       | 0       | 1      |
|                     | (0.1%) | (\      |         |         | (0.4%) |
|                     |        | < 0.1%) |         |         |        |
+---------------------+--------+---------+---------+---------+--------+
| Bronchiolitis       | 1      | 0       | 0       | 0       | 0      |
|                     | (\<    |         |         |         |        |
|                     |  0.1%) |         |         |         |        |
+---------------------+--------+---------+---------+---------+--------+
| Atrial fibrillation | 1      | 0       | 0       | 0       | 0      |
|                     | (\<    |         |         |         |        |
|                     |  0.1%) |         |         |         |        |
+---------------------+--------+---------+---------+---------+--------+
| Psoriasis           | 1      | 3       | 0       | 0       | 0      |
|                     | (\<    | (0.3%)  |         |         |        |
|                     |  0.1%) |         |         |         |        |
+---------------------+--------+---------+---------+---------+--------+
| Deep vein           | 0      | 2       | 1       | 0       | 0      |
| thrombophlebitis    |        | (0.2%)  | (0.3%)  |         |        |
+---------------------+--------+---------+---------+---------+--------+
| GI carcinoma        | 0      | 2       | 0       | 0       | 1      |
|                     |        | (0.2%)  |         |         | (0.4%) |
+---------------------+--------+---------+---------+---------+--------+
| GI disorder         | 0      | 2       | 0       | 0       | 0      |
|                     |        | (0.2%)  |         |         |        |
+---------------------+--------+---------+---------+---------+--------+
| Infection           | 0      | 0       | 0       | 0       | 0      |
+---------------------+--------+---------+---------+---------+--------+
| Anemia              | 0      | 0       | 0       | 0       | 0      |
+---------------------+--------+---------+---------+---------+--------+
| FE = first          |        |         |         |         |        |
| exposure;           |        |         |         |         |        |
| GI                  |        |         |         |         |        |
| = gastrointestinal. |        |         |         |         |        |
|                     |        |         |         |         |        |
| ^a^ Comparisons     |        |         |         |         |        |
| were made with      |        |         |         |         |        |
| subjects treated    |        |         |         |         |        |
| with Raptiva from   |        |         |         |         |        |
| the subset of       |        |         |         |         |        |
| subjects eligible   |        |         |         |         |        |
| for continued       |        |         |         |         |        |
| treatment beyond    |        |         |         |         |        |
| the initial 12      |        |         |         |         |        |
| weeks. The          |        |         |         |         |        |
| Raptiva‑treated     |        |         |         |         |        |
| groups were         |        |         |         |         |        |
| combined.           |        |         |         |         |        |
+---------------------+--------+---------+---------+---------+--------+

The long‑term treatment data, based on over 1,000 subjects treated for
over 24 weeks and over 200 subjects treated for over 1 year, are
consistent with lack of increased toxicity with extended treatment.

6.5 RETREATMENT RESULTS

The safety of retreatment was assessed in subjects who received two
12‑week treatment courses separated by a break of at least 35 days.

For the assessment of adverse event rates associated with retreatment,
comparisons are made to the first exposure adverse event rates reported
for the subset of subjects who were eligible for retreatment. This
subset serves as the best available comparison group in the absence of
concurrent placebo; however, because this was not a randomized,
concurrently treated cohort, comparisons should be interpreted with
caution.

During the first 12‑week retreatment period, the percentage of subjects
with at least one adverse event was approximately 15% lower than that
observed during the first exposure period of subjects who were eligible
for retreatment. No new pattern of adverse events during retreatment was
evident (see Table 37). Acute adverse reactions appeared less common
during the second course of Raptiva treatment.

+--------------------------+---------------------+---------------------+
| Table 37                 |                     |                     |
|                          |                     |                     |
| Adverse Events           |                     |                     |
| Experienced by ≥ 5% of   |                     |                     |
| Subjects Treated with    |                     |                     |
| Raptiva following a      |                     |                     |
| Period of Non‑Treatment  |                     |                     |
+--------------------------+---------------------+---------------------+
|                          | Raptiva             |                     |
+--------------------------+---------------------+---------------------+
| Adverse Event            | First 12 Weeks ^a^\ | Retreatment\        |
|                          | (n = 1,064)         | (n = 341)           |
+--------------------------+---------------------+---------------------+
| Total ^b^                | 899 (84.5%)         | 238 (69.8%)         |
+--------------------------+---------------------+---------------------+
| Headache                 | 367 (34.5%)         | 77 (22.6%)          |
+--------------------------+---------------------+---------------------+
| Infection                | 155 (14.6%)         | 57 (16.7%)          |
+--------------------------+---------------------+---------------------+
| Chills                   | 125 (11.7%)         | 20 (5.9%)           |
+--------------------------+---------------------+---------------------+
| Pain                     | 121 (11.4%)         | 25 (7.3%)           |
+--------------------------+---------------------+---------------------+
| Pharyngitis              | 79 (7.4%)           | 17 (5.0%)           |
+--------------------------+---------------------+---------------------+
| Rhinitis                 | 67 (6.3%)           | 19 (5.6%)           |
+--------------------------+---------------------+---------------------+
| Psoriasis                | 42 (3.9%)           | 18 (5.3%)           |
+--------------------------+---------------------+---------------------+
| Pruritus                 | 42 (3.9%)           | 17 (5.0%)           |
+--------------------------+---------------------+---------------------+
| ^a^ Comparisons were     |                     |                     |
| made with subjects who   |                     |                     |
| completed their first    |                     |                     |
| exposure to Raptiva and  |                     |                     |
| who were eligible for    |                     |                     |
| retreatment.             |                     |                     |
|                          |                     |                     |
| ^b^ Represents the       |                     |                     |
| number of subjects with  |                     |                     |
| at least one adverse     |                     |                     |
| event.                   |                     |                     |
+--------------------------+---------------------+---------------------+

Serious adverse events that occurred during a second course of Raptiva
treatment are presented in Table 38. Overall, the rates of serious
adverse events did not increase with repeat exposure to Raptiva.

+--------------------------+---------------------+---------------------+
| Table 38                 |                     |                     |
|                          |                     |                     |
| Serious Adverse Events   |                     |                     |
| Reported for 2 or More   |                     |                     |
| Subjects during the      |                     |                     |
| First or Second Raptiva  |                     |                     |
| Treatment Course in the  |                     |                     |
| Placebo‑Controlled and   |                     |                     |
| Open‑Label Studies       |                     |                     |
+--------------------------+---------------------+---------------------+
|                          | Raptiva             |                     |
+--------------------------+---------------------+---------------------+
| Adverse Event            | First 12 Weeks ^a^\ | Retreatment\        |
|                          | (n = 1,064)         | (n = 341)           |
+--------------------------+---------------------+---------------------+
| Total ^b^                | 25 (2.3%)           | 5 (1.5%)            |
+--------------------------+---------------------+---------------------+
| Cellulitus               | 3 (0.3%)            | 0                   |
+--------------------------+---------------------+---------------------+
| Accidental Injury        | 2 (0.2%)            | 0                   |
+--------------------------+---------------------+---------------------+
| Arthritis                | 2 (0.2%)            | 0                   |
+--------------------------+---------------------+---------------------+
| Gastroenteritis          | 2 (0.2%)            | 0                   |
+--------------------------+---------------------+---------------------+
| Kidney calculus          | 2 (0.2%)            | 0                   |
+--------------------------+---------------------+---------------------+
| ^a^ Comparisons were     |                     |                     |
| made with subjects who   |                     |                     |
| completed their first    |                     |                     |
| exposure to Raptiva and  |                     |                     |
| who were eligible for    |                     |                     |
| retreatment.             |                     |                     |
|                          |                     |                     |
| ^b^ Represents the       |                     |                     |
| number of subjects with  |                     |                     |
| at least one serious     |                     |                     |
| adverse event.           |                     |                     |
+--------------------------+---------------------+---------------------+

6.6 WITHDRAWAL RESULTS

Of the 1,166 subjects observed during 12 weeks of withdrawal or washout
from Raptiva, 737 (63.2%) had at least one adverse event. Five types of
adverse events (infection, pain, peripheral edema, psoriasis, and
pruritus) were reported for ≥ 5% of subjects during washout from
treatment with Raptiva. With the exception of psoriasis (13.0%),
pruritus (5.6%), and peripheral edema (5.1%), these events occurred at
percentages less than, or similar to, those observed for subjects in the
first 12‑week treatment period of the first exposure cohort (see Section
6.2.4).

Forty subjects (3.4% of 1,166) reported one or more serious adverse
events during the 12 weeks after Raptiva discontinuation. The two most
common types of serious adverse events were psoriasis (6 subjects, 0.5%)
and arthritis (3 subjects, 0.3%). The following types of serious adverse
events were each reported for 2 subjects (0.2%): accidental injury,
anemia, bone disorder (disc herniation), infection, and pneumonia. All
other types of serious adverse events occurred in a single subject.

The effects of Raptiva on immune function are reversible, and therefore
psoriasis and arthritis return after discontinuation of treatment.
Serious and non‑serious adverse events of psoriasis were presented in
Section 6.2.11. The severity of psoriasis experienced after Raptiva
withdrawal was further assessed by examination of PASI scores before,
during, and after Raptiva treatment. In general, most subjects
experienced a gradual return of PASI score to baseline or somewhat
better over a period of weeks (see Figure 13).

Figure 13

Percent PASI Improvement during Raptiva Treatment and Washout\
for Two Cohorts in Study 2059

![](media/image15.png){width="5.9944444444444445in"
height="3.527083333333333in"}

In a minority of subjects, the PASI score returned to worse than
baseline. The rate of psoriasis overshoot, as defined by the proportion
of subjects who had a PASI score at least 25% higher than at baseline at
any point during the 12 weeks of follow‑up after discontinuation of
drug, varied from study to study but was highest in Study 2059, with a
rate of 18.2%.

Variability in the natural course of psoriasis as well as in repeat PASI
measurements could contribute to the rate of PASI overshoot. An estimate
of the extent of variability was obtained using patients who received
placebo during the first 12 weeks of the placebo‑controlled studies. In
Study 2059, 17.8% of placebo subjects experienced a PASI score at least
25% greater than baseline. This suggests that the variability of PASI
measurements and the natural history of psoriasis are such that a PASI
overshoot rate of\
15%--20% is not unexpected over a 12‑week period in a group of subjects
with moderate to severe plaque psoriasis not receiving therapy for
psoriasis.

Consistent with this interpretation, the rate of PASI overshoot in the
non‑responders (\< PASI‑50 response) was greater than in the responders
(PASI‑75 response). In subjects who had less than a PASI‑50 response,
the rate of PASI overshoot was 29.3%, in subjects who had a PASI‑50 (but
\< PASI‑75) response, the rate was 10.6%, and in those who had a PASI‑75
response, the rate was 10.0%. Subjects whose PASI scores were near
baseline were more likely to have a PASI measurement 25% higher than
baseline, probably due to the natural variability of the scores and
disease over time.

6.7 Drug--drug and drug--demographic interactions

6.7.1 Drug--Drug Interactions

Concomitant medications used during the first 12‑week treatment period
of the Phase III, placebo‑controlled studies were reviewed to determine
whether they altered the effect of Raptiva on adverse event rates. No
pattern suggestive of an interaction between Raptiva and concomitant
medications emerged from this review.

Concomitant medications used during the first 12‑week treatment period
of the Phase III, placebo‑controlled studies were reviewed to determine
whether they altered the effect of Raptiva on laboratory parameters.
There was no indication of any significant interaction between
concomitant medications and Raptiva in the effect on laboratory
parameters.

6.7.2 Drug--Demographic Interactions

To evaluate the impact of various intrinsic factors on the safety
profile of Raptiva, the incidence of adverse events in certain
subpopulations of subjects was analyzed for the first 12‑week treatment
period of Studies 2390, 2600, 2058, and 2059. The following are the
intrinsic factors that were analyzed: sex, age, race/ethnicity, baseline
PASI category, BMI, and selected conditions in the subject's medical
history (allergic reaction, arthritis, autoimmune disease, diabetes
mellitus, hyperlipidemia, hypertension, ischemic cardiovascular disease,
liver disease, malignancy, and pulmonary disease).

The overall differences between the incidence of adverse events in those
with and without the various intrinsic factors were minor and did not
appear to indicate any consistent trend other than what would be
expected from the underlying condition, and subjects in various
intrinsic factor groups did not appear to be at increased risk with
Raptiva treatment beyond the inherent risk from their underlying
condition.

6.8 Drug abuse, overdose, and withdrawal effects

No episodes of abuse of Raptiva were identified during the clinical
trial program. The potential for drug abuse appears to be very low.

6.9 Self‑Administration of subcutaneous Raptiva

Home dosing was permitted following the initial 12‑week treatment period
in both placebo‑controlled and open‑label clinical trials. Subjects and
caregivers received training and were required to demonstrate ability to
self‑administer drug. During the second 12 weeks of treatment in Studies
2058 and 2059, between one‑third and one‑half of the subjects
self‑administered Raptiva.

The percentages of subjects achieving a PASI‑75 at the end of a second
12 weeks of treatment are given in Table 39 for subjects who had not
achieved a PASI‑75 at the end of the first 12 weeks of treatment with
Raptiva. The PASI‑75 rates are consistent between those subjects treated
in the clinic and those who received a combination of doses in the
clinic and at home during Studies 2058 and 2059.

+------------+------------------+------------------+------------------+
| Table 39   |                  |                  |                  |
|            |                  |                  |                  |
| Home       |                  |                  |                  |
| Dosing:    |                  |                  |                  |
| Subjects   |                  |                  |                  |
| without    |                  |                  |                  |
| PASI‑75    |                  |                  |                  |
| Response   |                  |                  |                  |
| during the |                  |                  |                  |
| First      |                  |                  |                  |
| 12 Weeks   |                  |                  |                  |
| of         |                  |                  |                  |
| Treatment  |                  |                  |                  |
| Achieving  |                  |                  |                  |
| PASI‑75    |                  |                  |                  |
| during     |                  |                  |                  |
| the\       |                  |                  |                  |
| Second     |                  |                  |                  |
| 12 Weeks   |                  |                  |                  |
| of         |                  |                  |                  |
| Treatment  |                  |                  |                  |
+------------+------------------+------------------+------------------+
| Study      | Location         | Placebo          | All Raptiva      |
+------------+------------------+------------------+------------------+
| 2058       | Clinic only      | 7.9% (n = 38)    | 20.3% (n = 59)   |
+------------+------------------+------------------+------------------+
|            | Clinic and home  | 4.5% (n = 22)    | 20.3% (n = 64)   |
+------------+------------------+------------------+------------------+
| 2059       | Clinic only      | 3.9% (n = 77)    | 25.5% (n = 141)  |
+------------+------------------+------------------+------------------+
|            | Clinic and home  | 0 (n = 28)       | 24.6% (n = 69)   |
+------------+------------------+------------------+------------------+

Study 2062 also included subjects or their caregivers who received
training and demonstrated ability to self‑administer drug during the
first three clinic visits to dose at home. A subject assessment of home
dosing was conducted at Day 84. Approximately 60% of the subjects in
Study 2062 elected to self‑administer their Raptiva treatment. Of these
subjects, nearly 90% found it easy to self‑inject Raptiva and were
comfortable with the procedure. More than 70% of these subjects felt
Raptiva was more convenient than other psoriasis treatments and were
satisfied with their response to Raptiva.

10. SAFETY DATA FROM OTHER INDICATIONS

In addition to psoriasis patients, Raptiva has been studied in normal
volunteers, asthma patients, transplant patients, rheumatoid arthritis
patients, and psoriatic arthritis patients. There were no clinically
significant safety signals observed in the normal volunteer and asthma
studies. In the transplant study, 2 subjects receiving quadruple
immunosuppressive therapy (cyclosporine, prednisone, mycophenolate
mofetil, and 2.0 mg/kg/wk Raptiva) and 1 subject who received quintuple
immunosuppressive therapy (cyclosporine, prednisone, mycophenolate
mofetil, OKT3, and 2.0 mg/kg/wk Raptiva) developed post‑transplant
lymphoproliferative disorder (PTLD). In 2 subjects, the PTLD resolved, 1
spontaneously and 1 with chemotherapy. The third subject died from
sepsis. None of the subjects receiving lower doses of Raptiva in
combination with these other immunosuppressive therapies developed PTLD.
A Phase II study evaluating the safety and efficacy of Raptiva in
rheumatoid arthritis was recently stopped due to lack of clinical
benefit. There were no malignancies or infectious serious adverse
events. The psoriatic arthritis study is ongoing. To date, there have
been no malignancies or infectious serious adverse events.

6.11 Clinical Safety Summary and Conclusions

Based on data from 2,762 Raptiva‑treated subjects with moderate to
severe plaque psoriasis, Raptiva appears to be safe and well tolerated.
There was no evidence of increased risk for adverse events with
increased duration of exposure and no evidence of lymphocyte depletion
or clinically significant toxicity affecting bone marrow, liver, kidney,
or other organ systems.

The most frequent adverse events were acute adverse reactions (headache,
chills, fever, nausea, myalgia), which tended to occur following the
initial two injections and were generally mild and self‑limited. During
the placebo‑controlled portions of the Phase III trials, the rates of
serious adverse events were low and similar for subjects receiving
1.0 mg/kg/wk SC Raptiva or placebo.

Overall rates of infection and malignancies were low and consistent with
the expected background rates. Reversible thrombocytopenia consistent
with a drug‑induced effect was observed in 6 (0.2%) subjects, but a
relationship to Raptiva has not been established. During Raptiva
washout, a minority of the subjects experienced an adverse event of
psoriasis, possibly due to the restrictions placed on concomitant
medications during the washout period.

7\. BENEFITS AND RISKS

7.1 unmet medical need

Psoriasis is frequently disabling and often compromises quality of life.
Common physical symptoms that produce impairment include skin pain,
itching (often severe), skin tightness, and bleeding. Embarrassment,
frustration, fear, and depression are commonly experienced by patients
with psoriasis. For many patients, psoriasis is a chronic, life‑long
disease that impairs quality of life to an extent comparable with
arthritis, diabetes, heart disease, or cancer (Koo 1996; Rapp et al.
1999).

Topical medications, such as corticosteroid preparations, calcipotriene
(a vitamin D derivative), and tazarotene (a vitamin A derivative) are
insufficient to control moderate to severe disease. Currently approved
therapies for moderate to severe psoriasis include phototherapy,
systemic retinoids, and powerful, relatively non‑selective
immunosuppressive agents such as cyclosporine and methotrexate (Roenigk
et al. 1988; Gottlieb 1998; Lebwohl et al. 1998; Koo 1999; Lebwohl
2000). Although effective, these therapies have significant limitations
related to toxicity and accessibility, as listed below.

-   Cyclosporine: nephrotoxicity, hypertension, hepatoxicity,
    vasculopathy, neuropathy, and skin cancer

-   Methotrexate: bone marrow failure, liver failure and cirrhosis,
    severe pulmonary reactions, lymphoma, and severe skin reactions

Liver biopsies are required after each incremental exposure of 1.5 g.

-   Acitretin: long‑lasting teratogenicity (3 years after last dose),
    hyperlipidemia, hepatotoxicity, pancreatitis, hyperostosis,
    alopecia, and mucosal side effects

-   Phototherapy: cutaneous cancers and melanoma

Access to specialized phototherapy units is limited, and phototherapy
requires frequent clinic visits.

There is a clear unmet medical need for the development of safe,
convenient, and effective therapies for this serious condition that
provide both short‑ and long‑term control.

7.2 benefit--risk conclusions

Subjects receiving Raptiva therapy experience rapid and sustained
improvement in their signs and symptoms of psoriasis. Close to one‑third
of the subjects experienced a ≥75% reduction in their PASI score
12 weeks after initiation of therapy, while well over 40% experienced
this benefit by 24 weeks after treatment. The number of subjects who had
≥50% reduction in PASI score at these timepoints was even higher: nearly
two‑thirds of subjects achieved a PASI‑50 response by 24 weeks of
therapy. Other symptoms, including itching and quality‑of‑life, also
significantly improved and maintained while subjects were on therapy.

Raptiva has been studied in a large number of subjects and was shown to
be well tolerated. There were few serious adverse events observed in
subjects receiving Raptiva therapy, and no evidence of increased
incidence of malignancy, lymphocyte suppression, bone marrow
suppression, or other serious organ toxicity with long‑term therapy.
Discontinuations, particularly discontinuations due to adverse events,
were infrequent. Most of the non‑serious adverse events were transient
and resolved after initiation of appropriate therapy.

Therapy with Raptiva has been demonstrated to offer convenient,
continuous control of psoriasis with an acceptable safety and
tolerability profile. The benefits experienced by most subjects treated
with Raptiva outweigh any potential, infrequent risks. In addition, the
absence of specific cumulative organ toxicity appears to obviate the
need for rotational therapy with this agent. Raptiva provides a
significant new, safe, and efficacious alternative for patients with
moderate to severe plaque psoriasis.

REFERENCE LIST

Austin LM, Ozawa M, Kikuchi T, Walters IB, Krueger JG. The majority of
epidermal T cells in Psoriasis vulgaris lesions can produce type 1
cytokines, interferon‑γ, interleukin‑2, and tumor necrosis factor‑α,
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--9.

Bos JD, De Rie MA. The pathogenesis of psoriasis: immunological facts
and speculations. Immunol Today 1999;20:40--6.

Camisa C, editor. Handbook of psoriasis. Malden (MA): Blackwell Science
1998.

Chren MM, Lasek RJ, Quinn LM, Mostow EN, Zyzanski SJ. Skindex, a
quality‑of‑life measure for patients with skin disease: reliability,
validity, and responsiveness. J Invest Dermatol 1996;107:707--13.

Fleischer AB Jr, Feldman SR, Bradham DD. Office‑based physician services
provided by dermatologists in the United States in 1990. J Invest
Dermatol 1994;102:93--7.

Fredriksson T, Lassus A, Salde L. Reproducibility of clinical trials of
topical glucocorticosteroids. Int J Dermatol 1983:22(9):536--9.

Gottlieb AB. Psoriasis. DMCO 1998;1:195--202.

Griffiths TW, Griffiths CEM, Voorhees JJ. Immunopathogenesis and
immunotherapy of psoriasis. Dermatol Clin 1995;13:739--49.

Koo J. Population‑based epidemiologic study of psoriasis with emphasis
on quality of life assessment. Dermatol Clin 1996;14(3):485--96.

Krueger GG, Duvic M. Epidemiology of psoriasis: clinical issues. J
Invest Dermatol 1994;102:14S--8S.

Krueger GG, Feldman ST, Camisa C, Duvic M, Elder JT, Gottlieb AB, 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(Pt1):\
281--5.

Krueger JG. The immunologic basis for the treatment of psoriasis with
new biologic agents. J Am Acad Dermatol 2002;46(1):1--23.

Lebwohl M. Advances in psoriasis therapy. Dermatol Clin 2000;18:13--9,
vii.

Lebwohl M, Ellis C, Gottlieb A, Koo J, Krueger G, Linden K, et al.
Cyclosporine consensus conference: with emphasis of the treatment of
psoriasis. J Am Acad Dermatol 1998;39:464--75.

Marcil I, Stern R. Squamous‑cell cancer of the skin in patients given
PUVA and ciclosporin: nested cohort crossover study. Lancet
2001;358:1042--5.

Margolis D, Bilker W, Hennessy S, Vittorio C, Strom BL. The risk of
malignancy associated with psoriasis. Arch Dermatol 2001;137:778--83

National Ambulatory Medical Care Survey. U.S. Department of Health and
Human Services, National Center for Health Statistics, 1998.

NEORAL^^ \[package insert\]. East Hanover, NJ: Novartis Pharmaceuticals
Corp; 2001.

Nickoloff BJ. Skin innate immune system in psoriasis: friend or foe? J
Clin Invest 1999;104:1161--4.

Nickoloff BJ, Griffiths CE, Barker JN. The role of adhesion molecules,
chemotactic factors, and cytokines in inflammatory and neoplastic skin
disease--1990 update \[review\]. J Invest Dermatol
1990;94(6 Suppl):151S--7S.

Peckham PE, Weinstein GD, McCullough JL. The treatment of severe
psoriasis. A national survey. Arch Dermatol 1987;123:1303--7.

Rapp SR, Feldman SR, Exum ML, Fleischer AB Jr, Reboussin DM. Psoriasis
causes as much disability as other major medical diseases. J Am Acad
Dermatol 1999;41(3Pt1):401--7.

Roenigk HH, Auerbach R, Maibach HI, Weinstein GD, Lebwohl M.
Methotrexate in psoriasis: revised guidelines. J Am Acad Dermatol
1988;19:145--56.

Stern RS. Epidemiology of psoriasis. Dermatol Clin 1995;13:717--22.

Storer RD, French JE, Haseman J, Hajian G, LeGrand EK, Long GG, et al.
P53^+/‑^ hemizygous knockout mouse: overview of available data. Toxicol
Pathol 2001;29(Suppl):30−50.

RAPTIVA\
\[Efalizumab\]

DESCRIPTION

RAPTIVA (Efalizumab) is a recombinant humanized IgG1 kappa isotype
monoclonal antibody that selectively binds to human CD11a. CD11a is the
α subunit of leukocyte function antigen‑1 (LFA‑1), a β2 integrin, and is
expressed on all leukocytes. Efalizumab contains human framework regions
with the complementarity‑determining regions of a humanized murine
antibody that binds to CD11a (1). Efalizumab is produced by recombinant
DNA technology in a Chinese Hamster Ovary mammalian cell expression
system in a nutrient medium containing the antibiotic gentamicin and is
purified by a process that includes specific viral inactivation and
removal steps. Gentamicin is not detectable in the final product.
Efalizumab consists of 1328 amino acids and has a molecular weight of
approximately 150 kilodaltons.

RAPTIVA is supplied as a sterile, white to off‑white, lyophilized powder
in single‑use glass vials for subcutaneous (SC) injection. After
reconstitution with 1.3 mL of supplied Sterile Water for Injection for
Reconstitution, the solution of RAPTIVA is clear to pale yellow with a
pH of approximately 6.2. Each vial contains approximately 1.5 mL of
solution to deliver 1.25 mL (125 mg) of drug product. Each 1.25 mL
RAPTIVA contains 125 mg efalizumab, 9.25 mg histidine, 102.7 mg sucrose,
and 2.5 mg polysorbate 20.

CLINICAL PHARMACOLOGY

General

The interaction between LFA‑1 and intercellular adhesion
molecule‑1 (ICAM‑1) plays a major role in the dermal and epidermal
accumulation of lymphocytes in psoriasis. Overall the engagement of
LFA‑1 and ICAM‑1 results in the initiation and maintenance of multiple
functions, including activation of T lymphocytes, adhesion of
T lymphocytes to endothelial cells, and migration of T lymphocytes to
sites of inflammation. In psoriatic skin, ICAM‑1 is upregulated on
endothelium and keratinocytes. Efalizumab binds specifically to CD11a
(the α subunit of LFA‑1) on T lymphocytes, inhibits the binding of LFA‑1
to ICAM‑1, and results in inhibition of T lymphocyte adhesion to other
cell types. This results in reduced inflammation by any or all of the
following mechanisms: inhibition of CD11a expression; inhibition of
T lymphocyte proliferation, interleukin‑2 receptor expression and
cytokine release; inhibition of T lymphocyte trafficking to psoriatic
lesions; inhibition of T lymphocyte interaction with keratinocytes.

CD11a is also expressed on the surface of B lymphocytes, monocytes,
neutrophils, natural killer cells and other leukocytes. Therefore, the
potential exists for RAPTIVA to affect the activation, adhesion and
numbers of cells other than T lymphocytes.

Pharmacokinetics

In patients with moderate to severe plaque psoriasis, using an initial
SC RAPTIVA dose of 0.7 mg/kg followed by 11 weekly SC doses of
1 mg/kg/wk, serum concentrations reached a steady‑state by 4 weeks with
mean trough and peak concentrations of approximately 9 μg/mL and
12 μg/mL, respectively. Steady‑state clearance was 24 mL/kg/day (range
 = 5−76 mL/kg/day, n  = 25). Average time taken to eliminate RAPTIVA
after the last steady‑state dose was 25 days (range  = 13−35 days, n
 = 17). Average RAPTIVA SC bioavailability was estimated to be 50%.
Weight was found to be the most significant covariate affecting RAPTIVA
clearance. RAPTIVA clearance was not significantly affected by gender,
race, age, baseline PASI, or baseline lymphocyte count.

The pharmacokinetics of RAPTIVA in pediatric patients have not been
studied. The effects of renal or hepatic impairment on the
pharmacokinetics of RAPTIVA have not been studied.

Pharmacodynamics

At a dose of 1 mg/kg/wk SC, RAPTIVA reduced expression of CD11a on
circulating T lymphocytes to approximately 15−25% of pre‑dose values and
saturated CD11a to  \< 5% of baseline available CD11a binding sites.
Full effect was seen within 1−2 days after the first dose, and was
maintained between weekly doses. CD11a levels returned to within 25% of
baseline within 5−8 weeks following the discontinuation of RAPTIVA.

In clinical trials, RAPTIVA therapy resulted in a doubling of mean
lymphocyte counts relative to baseline presumably due to the reversal of
leukocyte adhesion to the blood vessel walls. The mean absolute
lymphocyte count was within the normal range during treatment; however
lymphocyte counts did increase above normal limits for some patients.
Lymphocyte counts did not increase further with continued treatment and
returned to baseline values approximately 6 weeks after drug
discontinuation.

CLINICAL STUDIES

RAPTIVA was evaluated in three randomized, double‑blind,
placebo‑controlled studies in adults with chronic ( \>  6 months) plaque
psoriasis and a minimum body surface area involvement of 10%. Doses of
1 mg/kg or 2 mg/kg or placebo were administered once a week for
12 consecutive weeks. Results from patients receiving 1 mg/kg/wk are
presented as that is the recommended dose. Patients could receive
concomitant low potency topical steroids. No other concomitant psoriasis
therapies were allowed during treatment or the follow‑up period.

Table 1 shows the primary endpoint results for the first 12‑week
treatment course of Studies 1, 2 and 3. The primary endpoint was defined
as the proportion of patients with a reduction in score on the Psoriasis
Area and Severity Index (PASI) of at least 75% from baseline at one week
following the 12‑week treatment period.

+-----------------+-----------------+-----------------+-----------------+
| **Table 1**\    |                 |                 |                 |
| Primary         |                 |                 |                 |
| Endpoint:       |                 |                 |                 |
| Proportion of   |                 |                 |                 |
| Patients with   |                 |                 |                 |
|  ≥ 75%          |                 |                 |                 |
| Improvement\    |                 |                 |                 |
| in PASI After   |                 |                 |                 |
| 12 Weeks of     |                 |                 |                 |
| Treatment       |                 |                 |                 |
| (PASI‑75)       |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
|                 | Placebo         | RAPTIVA^\       | Difference\     |
|                 |                 | ^1 mg/kg/wk     | (95%CI)         |
+-----------------+-----------------+-----------------+-----------------+
| Study 1         | 4%\             | 27%^a\          | 22%\            |
|                 | n = 187         | ^n = 369        | (16%, 29%)      |
+-----------------+-----------------+-----------------+-----------------+
| Study 2 ^b,\ c^ | 2%\             | 39%^a\          | 37%\            |
|                 | n = 170         | ^n = 162        | (28%, 46%)      |
+-----------------+-----------------+-----------------+-----------------+
| Study 3 ^b,\ c^ | 5%\             | 22%^a\          | 18%\            |
|                 | n = 122         | ^n = 232        | (9%, 27%)       |
+-----------------+-----------------+-----------------+-----------------+
| ^a^ p  \< 0.001 |                 |                 |                 |
| for comparison  |                 |                 |                 |
| of              |                 |                 |                 |
| Raptiva‑treated |                 |                 |                 |
| group with      |                 |                 |                 |
| placebo‑treated |                 |                 |                 |
| group using     |                 |                 |                 |
| Fisher's exact  |                 |                 |                 |
| test within     |                 |                 |                 |
| each study.     |                 |                 |                 |
|                 |                 |                 |                 |
| ^b^ Studies     |                 |                 |                 |
| performed with  |                 |                 |                 |
| a closely       |                 |                 |                 |
| related         |                 |                 |                 |
| efalizumab by a |                 |                 |                 |
| different       |                 |                 |                 |
| manufacturer.   |                 |                 |                 |
|                 |                 |                 |                 |
| ^c^ Studies     |                 |                 |                 |
| also evaluated  |                 |                 |                 |
| 2 mg/kg/wk      |                 |                 |                 |
| RAPTIVA.        |                 |                 |                 |
| Response rates  |                 |                 |                 |
| of patients     |                 |                 |                 |
| receiving       |                 |                 |                 |
| 2 mg/kg/wk were |                 |                 |                 |
| similar to      |                 |                 |                 |
| those presented |                 |                 |                 |
| for 1 mg/kg/wk. |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+

Other efficacy endpoints listed in Table 2 included the proportion of
patients who achieved a score of "minimal" or "clear" by the Overall
Lesion Severity (OLS); "excellent" or "clear" by the Physician's Global
Assessment of Change (PGA); the proportion of patients with a reduction
in PASI of at least 50% from baseline one week following the 12 week
treatment period.

+----------------------------+-------------+-------------+-------------+
| **Table 2**\               |             |             |             |
| Secondary Endpoints: After |             |             |             |
| 12 Weeks of Treatment      |             |             |             |
+----------------------------+-------------+-------------+-------------+
|                            | Study       | Placebo     | RAPTIVA\    |
|                            |             |             | 1 mg/kg/wk  |
+----------------------------+-------------+-------------+-------------+
| OLS: Minimal or Clear      | Study 1\    | 3%\         | 26%^a\      |
|                            | Study 2\    | 3%\         | ^32%^a\     |
|                            | Study 3     | 3%          | ^19%^a^     |
+----------------------------+-------------+-------------+-------------+
| PGA: Excellent or Cleared  | Study 1\    | 5%\         | 33%^a\      |
|                            | Study 2\    | 4%\         | ^39%^a\     |
|                            | Study 3     | 4%          | ^22%^a^     |
+----------------------------+-------------+-------------+-------------+
| Proportion of Patients     | Study 1\    | 14%\        | 59%^a^\     |
| with ≥50% improvement in   | Study 2^b^\ | 15%^\       | 61%^a^\     |
| PASI after 12 weeks of     | Study 3^b^  | ^16%        | 52%^a^      |
| treatment (PASI‑50)        |             |             |             |
+----------------------------+-------------+-------------+-------------+
| ^a^ p  \< 0.001 for        |             |             |             |
| comparison of              |             |             |             |
| Raptiva‑treated group to   |             |             |             |
| placebo‑treated group      |             |             |             |
| using Fisher's exact test. |             |             |             |
|                            |             |             |             |
| ^b^ PASI‑50 was not a      |             |             |             |
| prespecified endpoint in   |             |             |             |
| this study.                |             |             |             |
+----------------------------+-------------+-------------+-------------+

Mean psoriasis body surface area involvement at baseline was
approximately 30%. With Raptiva treatment, the percentage of body
surface area affected by psoriasis decreased to approximately 18% among
Raptiva treated patients compared with approximately 28% among placebo
treated patients.

Between baseline and week 12, Raptiva treated patients experienced
significantly greater improvement than placebo in health outcomes as
assessed by the Dermatology Life Quality Index (DLQI, Figure 1) (2), the
Psoriasis Symptom Assessment Frequency and Severity sub‑scales, and
Itch‑specific scales (all p \< 0.001). The improvement in DLQI for
RAPTIVA treated patients compared with placebo treated patients was
observed for all domains (Symptoms and Feelings, Daily Activities,
Leisure, Work and School, Personal Relationships, Treatment). For
Study 1, 70% of the DLQI improvement was observed by week 4 of
treatment.

**Figure 1\
**Mean Improvement in DLQI Versus Study Day during\
First 12 Weeks of Treatment in Study 1 (Mean ± SEM)^a^

![](media/image16.png){width="4.999305555555556in" height="3.575in"}

^a^ The mean improvement in DLQI overall score, baseline to Day 84, was
5.6 for RAPTIVA and 1.6 for placebo (p  \< 0.001; Wilcoxon rank‑sum test
of difference in DLQI change score, RAPTIVA vs. placebo).

There was a significantly greater improvement in the PASI score in the
Raptiva treated patients compared with placebo treated patients after
2 weeks of treatment, and there was continuous improvement over the
12‑week treatment period for the Raptiva treated patients (Figure 2). In
controlled trials of continuous RAPTIVA treatment greater than 12 weeks,
the percent of patients who have more than a 75% reduction in PASI
continues to increase.

**Figure 2**\
Percent PASI Improvement Versus Study Day during\
First 12 Weeks of Treatment in Study 1 (Mean ± SEM)

![](media/image17.png){width="4.998611111111111in"
height="3.6180555555555554in"}

After 12 weeks of treatment with 1 mg/kg, the median duration of
response (defined as maintenance of a 75% or greater reduction in PASI)
was approximately 55 days for RAPTIVA treated patients.

In an open‑label study of 290 patients treated with RAPTIVA who achieved
50% or greater reduction in PASI or an OLS rating of Clear, Minimal or
Mild after the first 12‑weeks of RAPTIVA treatment and were continuously
treated for one year (48 weeks), approximately 57% of patients achieved
a 75% or greater reduction in PASI. A controlled retreatment study
(Study 2) demonstrated that after a treatment interruption, patients
could restart RAPTIVA treatment and achieve improvements in PASI. In
Study 3, patients who reached a 75% or greater reduction in PASI after
12 weeks of RAPTIVA treatment with 1 mg/kg/wk or 2 mg/kg/wk maintained a
50% or greater reduction in PASI with an additional 12 weeks of
treatment at a dose of 2 mg/kg every other week.

INDICATIONS AND USAGE

RAPTIVA is indicated for the treatment of adult patients (18 years or
older) with moderate to severe plaque psoriasis.

CONTRAINDICATIONS

RAPTIVA should not be administered to patients with known
hypersensitivity to RAPTIVA or any of its components.

WARNINGS

None.

PRECAUTIONS

General

Abrupt discontinuation of RAPTIVA may be followed by worsening of
psoriasis or emergence of new psoriasis morphologies, including
erythrodermic and pustular psoriasis.

Immunosuppression

RAPTIVA has not been studied extensively in combination with
immunosuppressive agents in psoriasis patients and should be used
cautiously in this setting.

The possibility exists for any therapy that affects immune function,
including RAPTIVA, to affect host defenses against infections and
malignancies.

The role of RAPTIVA in the development and course of malignancies as
well as active and/or chronic infections is not fully understood (see
ADVERSE REACTIONS). The safety and efficacy of RAPTIVA in psoriasis
patients with pre‑existing immunosuppression or chronic infections have
not been evaluated.

Immunizations

The safety and efficacy of vaccines specifically live or live‑attenuated
vaccines, administered to patients being treated with RAPTIVA have not
been studied.

Information for Patients

If a patient or caregiver is to administer RAPTIVA, he/she should be
instructed regarding injection techniques and how to measure the correct
dose to ensure proper administration of RAPTIVA. A puncture‑resistant
container for disposal of needles and syringes should be used. Patients
and caregivers should be instructed regarding technique as well as
proper syringe and needle disposal and be cautioned against reuse of
these items (see Information for Patients and Caregivers).

Patients should be advised to inform their physician promptly if they
develop any signs of an infection or malignancy while undergoing
treatment with RAPTIVA.

Female patients should also be advised to notify their physicians if
they become pregnant while taking RAPTIVA.

Drug Interactions

There have been no formal drug interaction studies performed with
RAPTIVA. Caution should be employed when RAPTIVA is used with
immunosuppressive drugs (see PRECAUTIONS, Immunosuppression).

RAPTIVA has been used in combination with topical tar or corticosteroids
(Classes I to VII) and ultraviolet B in psoriasis patients. Concomitant
use of these treatments did not appear to affect safety.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long‑term animal studies have not been conducted to evaluate the
carcinogenic potential of RAPTIVA. No lymphomas were observed when mice
susceptible to develop lymphoma were treated for 6 months with an
anti‑mouse CD11a antibody; one lymphoma was observed in placebo treated
mice. This strain of mice was previously shown to develop lymphomas
during 6 months of cyclosporine treatment (3).

In a fertility and general reproduction study with an anti‑mouse CD11a
antibody, no adverse effects were noted on mating, fertility, or
reproduction parameters in male and female mice.

Mutagenicity studies were not conducted.

Pregnancy Category B

Women of childbearing potential make up a considerable segment of the
patient population affected by psoriasis. Since the effect of RAPTIVA on
pregnancy and fetal development (including immune system development) is
not known, RAPTIVA should be used during pregnancy only if clearly
needed.

Reproduction studies have not been conducted with RAPTIVA. It is not
known whether RAPTIVA can cause fetal harm when administered to a
pregnant woman or can affect reproduction capacity. In general,
immunoglobulins are known to cross the placental barrier; therefore,
RAPTIVA should be given to a pregnant woman only if clearly needed.

In a developmental toxicity study conducted in mice using an anti‑mouse
CD11a antibody, no evidence of maternal toxicity, embryotoxicity, or
teratogenicity was observed. No adverse effects on behavioral,
reproductive or growth parameters were observed in offspring of female
mice exposed to an anti‑mouse CD11a antibody during gestation and
lactation. At 11 weeks of age, the offspring had intact cell‑mediated
immunity and a reduction in the primary antibody response. At 25 weeks
of age, the offspring had a normal primary antibody response. Animal
studies, however, are not always predictive of human response and there
are no adequate and well‑controlled studies in pregnant women. Because
the risk to the development of the fetal immune system and postnatal
immune function in humans is unknown, RAPTIVA should be used during
pregnancy only if clearly needed. If pregnancy occurs while taking
RAPTIVA, continued use of the drug should be assessed.

Nursing Mothers

It is not known whether RAPTIVA is excreted in human milk. An anti‑mouse
CD11a antibody was detected in milk samples of exposed lactating mice.
Because many drugs are excreted in human milk, and because there exists
the potential for serious adverse reactions in nursing infants from
RAPTIVA, a decision should be made whether to discontinue nursing while
taking the drug or to discontinue the use of the drug, taking into
account the importance of the drug to the mother.

Geriatric Use

Of the 1620 patients who received RAPTIVA in controlled trials, 128 were
 ≥ 65 years of age, and 2 were  ≥ 75 years of age. No differences in
safety or efficacy were observed between older and younger patients, but
there were not sufficient data to exclude important differences. Because
the incidence of infections is higher in the elderly population, in
general, caution should be used in treating the elderly.

Pediatric Use

The safety and efficacy of RAPTIVA in pediatric patients have not been
studied. RAPTIVA is not indicated for pediatric patients.

ADVERSE REACTIONS

The most serious adverse reaction was:

-   Serious infections requiring hospitalization (see ADVERSE REACTIONS,
    Infections)

The most common adverse events associated with RAPTIVA exposure were a
symptom complex of mild to moderate headache, chills, fever, nausea or
myalgia within two days following the first two injections (Table 3). In
placebo‑controlled trials, 29% of patients treated with RAPTIVA 1 mg/kg
developed these symptoms following the first dose compared with 15% of
patients receiving placebo. Following the third and subsequent weekly
injections, only 4% and 3% of patients receiving RAPTIVA 1 mg/kg and
placebo, respectively, experienced these symptoms. Less than 1% of
patients discontinued RAPTIVA treatment because of these generally mild
to moderate adverse events.

+-----------------+----------------+----------------+----------------+
| **Table 3**\    |                |                |                |
| Adverse Events  |                |                |                |
| in Phase III    |                |                |                |
| Studies         |                |                |                |
| Reported at a   |                |                |                |
| Rate of at      |                |                |                |
| Least 5% in the |                |                |                |
| 1 mg/kg/wk,     |                |                |                |
| 2 mg/kg/wk      |                |                |                |
| RAPTIVA         |                |                |                |
| Treatment or    |                |                |                |
| Placebo‑treated |                |                |                |
| groups          |                |                |                |
+-----------------+----------------+----------------+----------------+
|                 | Placebo\       | RAPTIVA\       | RAPTIVA\       |
|                 | (n = 715)      | 1 mg/kg/wk\    | 2 mg/kg/wk\    |
|                 |                | (n = 1213)     | (n = 407)      |
+-----------------+----------------+----------------+----------------+
| Headache ^a^    | 159 (22%)      | 391 (32%)      | 151 (37%)      |
+-----------------+----------------+----------------+----------------+
| Infection ^b^   | 188 (26%)      | 350 (29%)      | 114 (28%)      |
+-----------------+----------------+----------------+----------------+
| Chills ^a^      | 32 (4%)        | 154 (13%)      | 53 (13%)       |
+-----------------+----------------+----------------+----------------+
| Nausea ^a^      | 51 (7%)        | 128 (11%)      | 56 (14%)       |
+-----------------+----------------+----------------+----------------+
| Pain            | 38 (5%)        | 122 (10%)      | 45 (11%)       |
+-----------------+----------------+----------------+----------------+
| Myalgia ^a^     | 35 (5%)        | 102 (8%)       | 32 (8%)        |
+-----------------+----------------+----------------+----------------+
| Pharyngitis     | 47 (7%)        | 88 (7%)        | 31 (8%)        |
+-----------------+----------------+----------------+----------------+
| Flu Syndrome    | 29 (4%)        | 83 (7%)        | 19 (5%)        |
+-----------------+----------------+----------------+----------------+
| Asthenia        | 37 (5%)        | 81 (7%)        | 38 (9%)        |
+-----------------+----------------+----------------+----------------+
| Rhinitis        | 46 (6%)        | 81 (7%)        | 17 (4%)        |
+-----------------+----------------+----------------+----------------+
| Fever ^a^       | 24 (3%)        | 80 (7%)        | 46 (11%)       |
+-----------------+----------------+----------------+----------------+
| Diarrhea        | 48 (7%)        | 72 (6%)        | 30 (7%)        |
+-----------------+----------------+----------------+----------------+
| Accidental      | 45 (6%)        | 68 (6%)        | 27 (7%)        |
| Injury          |                |                |                |
+-----------------+----------------+----------------+----------------+
| Sinusitis       | 34 (5%)        | 63 (5%)        | 14 (3%)        |
+-----------------+----------------+----------------+----------------+
| Back Pain       | 14 (2%)        | 50 (4%)        | 25 (6%)        |
+-----------------+----------------+----------------+----------------+
| ^a^ These       |                |                |                |
| events were     |                |                |                |
| mostly mild to  |                |                |                |
| moderate and    |                |                |                |
| usually         |                |                |                |
| occurred within |                |                |                |
| 48 hours of     |                |                |                |
| first two       |                |                |                |
| RAPTIVA         |                |                |                |
| injections.     |                |                |                |
|                 |                |                |                |
| ^b^ Includes    |                |                |                |
| diagnosed       |                |                |                |
| infections and  |                |                |                |
| other           |                |                |                |
| non‑specific    |                |                |                |
| infections.     |                |                |                |
| Most common     |                |                |                |
| non‑specific    |                |                |                |
| infection was   |                |                |                |
| upper           |                |                |                |
| respiratory     |                |                |                |
| infection.      |                |                |                |
+-----------------+----------------+----------------+----------------+

The proportion of patients who discontinued treatment due to non‑serious
adverse events during the placebo‑controlled portion of the Phase III
studies was 2.8% for patients taking RAPTIVA and 1.8% for placebo
treated patients. The most common non‑serious adverse events resulting
in discontinuation of RAPTIVA treatment were headache (0.6%), psoriasis
(0.6%), pain (0.4%), arthritis (0.4%) and arthralgia (0.3%).

Adverse events experienced during a second RAPTIVA treatment course were
similar to those observed during a first 12‑week course, with the
exception of fewer acute adverse reactions.

No new common adverse events emerged when RAPTIVA treatment was extended
up to 60 weeks.

Because clinical trials are conducted under widely varying conditions,
adverse reaction rates observed in the clinical trials of a drug cannot
be directly compared with rates in the clinical trials of another drug
and may not reflect the rates observed in practice. The adverse reaction
information from clinical trials does, however, provide a basis for
identifying the adverse events that appear to be related to drug use and
for approximating rates.

The data described below reflect exposure to RAPTIVA in a total of
2762 psoriasis patients in 13 studies of RAPTIVA. Approximately
2400 patients received RAPTIVA weekly for 12 weeks of continuous
treatment, 904 for 24 weeks of continuous treatment, and 218 for 1 year
of continuous treatment. Approximately 340 received two separate 12‑week
courses of RAPTIVA. Approximately 2335 psoriasis patients were studied
in Phase III, placebo‑controlled, double‑blind, randomized trials. The
population ranged in age from 18 to 75 years and included 67% men and
33% women. The patients were mostly Caucasian (89%), reflecting the
general psoriatic population. Disease severity at baseline was moderate
to severe psoriasis.

Malignancies

The overall incidence of malignancies was 1.7 per 100 patient‑years for
RAPTIVA treated patients compared with 1.6 per 100 patient‑years for
placebo treated patients.

Among the 2762 psoriasis patients who received RAPTIVA at any dose,
30 patients were diagnosed with 36 malignancies during RAPTIVA
treatment. The majority of these malignancies (26 cases in 20 patients,
0.7% of 2762 patients) were basal (13 cases) and squamous (13 cases)
cell cancers of the skin. The incidence of basal and squamous cell skin
cancers was comparable for RAPTIVA‑treated patients and those receiving
placebo. Eight solid tumor malignancies were observed. One lymphoma
diagnosed as Hodgkin's lymphoma and one malignant melanoma were also
observed. The incidence of non‑cutaneous solid tumors,
lymphoproliferative disorders, and malignant melanoma were within the
range expected for the general population.

Infections

The overall incidence of hospitalized infections was 1.6 per
100 patient‑years for RAPTIVA treated patients compared with 1.1 per
100 patient‑years for placebo treated patients. Twenty‑seven of
2475 RAPTIVA treated patients had infections leading to hospital
admission. These infections included cellulitis, pneumonia, abscess,
sepsis, bronchitis, gastroenteritis, aseptic meningitis, Legionnaire's
disease, and vertebral osteomyelitis. The observed number of infections
resulting in hospitalization was within the expected range for this
patient population. There were no deaths due to infection. Less than
1% of patients treated with RAPTIVA discontinued treatment because of an
infection.

Hypersensitivity Reactions

No episodes of anaphylaxis occurred in clinical trials of RAPTIVA.
Urticaria was observed in less than 1% of patients receiving placebo and
approximately 1% of patients receiving RAPTIVA during the initial
12‑week treatment period. For those patients who were rechallenged it
was without incident, so relationship to treatment is not evident. Other
adverse events possibly indicative of hypersensitivity included:
bronchiolitis obliterans, laryngospasm, angioedema, erythema multiforme,
asthma, allergic drug eruption and possible serum sickness.

Immunogenicity

Patients were tested for antibodies to RAPTIVA at multiple timepoints
during and after treatment. After RAPTIVA treatment ended, predominantly
low‑titer antibodies to RAPTIVA or other protein components of the
RAPTIVA drug product were detected in 6.3% (67/1063) of RAPTIVA treated
patients. There were no significant differences in pharmacokinetics,
pharmacodynamics, clinically important adverse events or clinical
response between antibody‑positive and antibody‑negative patients. The
long‑term immunogenicity of RAPTIVA is unknown.

The data reflect the percentage of patients whose test results were
considered positive for antibodies to RAPTIVA in the ELISA assay, and
are highly dependent on the sensitivity and specificity of the assay.
Additionally, the observed incidence of antibody positivity in an assay
may be influenced by several factors including sample handling, timing
of sample collection, concomitant medications, and underlying disease.
For these reasons, comparison of the incidence of antibodies to RAPTIVA
with the incidence of antibodies to other products may be misleading.

Other Observed Adverse Reactions from Clinical Trials

Less common events that were observed at a higher rate in RAPTIVA
treated patients include thrombocytopenia, arthritis, and new forms of
psoriasis including erythrodermic and pustular psoriasis.

OVERDOSAGE

Doses up to 4 mg/kg/wk SC for 10 weeks have been administered without
any toxic effect. The maximum administered single dose was 10 mg/kg IV.
This was administered to one patient, who subsequently was admitted to
the hospital for severe vomiting. In case of overdosage, it is
recommended that the patient be monitored for any signs or symptoms of
adverse reactions or effects and appropriate symptomatic treatment
instituted immediately.

DOSAGE AND ADMINISTRATION

Usual Dose

The recommended dose of RAPTIVA is a single 0.7 mg/kg SC conditioning
dose followed by weekly SC doses of 1 mg/kg (maximum single dose not to
exceed a total of 200 mg).

RAPTIVA is intended for use under the guidance and supervision of a
physician. Patients may self‑inject RAPTIVA if their physician
determines that it is appropriate and with medical follow‑up, as
necessary, after proper training of injection technique.

Preparation for Administration

RAPTIVA should be administered using the sterile, disposable syringe and
needles provided (see How Supplied section). Remove the cap from the
pre‑filled syringe containing Sterile Water for Injection for
Reconstitution. Attach needle to syringe. Before needle insertion,
remove the plastic cap protecting the rubber stopper of the RAPTIVA
vial. Do not touch the top of the vial. To prepare the RAPTIVA solution,
slowly inject the 1.3 mL of Sterile Water for Injection for
Reconstitution in the provided pre‑filled syringe into the RAPTIVA vial.
Swirl the product vial with a GENTLE rotary motion. DO NOT SHAKE.
Shaking will cause foaming of the RAPTIVA solution. Generally,
dissolution of RAPTIVA takes less than 5 minutes. The reconstituted
solution should be clear to pale yellow. Because RAPTIVA contains no
antibacterial preservatives it should be reconstituted immediately
before use and used once only. If the reconstituted RAPTIVA is not used
immediately, store the RAPTIVA vial at room temperature and use within
8 hours.

Administration

The solution in the vial should be carefully inspected visually for
particulate matter and discoloration prior to subcutaneous
administration. If particulates and discolorations are noted, the
product should not be used.

Replace the needle on the syringe with a new needle. Insert the needle
into the vial containing the RAPTIVA solution, invert the vial and,
taking care to keep the needle below the level of the liquid, withdraw
the solution into the syringe, removing from the vial only the dose to
be given.

No other medications should be added to solutions containing RAPTIVA,
and RAPTIVA should not be reconstituted with other diluents.

Sites for injection include thigh, abdomen, buttocks or upper arm.
Injection sites should be rotated.

Following administration, discard any unused reconstituted RAPTIVA
solution.

Stability and Storage

Do not use a vial beyond the expiration date stamped on the carton or
vial label. RAPTIVA (lyophilized powder) must be refrigerated at
2−8°C (36−46°F). Protect the vial from exposure to light. Store in
original carton until time of use.

HOW SUPPLIED

RAPTIVA is supplied as a lyophilized, sterile powder, designed to
deliver 125 mg of efalizumab per vial.

Each RAPTIVA carton contains four trays. Each tray contains one
125 mg vial of RAPTIVA, one 1.3 mL pre‑filled syringe containing Sterile
Water for Injection for Reconstitution, two alcohol prep pads, and two
25  × 5/8\" needles. Carton NDC 50242‑058‑04.

REFERENCES

Werther WA, Gonzalez TN, O\'Connor SJ, McCabe S, Chan B, Hotaling T, et
al. Humanization of an anti‑lymphocyte function‑associated antigen
(LFA)‑1 monoclonal antibody and reengineering of the humanized antibody
for binding to rhesus LFA‑1. J Immunol 1996;157:4986--95.

Finlay AY, Kahn GK. Dermatology Life Quality Index (DLQI)---a simple
practical measure for routine clinical use. Clin Exp Dermatol
1994;19:210--6.

Storer RD, French JE, Haseman J, Hajian G, LeGrand EK, Long GG, et al.
P53^+/‑^ hemizygous knockout mouse: overview of available data.
Toxicologic Pathology 2001;29(Suppl):30−50.

  ------------------------------------ ----------------------------------
  **RAPTIVA \[Efalizumab\]**          

  Manufactured by:\                    4826400 (974)\
  **Genentech, Inc.\                   FDA Approval Date (Month) (Year)\
  **1 DNA Way\                         ^^2003 Genentech, Inc.
  South San Francisco, CA 94080‑4990   
  ------------------------------------ ----------------------------------

APPENDIX B

Psoriasis Area and Severity Index

Evaluator Requirements

-   The evaluator must be a dermatologist or experienced physician.

-   The evaluator must have attended the Investigator Meeting or have
    been trained by someone who attended the Investigator Meeting.

-   The same evaluator must determine all PASIs for any individual
    subject throughout the trial.

A backup evaluator is only allowed in case of emergency or special
situation when the designated evaluator is unable to perform the
evaluation. The backup evaluator must be a dermatologist or an
experienced physician and have attended the Investigator meeting or have
been trained by someone who attended the Investigator meeting.

General Instructions

1.  For each area of the body, rate erythema, scaling, and thickness for
    the **average** plaque or the overall condition of plaques in that
    region.

2.  Rate plaques as they are actually seen on the day of examination. Do
    not rate in comparison with baseline condition.

PASI Scoring

PASI scores can range from 0 to 72. Dermatologic disease severity is to
be scored as follows:

Body Areas

Four main body areas will be assessed, the head (h), the trunk (t), the
upper extremities (u), and the lower extremities (l) corresponding to
10%, 30%, 20%, and 40% of the total body surface area (BSA),
respectively.

APPENDIX B (cont'd)

Psoriasis Area and Severity Index

The area of psoriatic involvement for each body area (Ah, At, Au, Al)
will be assigned a numerical value according to degree of involvement as
follows:

0 = no involvement\
1 = \<10% involvement\
2 = 10% to \<30% involvement\
3 = 30% to \<50% involvement\
4 = 50% to \<70% involvement\
5 = 70% to \<90% involvement\
6 = 90% to 100% involvement

Conventions for estimating BSA include the following:

Include only currently active disease in affected area:

For small, scattered lesions do not include the skin between the lesions
in the estimate;

For a centrally cleared plaque, count only area of inflamed outer ring;

Do not include residual hyperpigmentation, hypopigmentation, pigmented
macules, or diffuse slight pink coloration

-   Assignments for the following body segments are:

Neck: include with the head\
Buttocks: include with the lower extremities\
Axillae: include with trunk\
Genitals: include with the trunk\
Separation of trunk and lower extremities: the inguinal canal separates
the trunk and legs anteriorly

Psoriatic Lesion Signs

In addition, the severity of the psoriatic lesions in three main
signs---erythema (E), thickness (T), and scaling (S)---will be assessed
for each body area according to a scale (0--4) in which 0 represents a
complete lack of cutaneous involvement and 4 represents the most severe
possible involvement.

APPENDIX B (cont'd)

Psoriasis Area and Severity Index

  -------------------- ---------------- --------------------- --------------------
                       Erythema ^a^     Scaling               Thickness

  0=none               No redness       No scaling            No elevation over
                                                              normal skin

  1=slight             Faint redness    Fine scale partially  Slight but definite
                                        covering lesions      elevation, typically
                                                              edges indistinct or
                                                              sloped

  2=moderate           Red coloration   Fine to coarse scale  Moderate elevation
                                        covering most of all  with rough or sloped
                                        of the lesions        edges

  3=severe             Very or bright   Coarse, non‑tenacious Marked elevation
                       red coloration   scale predominates    typically with hard
                                        covering most or all  or sharp edges
                                        of the lesions        

  4=very severe        Extreme red      Coarse, thick,        Very marked
                       coloration;      tenacious scale over  elevation typically
                       dusky to deep    most or all lesions;  with hard sharp
                       red coloration   rough surface         edges

  ^a^ Do not include                                          
  residual                                                    
  hyperpigmentation,                                          
  hypopigmentation,                                           
  pigmented macules,                                          
  or diffuse slight                                           
  pink coloration as                                          
  erythema.                                                   
  -------------------- ---------------- --------------------- --------------------

APPENDIX B (cont'd)

Psoriasis Area and Severity Index

Calculating PASI

To calculate the PASI, the sum of the severity rating for the three main
signs will be multiplied with the numerical value of the area affected
and with the various percentages of the four body areas. These values
will then be added to complete the formula as follows:

  -------- --------------------------------------------------------------
  PASI =   0.1 (Eh + Th + Sh) Ah + 0.3 (Et + Tt + St) At +\
           0.2 (Eu + Tu + Su) Au + 0.4 (El + Tl + Sl) Al

  -------- --------------------------------------------------------------

+---+-----------------+----------+-----------+---+-----------+-----------+---+---+
| R |                 | Head     | Trunk     |   | Upper     | Lower     |   |   |
| o |                 |          |           |   | Limbs     | Limbs     |   |   |
| w |                 |          |           |   |           |           |   |   |
+---+-----------------+----------+-----------+---+-----------+-----------+---+---+
| 1 | Erythema ^a^    |          |           |   |           |           |   |   |
+---+-----------------+----------+-----------+---+-----------+-----------+---+---+
| 2 | Thickness ^a^   |          |           |   |           |           |   |   |
+---+-----------------+----------+-----------+---+-----------+-----------+---+---+
| 3 | Scaling ^a^     |          |           |   |           |           |   |   |
+---+-----------------+----------+-----------+---+-----------+-----------+---+---+
| 4 | Total each      |          |           |   |           |           |   |   |
|   | column          |          |           |   |           |           |   |   |
+---+-----------------+----------+-----------+---+-----------+-----------+---+---+
| 5 | Degree of       |          |           |   |           |           |   |   |
|   | involvement ^b^ |          |           |   |           |           |   |   |
+---+-----------------+----------+-----------+---+-----------+-----------+---+---+
| 6 | Multiply Row 4  |          |           |   |           |           |   |   |
|   | by Row 5        |          |           |   |           |           |   |   |
+---+-----------------+----------+-----------+---+-----------+-----------+---+---+
| 7 |                 | × 0.10   | × 0.30    |   | × 0.20    | × 0.40    |   |   |
+---+-----------------+----------+-----------+---+-----------+-----------+---+---+
| 8 | Multiply Row 6  |          |           |   |           |           |   |   |
|   | by Row 7        |          |           |   |           |           |   |   |
+---+-----------------+----------+-----------+---+-----------+-----------+---+---+
| 9 | Total PASI (add |          |           |   |           |           |   |   |
|   | together each   |          |           |   |           |           |   |   |
|   | column from Row |          |           |   |           |           |   |   |
|   | 8)              |          |           |   |           |           |   |   |
+---+-----------------+----------+-----------+---+-----------+-----------+---+---+
| > |                 |          |           |   |           |           |   |   |
|   |                 |          |           |   |           |           |   |   |
| ^ |                 |          |           |   |           |           |   |   |
| a |                 |          |           |   |           |           |   |   |
| ^ |                 |          |           |   |           |           |   |   |
| > |                 |          |           |   |           |           |   |   |
|   |                 |          |           |   |           |           |   |   |
| R |                 |          |           |   |           |           |   |   |
| a |                 |          |           |   |           |           |   |   |
| n |                 |          |           |   |           |           |   |   |
| k |                 |          |           |   |           |           |   |   |
| > |                 |          |           |   |           |           |   |   |
|   |                 |          |           |   |           |           |   |   |
| s |                 |          |           |   |           |           |   |   |
| e |                 |          |           |   |           |           |   |   |
| v |                 |          |           |   |           |           |   |   |
| e |                 |          |           |   |           |           |   |   |
| r |                 |          |           |   |           |           |   |   |
| i |                 |          |           |   |           |           |   |   |
| t |                 |          |           |   |           |           |   |   |
| y |                 |          |           |   |           |           |   |   |
| > |                 |          |           |   |           |           |   |   |
|   |                 |          |           |   |           |           |   |   |
| o |                 |          |           |   |           |           |   |   |
| f |                 |          |           |   |           |           |   |   |
| > |                 |          |           |   |           |           |   |   |
|   |                 |          |           |   |           |           |   |   |
| p |                 |          |           |   |           |           |   |   |
| s |                 |          |           |   |           |           |   |   |
| o |                 |          |           |   |           |           |   |   |
| r |                 |          |           |   |           |           |   |   |
| i |                 |          |           |   |           |           |   |   |
| a |                 |          |           |   |           |           |   |   |
| t |                 |          |           |   |           |           |   |   |
| i |                 |          |           |   |           |           |   |   |
| c |                 |          |           |   |           |           |   |   |
| > |                 |          |           |   |           |           |   |   |
|   |                 |          |           |   |           |           |   |   |
| l |                 |          |           |   |           |           |   |   |
| e |                 |          |           |   |           |           |   |   |
| s |                 |          |           |   |           |           |   |   |
| i |                 |          |           |   |           |           |   |   |
| o |                 |          |           |   |           |           |   |   |
| n |                 |          |           |   |           |           |   |   |
| s |                 |          |           |   |           |           |   |   |
| : |                 |          |           |   |           |           |   |   |
| > |                 |          |           |   |           |           |   |   |
|   |                 |          |           |   |           |           |   |   |
| 0 |                 |          |           |   |           |           |   |   |
| = |                 |          |           |   |           |           |   |   |
| n |                 |          |           |   |           |           |   |   |
| o |                 |          |           |   |           |           |   |   |
| n |                 |          |           |   |           |           |   |   |
| e |                 |          |           |   |           |           |   |   |
| , |                 |          |           |   |           |           |   |   |
| > |                 |          |           |   |           |           |   |   |
|   |                 |          |           |   |           |           |   |   |
| 1 |                 |          |           |   |           |           |   |   |
| = |                 |          |           |   |           |           |   |   |
| s |                 |          |           |   |           |           |   |   |
| l |                 |          |           |   |           |           |   |   |
| i |                 |          |           |   |           |           |   |   |
| g |                 |          |           |   |           |           |   |   |
| h |                 |          |           |   |           |           |   |   |
| t |                 |          |           |   |           |           |   |   |
| , |                 |          |           |   |           |           |   |   |
| > |                 |          |           |   |           |           |   |   |
|   |                 |          |           |   |           |           |   |   |
| 2 |                 |          |           |   |           |           |   |   |
| = |                 |          |           |   |           |           |   |   |
| m |                 |          |           |   |           |           |   |   |
| o |                 |          |           |   |           |           |   |   |
| d |                 |          |           |   |           |           |   |   |
| e |                 |          |           |   |           |           |   |   |
| r |                 |          |           |   |           |           |   |   |
| a |                 |          |           |   |           |           |   |   |
| t |                 |          |           |   |           |           |   |   |
| e |                 |          |           |   |           |           |   |   |
| , |                 |          |           |   |           |           |   |   |
| > |                 |          |           |   |           |           |   |   |
|   |                 |          |           |   |           |           |   |   |
| 3 |                 |          |           |   |           |           |   |   |
| = |                 |          |           |   |           |           |   |   |
| s |                 |          |           |   |           |           |   |   |
| e |                 |          |           |   |           |           |   |   |
| v |                 |          |           |   |           |           |   |   |
| e |                 |          |           |   |           |           |   |   |
| r |                 |          |           |   |           |           |   |   |
| e |                 |          |           |   |           |           |   |   |
| , |                 |          |           |   |           |           |   |   |
| > |                 |          |           |   |           |           |   |   |
|   |                 |          |           |   |           |           |   |   |
| 4 |                 |          |           |   |           |           |   |   |
| = |                 |          |           |   |           |           |   |   |
| v |                 |          |           |   |           |           |   |   |
| e |                 |          |           |   |           |           |   |   |
| r |                 |          |           |   |           |           |   |   |
| y |                 |          |           |   |           |           |   |   |
| > |                 |          |           |   |           |           |   |   |
|   |                 |          |           |   |           |           |   |   |
| s |                 |          |           |   |           |           |   |   |
| e |                 |          |           |   |           |           |   |   |
| v |                 |          |           |   |           |           |   |   |
| e |                 |          |           |   |           |           |   |   |
| r |                 |          |           |   |           |           |   |   |
| e |                 |          |           |   |           |           |   |   |
| . |                 |          |           |   |           |           |   |   |
| > |                 |          |           |   |           |           |   |   |
| > |                 |          |           |   |           |           |   |   |
|   |                 |          |           |   |           |           |   |   |
| ^ |                 |          |           |   |           |           |   |   |
| b |                 |          |           |   |           |           |   |   |
| ^ |                 |          |           |   |           |           |   |   |
| > |                 |          |           |   |           |           |   |   |
|   |                 |          |           |   |           |           |   |   |
| R |                 |          |           |   |           |           |   |   |
| a |                 |          |           |   |           |           |   |   |
| n |                 |          |           |   |           |           |   |   |
| k |                 |          |           |   |           |           |   |   |
| > |                 |          |           |   |           |           |   |   |
|   |                 |          |           |   |           |           |   |   |
| a |                 |          |           |   |           |           |   |   |
| r |                 |          |           |   |           |           |   |   |
| e |                 |          |           |   |           |           |   |   |
| a |                 |          |           |   |           |           |   |   |
| > |                 |          |           |   |           |           |   |   |
|   |                 |          |           |   |           |           |   |   |
| o |                 |          |           |   |           |           |   |   |
| f |                 |          |           |   |           |           |   |   |
| > |                 |          |           |   |           |           |   |   |
|   |                 |          |           |   |           |           |   |   |
| p |                 |          |           |   |           |           |   |   |
| s |                 |          |           |   |           |           |   |   |
| o |                 |          |           |   |           |           |   |   |
| r |                 |          |           |   |           |           |   |   |
| i |                 |          |           |   |           |           |   |   |
| a |                 |          |           |   |           |           |   |   |
| t |                 |          |           |   |           |           |   |   |
| i |                 |          |           |   |           |           |   |   |
| c |                 |          |           |   |           |           |   |   |
| > |                 |          |           |   |           |           |   |   |
|   |                 |          |           |   |           |           |   |   |
| i |                 |          |           |   |           |           |   |   |
| n |                 |          |           |   |           |           |   |   |
| v |                 |          |           |   |           |           |   |   |
| o |                 |          |           |   |           |           |   |   |
| l |                 |          |           |   |           |           |   |   |
| v |                 |          |           |   |           |           |   |   |
| e |                 |          |           |   |           |           |   |   |
| m |                 |          |           |   |           |           |   |   |
| e |                 |          |           |   |           |           |   |   |
| n |                 |          |           |   |           |           |   |   |
| t |                 |          |           |   |           |           |   |   |
| : |                 |          |           |   |           |           |   |   |
| > |                 |          |           |   |           |           |   |   |
|   |                 |          |           |   |           |           |   |   |
| 0 |                 |          |           |   |           |           |   |   |
| = |                 |          |           |   |           |           |   |   |
| n |                 |          |           |   |           |           |   |   |
| o |                 |          |           |   |           |           |   |   |
| n |                 |          |           |   |           |           |   |   |
| e |                 |          |           |   |           |           |   |   |
| , |                 |          |           |   |           |           |   |   |
| > |                 |          |           |   |           |           |   |   |
|   |                 |          |           |   |           |           |   |   |
| 1 |                 |          |           |   |           |           |   |   |
| = |                 |          |           |   |           |           |   |   |
| > |                 |          |           |   |           |           |   |   |
|   |                 |          |           |   |           |           |   |   |
| \ |                 |          |           |   |           |           |   |   |
| < |                 |          |           |   |           |           |   |   |
| 1 |                 |          |           |   |           |           |   |   |
| 0 |                 |          |           |   |           |           |   |   |
| % |                 |          |           |   |           |           |   |   |
| , |                 |          |           |   |           |           |   |   |
| > |                 |          |           |   |           |           |   |   |
|   |                 |          |           |   |           |           |   |   |
| 2 |                 |          |           |   |           |           |   |   |
| = |                 |          |           |   |           |           |   |   |
| 1 |                 |          |           |   |           |           |   |   |
| 0 |                 |          |           |   |           |           |   |   |
| % |                 |          |           |   |           |           |   |   |
| > |                 |          |           |   |           |           |   |   |
|   |                 |          |           |   |           |           |   |   |
| t |                 |          |           |   |           |           |   |   |
| o |                 |          |           |   |           |           |   |   |
| > |                 |          |           |   |           |           |   |   |
|   |                 |          |           |   |           |           |   |   |
| \ |                 |          |           |   |           |           |   |   |
| < |                 |          |           |   |           |           |   |   |
| 3 |                 |          |           |   |           |           |   |   |
| 0 |                 |          |           |   |           |           |   |   |
| % |                 |          |           |   |           |           |   |   |
| , |                 |          |           |   |           |           |   |   |
| > |                 |          |           |   |           |           |   |   |
|   |                 |          |           |   |           |           |   |   |
| 3 |                 |          |           |   |           |           |   |   |
| = |                 |          |           |   |           |           |   |   |
| 3 |                 |          |           |   |           |           |   |   |
| 0 |                 |          |           |   |           |           |   |   |
| % |                 |          |           |   |           |           |   |   |
| > |                 |          |           |   |           |           |   |   |
|   |                 |          |           |   |           |           |   |   |
| t |                 |          |           |   |           |           |   |   |
| o |                 |          |           |   |           |           |   |   |
| > |                 |          |           |   |           |           |   |   |
|   |                 |          |           |   |           |           |   |   |
| \ |                 |          |           |   |           |           |   |   |
| < |                 |          |           |   |           |           |   |   |
| 5 |                 |          |           |   |           |           |   |   |
| 0 |                 |          |           |   |           |           |   |   |
| % |                 |          |           |   |           |           |   |   |
| , |                 |          |           |   |           |           |   |   |
| \ |                 |          |           |   |           |           |   |   |
| > |                 |          |           |   |           |           |   |   |
|   |                 |          |           |   |           |           |   |   |
| 4 |                 |          |           |   |           |           |   |   |
| = |                 |          |           |   |           |           |   |   |
| 5 |                 |          |           |   |           |           |   |   |
| 0 |                 |          |           |   |           |           |   |   |
| % |                 |          |           |   |           |           |   |   |
| > |                 |          |           |   |           |           |   |   |
|   |                 |          |           |   |           |           |   |   |
| t |                 |          |           |   |           |           |   |   |
| o |                 |          |           |   |           |           |   |   |
| > |                 |          |           |   |           |           |   |   |
|   |                 |          |           |   |           |           |   |   |
| \ |                 |          |           |   |           |           |   |   |
| < |                 |          |           |   |           |           |   |   |
| 7 |                 |          |           |   |           |           |   |   |
| 0 |                 |          |           |   |           |           |   |   |
| % |                 |          |           |   |           |           |   |   |
| , |                 |          |           |   |           |           |   |   |
| > |                 |          |           |   |           |           |   |   |
|   |                 |          |           |   |           |           |   |   |
| 5 |                 |          |           |   |           |           |   |   |
| = |                 |          |           |   |           |           |   |   |
| 7 |                 |          |           |   |           |           |   |   |
| 0 |                 |          |           |   |           |           |   |   |
| % |                 |          |           |   |           |           |   |   |
| > |                 |          |           |   |           |           |   |   |
|   |                 |          |           |   |           |           |   |   |
| t |                 |          |           |   |           |           |   |   |
| o |                 |          |           |   |           |           |   |   |
| > |                 |          |           |   |           |           |   |   |
|   |                 |          |           |   |           |           |   |   |
| \ |                 |          |           |   |           |           |   |   |
| < |                 |          |           |   |           |           |   |   |
| 9 |                 |          |           |   |           |           |   |   |
| 0 |                 |          |           |   |           |           |   |   |
| % |                 |          |           |   |           |           |   |   |
| , |                 |          |           |   |           |           |   |   |
| > |                 |          |           |   |           |           |   |   |
|   |                 |          |           |   |           |           |   |   |
| 6 |                 |          |           |   |           |           |   |   |
| = |                 |          |           |   |           |           |   |   |
| 9 |                 |          |           |   |           |           |   |   |
| 0 |                 |          |           |   |           |           |   |   |
| % |                 |          |           |   |           |           |   |   |
| > |                 |          |           |   |           |           |   |   |
|   |                 |          |           |   |           |           |   |   |
| t |                 |          |           |   |           |           |   |   |
| o |                 |          |           |   |           |           |   |   |
| > |                 |          |           |   |           |           |   |   |
|   |                 |          |           |   |           |           |   |   |
| 1 |                 |          |           |   |           |           |   |   |
| 0 |                 |          |           |   |           |           |   |   |
| 0 |                 |          |           |   |           |           |   |   |
| % |                 |          |           |   |           |           |   |   |
| . |                 |          |           |   |           |           |   |   |
+---+-----------------+----------+-----------+---+-----------+-----------+---+---+

APPENDIX C

Physicians Global Assessment

(Formerly known as the Overall Lesion Severity Scale)

The degree of overall lesion severity will be evaluated using the
following categories:

  ----------------- ----------- --------------------------------------------------
  Score             Category    Category Description

  0                 Clear       Plaque elevation = 0 (no elevation over normal
                                skin)\
                                Scaling = 0 (no scale)\
                                Erythema = ± (hyperpigmentation, pigmented
                                macules, diffuse faint pink or red coloration)

  1                 Minimal     Plaque elevation = ± (possible but difficult to
                                ascertain whether there is a slight elevation
                                above normal skin)\
                                Scaling = ± (surface dryness with some white
                                coloration)\
                                Erythema = up to moderate (up to definite red
                                coloration)

  2                 Mild        Plaque elevation = slight (slight but definite
                                elevation, typically edges are indistinct or
                                sloped)\
                                Scaling = fine (fine scale partially or mostly
                                covering lesions)\
                                Erythema = up to moderate (up to definite red
                                coloration)

  3                 Moderate    Plaque elevation = moderate (moderate elevation
                                with rough or sloped edges)\
                                Scaling = coarser (coarse scale covering most of
                                all of the lesions)\
                                Erythema = moderate (definite red coloration)

  4                 Severe      Plaque elevation = marked (marked elevation
                                typically with hard or sharp edges)\
                                Scaling = coarse (coarse, non‑tenacious scale
                                predominates covering most or all of the lesions)\
                                Erythema = severe (very bright red coloration)

  5                 Very severe Plaque elevation = very marked (very marked
                                elevation typically with hard sharp edges)\
                                Scaling = very coarse (coarse, thick tenacious
                                scale over most of all of the lesions; rough
                                surface)\
                                Erythema = very severe (extreme red coloration;
                                dusky to deep red coloration)

  Note: Presented               
  by Hon‑Sum Ko,                
  M.D., Medical                 
  Officer, Division             
  of Dermatologic               
  and Dental Drug               
  Products, Center              
  for Drug                      
  Evaluation and                
  Research, Food                
  and Drug                      
  Administration.               
  Bethesda (MD):                
  Dermatologic and              
  Ophthalmic                    
  Advisory                      
  Committee 49th                
  Meeting; 20 March             
  1998.                         
  ----------------- ----------- --------------------------------------------------

APPENDIX C (cont'd)

Physicians Global Assessment

(Formerly known as the Overall Lesion Severity Scale)

The PGA score should be selected using the descriptors that best
describe the overall appearance of the lesions. It is not necessary that
all three criteria be fulfilled. In some subjects either scale or
erythema will dominate the clinical presentation. In those cases, the
PGA score should be based on a combination of plaque elevation and the
dominant feature (either erythema or scale). Because plaque elevation is
the most robust finding, it should be the dominant feature influencing
the PGA rating for indeterminant cases.

Evaluator Requirements

The evaluator must be a dermatologist or an experienced physician.

The evaluator must have attended the Investigator meeting or have been
trained by someone who attended the Investigator meeting.

The same evaluator should determine all PGA ratings for any individual
subject throughout the trial.

A backup evaluator is only allowed in case of emergency or special
situation when the designated evaluator is unable to perform the
evaluation. The backup evaluator must be a dermatologist or experienced
physician and have attended the Investigator meeting or have been
trained by someone who attended the Investigator meeting.

APPENDIX D

Physician's Global Assessment of Change

The global response of all psoriatic lesions to therapy compared with
the baseline condition using Day 0 photographs will be evaluated using
the following categories:

  ------------ ------------- ----------------------------------------------
  Category     Percent       Category Description
               Improvement   

  Cleared      100%          Remission of all clinical signs and symptoms
                             compared with baseline, except for residual
                             manifestations such as mild erythema

  Excellent    75%--99%      Improvement of all clinical signs and symptoms
                             compared with baseline, except for residual
                             manifestations such as mild erythema

  Good         50%--74%      Improvement of all clinical signs and symptoms
                             compared with baseline

  Fair         25%--49%      Improvement of all clinical signs and symptoms
                             compared with baseline

  Slight       1%--24%       Improvement of all clinical signs and symptoms
                             compared with baseline

  Unchanged                  Clinical signs and symptoms unchanged from
                             baseline

  Worse                      Clinical signs and symptoms deteriorated from
                             baseline
  ------------ ------------- ----------------------------------------------

Instructions

-   All ratings must be determined using the FT Day 0 medical
    photographs for comparison.

-   The evaluator must be a dermatologist or experienced physician.

-   The evaluator must have attended the Investigator Meeting or been
    trained by someone who attended the Investigator Meeting.

-   The same evaluator must perform all determinations of PGAs for any
    individual subject throughout the study.

-   The PGA score should, at minimum, include and reflect a global
    consideration of erythema, scaling, plaque thickness, and percentage
    of total body surface area affected by psoriasis.

APPENDIX D (cont'd)

Physician's Global Assessment of Change

Instructions (cont'd)

-   The same evaluator should perform all determinations of PGA for any
    individual subject throughout the study.

A backup evaluator is only allowed in case of emergency or special
situation when the designated evaluator is unable to perform the
evaluation. The backup evaluator must be a dermatologist or experienced
physician and have attended the Investigator meeting or have been
trained by someone who attended the Investigator meeting.

-   The PGA score should, at a minimum, include and reflect a global
    consideration of erythema, scaling, plaque thickness, and percentage
    of total body surface area affected by psoriasis.

-   At each visit, the PGA should be performed after the determination
    of the Psoriasis Area and Severity Index, Overall Lesion Severity,
    Psoriasis body surface area, Itching Scale, and Psoriasis Symptom
    Assessment.

```{=html}
<!-- -->
```
-   Do not include residual marks from lesions (e.g., mild erythema,
    pigmented macules, hyperpigmentation, hypopigmentation) in
    determination of the PGA.

-   The evaluator may reference the CRFs, scales, source document notes,
    or any other relevant information from prior visits to assist him or
    her in determining the PGA.

Note: Percentages relate to **improvement for that subject**. They are
not a rating of how the subject's improvement corresponds to improvement
seen in other patients who are using other medications.

APPENDIX E

Copies of Publications

Copies of all manuscript articles listed in the reference list are
included in this appendix.