MEMORANDUM

**FROM** Elektra Papadopoulos, M.D. and Louis Marzella, M.D., Ph.D.,

> Immunology and Infectious Diseases Branch,
>
> and Claire Gnecco, Ph.D., Division of Biostatistics

**THROUGH** Jeffrey Siegel, M.D., Chief Immunology and Infectious
Diseases Branch

**TO** Marc Walton, M.D., Acting Director, Division of Clinical Trial
Design and Analysis, Office of Therapeutics Research and Review, CDER

and

Karen Weiss, M.D., Acting Deputy Office Director, Office of Therapeutics
Research and Review, CDER.

**TOPIC** Briefing Document:

> Biologic License Application STN BL 125075/0 for efalizumab for the
> treatment of moderate to severe chronic plaque psoriasis

TABLE OF CONTENTS

[1 INTRODUCTION 4](#introduction)

[1.1 Filing of License Application 4](#filing-of-license-application)

[1.2 Drug Product 4](#drug-product)

[1.3 Rationale and Hypothesis 4](#rationale-and-hypothesis)

[1.4 Proposed Indication: Plaque Psoriasis
4](#proposed-indication-plaque-psoriasis)

[1.5 Licensed Therapies for Psoriasis
5](#licensed-therapies-for-psoriasis)

[1.6 Licensing Status of Drug Product
7](#licensing-status-of-drug-product)

[1.7 Disclosure of Financial Interests and Arrangements of Clinical
Investigators
7](#disclosure-of-financial-interests-and-arrangements-of-clinical-investigators)

[1.8 Debarment Certification 7](#debarment-certification)

[2 CLINICAL STUDIES OF EFALIZUMAB AND REGULATORY HISTORY
7](#clinical-studies-of-efalizumab-and-regulatory-history)

[3 SUMMARY OF THE PHASE 1 AND 2 CLINICAL EXPERIENCE
9](#summary-of-the-phase-1-and-2-clinical-experience)

[4 PHASE 3 CLINICAL TRIALS 10](#phase-3-clinical-trials)

[4.1 Issues Explored in the Efficacy Trials
10](#issues-explored-in-the-efficacy-trials)

[4.2 Psoriasis Outcomes used in the Clinical Efficacy Trials
11](#psoriasis-outcomes-used-in-the-clinical-efficacy-trials)

[4.2.1 Primary efficacy outcome 11](#primary-efficacy-outcome)

[4.2.2 Secondary efficacy outcomes 12](#secondary-efficacy-outcomes)

[4.3 Protocol ACD2058g 14](#protocol-acd2058g)

[4.3.1 Study Title 14](#study-title)

[4.3.2 Study Objectives 14](#study-objectives)

[4.3.3 Study Design 14](#study-design)

[4.3.4 Study Results 23](#study-results)

[4.3.5 Summary of Efficacy: Study ACD2058g
43](#summary-of-efficacy-study-acd2058g)

[4.4 Protocol ACD2059g 44](#protocol-acd2059g)

[4.4.1 Study Title 44](#study-title-1)

[4.4.2 Study Objectives 44](#study-objectives-1)

[4.4.3 Study Design 44](#study-design-1)

[4.4.4 Study Results 49](#study-results-1)

[4.4.5 Summary of Efficacy: Study ACD2059g
61](#summary-of-efficacy-study-acd2059g)

[4.5 Protocol ACD2390g 62](#protocol-acd2390g)

[4.5.1 Study Title 62](#study-title-2)

[4.5.2 Study Objectives 62](#study-objectives-2)

[4.5.3 Study Design 62](#study-design-2)

[4.5.4 Study Results 66](#study-results-2)

[4.5.5 Summary of Efficacy: Study ACD2390g
78](#summary-of-efficacy-study-acd2390g)

[4.6 Protocol ACD2600g 78](#protocol-acd2600g)

[4.6.1 Study Title 78](#study-title-3)

[4.6.2 Study Objectives 78](#study-objectives-3)

[4.6.3 Study Design 78](#study-design-3)

[4.6.4 Study Results 80](#study-results-3)

[4.6.5 Summary of Efficacy: Study ACD2600g
85](#summary-of-efficacy-study-acd2600g)

[5 EXPLORATORY EFFICACY ANALYSES 85](#exploratory-efficacy-analyses)

[5.1 Effect of Use of Excluded Therapies
85](#effect-of-use-of-excluded-therapies)

[6 SUMMARY OF EFFICACY AND PATIENT POPULATION
87](#summary-of-efficacy-and-patient-population)

[7 INTEGRATED SAFETY REVIEW 87](#integrated-safety-review)

[7.1 Safety Database 88](#safety-database)

[7.2 Serious Adverse Events 89](#serious-adverse-events)

[7.2.2 Deaths and Serious Adverse Events in Other Indications
91](#deaths-and-serious-adverse-events-in-other-indications)

[7.2.3 Serious Infections 92](#serious-infections)

[7.2.4 Malignancies 97](#malignancies)

[7.2.5 Nonmelanomatous Skin Cancers 101](#nonmelanomatous-skin-cancers)

[7.2.6 CNS Adverse Events 102](#cns-adverse-events)

[7.2.7 Laboratory Adverse Events/ Changes
103](#laboratory-adverse-events-changes)

[7.2.8 Psoriasis Flares and Rebound 106](#psoriasis-flares-and-rebound)

[7.2.9 Arthritis-Related Adverse Events
111](#arthritis-related-adverse-events)

[7.2.10 Serious Vascular and Thrombotic Events
114](#serious-vascular-and-thrombotic-events)

[7.2.11 Serious Inflammatory and Autoimmune Reactions
115](#serious-inflammatory-and-autoimmune-reactions)

[7.3 Severe Adverse Events 116](#severe-adverse-events)

[7.4 Common Adverse Events 116](#common-adverse-events)

[7.5 Hypersensitivity Reactions (serious and non-serious)
118](#hypersensitivity-reactions-serious-and-non-serious)

[7.6 Immunogenicity 119](#immunogenicity)

[7.6.1 Anti-efalizumab Antibodies 119](#anti-efalizumab-antibodies)

[7.6.2 Other Laboratory Changes and Adverse Events Associated with
Efalizumab Therapy:
120](#other-laboratory-changes-and-adverse-events-associated-with-efalizumab-therapy)

[8 SUMMARY OF SAFETY 124](#summary-of-safety)

[9 USE OF EFALIZUMAB IN SPECIAL POPULATIONS
127](#use-of-efalizumab-in-special-populations)

[10 CONCLUSIONS: EFFICACY AND SAFETY OF EFALIZUMAB FOR THE TREATMENT OF
PATIENTS WITH MODERATE TO SEVERE PSORIASIS
127](#conclusions-efficacy-and-safety-of-efalizumab-for-the-treatment-of-patients-with-moderate-to-severe-psoriasis)

[11 APPENDIX 1: AUDIOLOGIC ASSESSMENTS
129](#appendix-1-audiologic-assessments)

[11.1 Audiology 129](#audiology)

[12 APPENDIX 2 Use of Efalizumab in Special Populations
131](#appendix-2-use-of-efalizumab-in-special-populations)

[12.1 Pediatric Studies 131](#pediatric-studies)

[12.2 Pregnancy 131](#pregnancy)

[12.3 Safety and Efficacy in the Geriatric Population
132](#safety-and-efficacy-in-the-geriatric-population)

[13 APPENDIX 3: Phase 1 study protocols
134](#appendix-3-phase-1-study-protocols)

[13.1 Selected Phase 1 Studies of Efalizumab in Patients with Psoriasis
134](#selected-phase-1-studies-of-efalizumab-in-patients-with-psoriasis)

[13.1.1 Protocol HU9602 134](#protocol-hu9602)

[13.1.2 Protocol HUPS249 136](#protocol-hups249)

[13.1.3 Protocol HUPS254 136](#protocol-hups254)

[13.1.4 Protocol HUPS256 139](#protocol-hups256)

[13.1.5 Protocol HUPS252 141](#protocol-hups252)

[13.1.6 Protocol ACD2389g 144](#protocol-acd2389g)

# INTRODUCTION

## Filing of License Application 

On December 27, 2002 Genentech submitted to the Center for Biologics
Evaluation and Research a Biologics License Application (STN BL
125075/0) for efalizumab for the treatment of psoriasis.

## Drug Product

Efalizumab is a recombinant humanized IgG1 kappa isotype monoclonal
antibody that selectively binds to human CD11a and has an approximate
molecular weight of 150 kD.

The protein is produced by Chinese hamster ovary cells.

The drug product is provided as a sterile lyophilized powder to deliver
125 mg of efalizumab. Reconstitution with 1.3 mL of supplied Sterile
Water for Injection yields a clear to slightly opalescent solution
containing 100 mg/mL efalizumab, 0.2% polysorbate 20, 40 mM histidine,
240 mM sucrose, and SWFI at a pH of 6.2. Although the drug is produced
in a suspension culture containing gentamicin, gentamicin is not
detectable in the final product.

## Rationale and Hypothesis 

CD11a is the α subunit of lymphocyte function-associated antigen
(LFA-1), a β2 integrin, and is expressed on all leukocytes. Efalizumab
binds specifically to the CD11a alpha chain of LFA-1 and blocks the
binding of LFA-1 to its ligand intercellular adhesion molecule 1
(ICAM-1). Binding of CD11a by efalizumab results in saturation of
available CD11a binding sites and down-modulation of cell surface CD11a
expression. This event is believed to decrease the activation of
lymphocytes and reduce their translocation to peripheral tissues (such
as in psoriatic plaques).

Activated T lymphocytes may play a role in autoimmune diseases including
plaque‑type psoriasis. Blocking or reducing T lymphocyte activation and
migration may improve the clinical manifestations of psoriasis.

## Proposed Indication: Plaque Psoriasis

Psoriasis is a chronic skin disorder characterized by erythematous,
scaly papules and plaques with a predisposition for the scalp, extensors
of the limbs, lumbosacral area and genitalia. The condition affects
between 1 and 3% of the general population. However, it is relatively
infrequent among African-Americans, in Japanese populations and in the
Native American population. Men and women are equally affected.

Psoriasis has a bimodal peak of onset, one in adolescents and young
adults (at 16 to 22 years of age) and the second in older persons (at
age 57-60). Onset is before the age of 15 in 27% of cases. Early onset
disease is strongly linked to HLA -Cw6 and DR7, while late onset disease
is linked to HLA-Cw2. The predisposition to psoriasis is thought to be
polygenic with expression triggered by environmental factors such as
streptococcal infection, stress, certain drugs, and HIV. The cause of
psoriasis is not fully known.

Psoriasis is characterized by excessive proliferation of keratinocytes
and inflammation. There is evidence that activated T cells are involved
in the pathogenesis of psoriasis. In addition, abnormalities in cytokine
expression, intracellular signaling, and polyamine metabolism may
mediate psoriasis.

Plaque psoriasis is the most common form. The lesions are
indurated/raised, erythematous and scaly. Approximately 1/3 of patients
have moderate to severe disease. The disease waxes and wanes.
Spontaneous remissions and relapses are the rule. Spontaneous durable
remissions may occur.

Guttate (drop-like) psoriasis is sometimes triggered by streptococcal
infection and is associated with development of chronic psoriasis.
Pustular psoriasis varies in severity from localized to generalized
forms with fever, malaise, and a relatively high mortality after
prolonged courses. Erythroderma can be complicated by sepsis,
temperature instability and high output cardiac failure. Psoriatic
arthritis is a complication in approximately 10% of all psoriasis
patients.

Patients with psoriasis report reduction in mental and physical
functioning comparable to that seen in patients with cancer or
arthritis. The chief complaints of patients with psoriasis are scaling,
itching, redness and tightness of the skin, bleeding and burning
sensations. In a 1998 National Psoriasis Foundation Patient-Membership
survey, patients reported depression, difficulties in the workplace and
socialization caused by psoriasis.

The goal of treatment of psoriasis is to decrease the severity and
extent of psoriasis to the point that it no longer interferes with the
patient's occupation, personal or social life, or well-being.

##  Licensed Therapies for Psoriasis

Topical Therapy

The initial treatment of stable plaque psoriasis affecting less than
10-20% of body surface area is topical. Topical therapies include
emollients, corticosteroids, anthralin, tar, retinoids, calcipotriene,
and salicylic acid. The mainstay of treatment is topical
corticosteroids. Topical corticosteroids induce skin atrophy, striae,
purpura and may be absorbed systemically leading to suppression of the
hypothalamic-pituitary-adrenal axis. Another possible limiting factor to
their use is tachyphylaxis. Other commonly used topical agents include
calcipotriene (a vitamin D analogue), tazarotine (a retinoid prodrug)
and anthralin. Salicylic acid is used as a keratolytic agent. Skin
irritation is the most common adverse effect of these topical agents.

Phototherapy

Phototherapy for psoriasis includes UVB, narrow band UVB, and psoralen,
a photosensitizer, plus UVA (PUVA). PUVA induces responses in a high
proportion of patients and can induce long-term remissions. PUVA causes
premature aging of skin and increases the risk of cutaneous malignancy
in a dose-related fashion. The relative increase in risk of a person
with sun-sensitive skin (e.g. Fitzpatrick Type I or II skin; always
burn; tan never/sometime) developing squamous cell carcinoma is at least
5 times greater than that of control.

Systemic Therapy

Methotrexate, cyclosporin, and retinoids, in general, induce moderate
improvement in the majority of treated patients. These products are
recommended for severe and/or recalcitrant psoriasis because they induce
serious toxicities. Methotrexate, an antimetabolite folate analogue, may
cause bone marrow toxicity with leukopenia, dose-dependent development
of cirrhosis of the liver, severe pneumonitis and lymphomas.
Methotrexate is also fetotoxic and an abortifacient. Cyclosporine, an
immunosuppressant calcineurin inhibitor, induces hypertension,
nephrotoxicity, increased risk of malignancy (especially B cell
lymphoma) and infection. Retinoids are the treatment of choice for
pustular psoriasis and have also been used in the treatment of
erythrodermic psoriasis. Of major consideration in women of childbearing
potential is teratogenicity of retinoids. Other serious adverse events
are hepatotoxicity, pancreatitis, depression, visual impairment, and
hyper-triglyceridemia.

Alefacept, an immunosuppressive and the first biologic agent to receive
FDA approval for the treatment of moderate-to-severe psoriasis, results
in 75% clearing in 10% (by IV route) 16% (by IM route) of patients.
Remissions may last for months. The drug induces lymphopenia and
requires monitoring of CD4+ T lymphocyte counts on a regular basis.

Immunosuppressive Agents and Anti-metabolites: Risk/benefit in Psoriasis

Psoriasis is a serious chronic disease associated with significant
morbidity and impairment. The disease is usually not life threatening
and does not induce irreversible injury to skin or other organs, with
the exception of psoriatic arthritis. A number of serious toxicities are
associated with the use of immunosuppressants and antimetabolites. These
include serious infections, and neoplasms. In the case of neoplasms
there may be a lag in the time to clinical detection and long-term
follow-up of treated patients may be required to assess the excess risk.
Therapies associated with significant risk of serious irreversible
toxicity or mortality should be reserved for patients with severe,
recalcitrant psoriasis. The goal of therapy is to bring disease under
control and change to the least toxic therapy.

## Licensing Status of Drug Product

At the time this application was submitted, efalizumab was not licensed
in any country, nor had it been withdrawn from the market in any
country.

## Disclosure of Financial Interests and Arrangements of Clinical Investigators

At the time this application was submitted, none of the clinical
investigators (from whom a response was received) disclosed financial
interest in either Genentech or Genentech's partner, XOMA, Ltd.

## Debarment Certification

Genentech has provided certification that it did not and will not use
the services of anyone debarred under Subsections A or B of Section 306
of the Food, Drug and Cosmetics Act in connection with this application.

# CLINICAL STUDIES OF EFALIZUMAB AND REGULATORY HISTORY

Two sponsors, XOMA, Ltd. and Genentech, Inc., participated in the
development of efalizumab for moderate to severe plaque psoriasis.

-   XOMA sponsored the phase 1 and 2 clinical studies and manufactured
    efalizumab used in those studies.

-   Genentech sponsored the phase 3 studies and is the current
    manufacturer of the to-be-marketed efalizumab product.

-   Study ACD2058g, the first phase 3 study, studied exclusively
    efalizumab manufactured by XOMA.

-   Most of the patients in study ACD2059g, received XOMA-manufactured
    efalizumab. In the latter part of the study Genentech-manufactured
    product was introduced.

    -   In this study, the PK, PD and clinical activity of the
        XOMA-manufactured and Genentech-manufactured efalizumab products
        were compared.

-   Subsequent phase 3 studies, ACD2390g and ACD2600g, studied
    exclusively the Genentech-manufactured product.

[September 2001:]{.underline}

The agency expressed concerns about the comparability of the efalizumab
manufactured by XOMA and Genentech and recommended that a PK
comparability study (ACD2389) be performed in healthy volunteers.

June 2002:

Study ACD2389g showed that the XOMA- and Genentech- produced efalizumab
were equivalent pharmacodynamically, but were not pharmacokinetically
equivalent. The Genentech-manufactured efalizumab appeared to have
higher bioavailability and/or slower clearance. The ratio of geometric
means for AUCinf of Genentech and XOMA

efalizumab was 1.32, with a 90% confidence interval of 1.19--1.47, above
the 0.80--1.25 range specified for comparability.

These results prompted the FDA to request additional phase 3 studies for
safety and efficacy of the Genentech-manufactured product.

[November 2002:]{.underline}

Study ACD2390g showed that 1 mg/kg/wk SC of the Genentech-manufactured
efalizumab was superior to placebo. The Agency agreed that the data were
adequate for filing a licensing application and recommended that the
XOMA- and Genentech-manufactured efalizumab databases be analyzed
separately and also be pooled for the BLA submission.

Table 1 provides a listing of the clinical studies of efalizumab in
patients with psoriasis and summarizes the number of patients treated
and the duration of treatment as of May 2003.

Table 1 Efalizumab Studies: Psoriasis Subjects Receiving at Least One
Dose of Efalizumab

+-------------+----------------+----------+---------+-------+--------+
|             |                |          |         | No.   |        |
|             |                |          |         | of    |        |
|             |                |          |         | Sub   |        |
|             |                |          |         | jects |        |
+-------------+----------------+----------+---------+-------+--------+
|             |                | Dose     | Tr      | Tr    |        |
|             |                |          | eatment | eated |        |
|             |                |          |         | 1^st^ |        |
|             |                |          |         |       |        |
|             |                |          |         | Time  |        |
|             |                |          |         | With  |        |
+-------------+----------------+----------+---------+-------+--------+
|             |                | (mg/kg)  | D       |       |        |
|             |                | and      | uration |       |        |
+-------------+----------------+----------+---------+-------+--------+
| Study       | Phase and      | Route    | (wk)    | XOMA  | GNE    |
|             | Design         |          |         |       |        |
+-------------+----------------+----------+---------+-------+--------+
| HU9602      | 1, open-label  | 0.       | 1       | 31    | NA     |
|             |                | 03--10.0 |         |       |        |
|             |                | IV       |         |       |        |
+-------------+----------------+----------+---------+-------+--------+
| HUPS249     | 1, open-label  | 0.1--1.0 | 7       | 39    | NA     |
|             |                | IV       |         |       |        |
+-------------+----------------+----------+---------+-------+--------+
| HUPS252     | 2,             | 0.1, 0.3 | 8       | 97    | NA     |
|             | plac           | IV       |         |       |        |
|             | ebo-controlled |          |         |       |        |
+-------------+----------------+----------+---------+-------+--------+
| HUPS254     | 1, open-label  | 0.5--2.0 | 1--8    | 52    | NA     |
|             |                | SC       |         |       |        |
+-------------+----------------+----------+---------+-------+--------+
| HUPS256     | 1, open-label  | 0.3--1.0 | 12      | 11    | NA     |
|             |                | IV       |         |       |        |
+-------------+----------------+----------+---------+-------+--------+
|             |                | 1.0--4.0 | 12      | 57    | NA     |
|             |                | SC       |         |       |        |
+-------------+----------------+----------+---------+-------+--------+
| ACD2058g    | 3,             | 1.0--2.0 | 12--24  | 462   | NA     |
|             | plac           | SC       |         |       |        |
|             | ebo-controlled |          |         |       |        |
+-------------+----------------+----------+---------+-------+--------+
| ACD2059g    | 3,             | 1.0--4.0 | 12--24  | 442   | 137    |
|             | plac           | SC       |         |       |        |
|             | ebo-controlled |          |         |       |        |
+-------------+----------------+----------+---------+-------+--------+
| ACD2062g    | 3, open-label  | 1.0--2.0 | 12      | 28    | 6      |
|             | extension      | SC       |         |       |        |
|             | study to       |          |         |       |        |
|             | ACD2058g       |          |         |       |        |
+-------------+----------------+----------+---------+-------+--------+
| ACD2142g    | 1, open-label  | 1.0--2.0 | 12      | NA    | 70     |
|             |                | SC       |         |       |        |
+-------------+----------------+----------+---------+-------+--------+
| ACD2243g    | 3, open-label  | 2.0 SC,  | 12      | NA    | 339    |
|             |                | then     |         |       |        |
+-------------+----------------+----------+---------+-------+--------+
|             |                | 1.0--2.0 | ≥ 48    |       |        |
|             |                | SC       |         |       |        |
+-------------+----------------+----------+---------+-------+--------+
| ACD2390g    | 3,             | 1.0 SC   | 12      | NA    | 368    |
|             | plac           |          |         |       |        |
|             | ebo-controlled |          |         |       |        |
+-------------+----------------+----------+---------+-------+--------+
| ACD2391g    | 3, open-label  | 1.0 SC   | 24      | NA    | 174    |
|             | extension to   |          |         |       |        |
|             | ACD2390g       |          |         |       |        |
+-------------+----------------+----------+---------+-------+--------+
| ACD2600g    | 3,             | 1.0 SC   | 12      | NA    | 449    |
|             | plac           |          |         |       |        |
|             | ebo-controlled |          |         |       |        |
+-------------+----------------+----------+---------+-------+--------+
| Subjects    |                |          |         | 1219  | 1543   |
| with        |                |          |         |       |        |
| psoriasis   |                |          |         |       |        |
| receiving   |                |          |         |       |        |
| efalizumab  |                |          |         |       |        |
| by          |                |          |         |       |        |
| m           |                |          |         |       |        |
| anufacturer |                |          |         |       |        |
+-------------+----------------+----------+---------+-------+--------+
| Subjects    |                |          |         |       | 2762   |
| with        |                |          |         |       |        |
| psoriasis   |                |          |         |       |        |
| receiving   |                |          |         |       |        |
| efalizumab  |                |          |         |       |        |
+-------------+----------------+----------+---------+-------+--------+

In addition to phase 1 and 2 trials, four phase 3 double blinded,
randomized, placebo controlled trials were conducted. Long-term exposure
data were provided by studies ACD2058g and ACD2059g (24 weeks of
treatment), by study ACD2243g (48 weeks of treatment), and by the
open-label extension studies. The total safety database consisted of
over 2500 patients exposed to efalizumab.

# SUMMARY OF THE PHASE 1 AND 2 CLINICAL EXPERIENCE

XOMA conducted the Phase 1 studies (trials HU9602, HUPS249, HUPS254, and
HUPS256), which characterized efalizumab's intravenous (IV) and
subcutaneous (SC) pharmacokinetic and pharmacodynamic properties in
patients with psoriasis and obtained preliminary evidence of activity in
psoriasis. Xoma also conducted one Phase 2 clinical study (HUPS252). It
was determined from single-dose studies that adverse events including
fever, headache and nausea were seen shortly after the intravenous
infusion of efalizumab. In multiple-dose studies, these adverse events
were most common after the first dose, hence the phenomenon was called a
"first-dose" effect. These adverse events were also dose-related. This
led to the development of an initial low "tolerization dose" that
decreased the incidence and severity of the adverse events associated
with dosing.

An efalizumab-treated patient experienced acute unilateral hearing loss
in the phase 2 study. This finding lead to the inclusion of audiologic
testing during the first of the phase 3 trials, Study ACD2058g (See
Appendix 1).

# PHASE 3 CLINICAL TRIALS

The four Phase 3, placebo-controlled studies were as follows:

-   [Study ACD2058g:]{.underline} a randomized, double-blind study
    evaluating 12 weeks of therapy with SC administered XOMA efalizumab,
    followed by a placebo-controlled period with either continued
    treatment for 12 additional weeks or retreatment for an additional
    12 weeks after relapse

```{=html}
<!-- -->
```
-   [Study ACD2059g]{.underline}: a randomized, placebo-controlled,
    double-blind study evaluating 12 weeks of therapy with SC
    administered efalizumab (\~75% XOMA, \~25% Genentech), followed by a
    second placebo-controlled period with either continued active
    treatment or placebo for 12 weeks

```{=html}
<!-- -->
```
-   [Study ACD2390g:]{.underline} a randomized, double-blind study
    evaluating 12 weeks of therapy with SC administered Genentech
    efalizumab

-   [Study ACD2600g:]{.underline} a randomized, double-blind,
    placebo-controlled trial, was conducted to provide additional
    controlled safety data with the Genentech-manufactured efalizumab.

The sponsor has also conducted two open-label phase 3 clinical trials.

-   Study ACD2062 was an open-label trial to assess the safety and
    efficacy of retreatment with efalizumab.

-   Study ACD2243g is an ongoing trial to evaluate the safety and
    efficacy of long-term maintenance with efalizumab. The interim data
    from this study provide the 1-year safety data to support this BLA
    submission.

## Issues Explored in the Efficacy Trials

Some of the issues explored in the efficacy trials were as follows:

-   The lack of comparability of the pharmacokinetics of the
    XOMA-manufactured and the Genentech-manufactured efalizumab made it
    necessary to further study the Genentech material for safety and
    efficacy.

-   The safety and efficacy of long-term continuous treatment and
    retreatment upon relapse were explored.

-   The safety of treatment discontinuation was evaluated.

-   Correlations of efficacy as measured by PASI and other measures such
    as static and dynamic physician's global assessment were performed.

Studies ACD2058g and ACD2059g were designed to evaluate the safety and
efficacy of continuous therapy for a total of 6 months. In addition,
retreatment upon relapse among patients classified as responders after
the first treatment course was studied in Study ACD2058g.

## Psoriasis Outcomes used in the Clinical Efficacy Trials

### Primary efficacy outcome

A 75% improvement from baseline in the PASI (Psoriasis Area and Severity
Index) score (Fredriksson et al, 1978) was the primary efficacy outcome
used in the clinical trials. PASI scoring is discussed below.

**PASI Scoring**

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

**Body Areas**

Four main body areas are 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, respectively.

The area of psoriatic involvement for each body area (Ah, At, Au, Al) is

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

The severity of the psoriatic lesions in three main signs---erythema
(E), thickness (T), and scaling (S)---are 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.

**Calculating PASI**

To calculate the PASI, the sum of the severity rating for the three main
signs are multiplied with the numerical value of the area affected and
with the various

percentages of the four body areas. These values are then 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

### Secondary efficacy outcomes

The principal secondary efficacy outcome used in the clinical efficacy
trials was a static physician's global assessment, the Overall Lesion
Severity (OLS) Scale. The scoring system is depicted in the following
table (Table 2).

Table 2 Overall Lesion Severity Scale

+-----------+---------+-----------------------------------------------+
| Score     | C       | Description                                   |
|           | ategory |                                               |
+-----------+---------+-----------------------------------------------+
| 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         | M       | Plaque elevation = moderate (moderate         |
|           | oderate | 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    | Plaque elevation = very marked (very marked   |
|           | severe  | 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)     |
+-----------+---------+-----------------------------------------------+

Clinical response was defined as "clear" or "minimal" at 12 weeks.

The Dermatology Life Quality Index (DLQI) (Finlay et al,1994) was one of
the secondary efficacy outcomes. The DLQI is a 10-item questionnaire
that attempts to assess how much a skin condition has affected the
subject's quality of life during the previous 7 days. Each question has
four possible responses: "not at all," "a little," "a lot," or "very
much," with scores of 0, 1, 2, and 3, respectively. The DLQI represents
the sum of the scores, ranging from 0 to 30 points.

> Dermatology Life Quality Index Questionnaire

1\. Over the last week, how **itchy**, **sore**, **painful** Very much

or **stinging** has your skin been? A lot

A little

Not at all

2\. Over the last week, how **embarrassed** or **self** Very much

**conscious** have you been because of your A lot

skin? A little

Not at all

3\. Over the last week, how much has your skin Very much

interfered with you going **shopping** or looking A lot

after your **home** or **garden**? A little

Not at all Not relevant

4\. Over the last week, how much has your skin Very much

influenced the **clothes** you wear? A lot

A little

Not at all Not relevant

5\. Over the last week, how much has your skin Very much

affected any **social** or **leisure** activities? A lot

A little

Not at all Not relevant

6\. Over the last week, how much has your skin Very much

made it difficult for you to do any **sport**? A lot

A little

Not at all Not relevant

7\. Over the last week, has your skin prevented Yes 

you from **working** or **studying**? No Not relevant 

If "No," over the last week how much has your A lot 

skin been a problem at **work** or **studying**? A little

Not at all 



8\. Over the last week, how much has your skin Very much 

created problems with your **partner** or any of A lot 

your **close friends** or **relatives**? A little

Not at all  Not relevant

 

9\. Over the last week, how much has your skin Very much 

caused any **sexual difficulties?** A lot 

A little 

Not at all Not relevant 

10 Over the last week, how much of a problem Very much 

. has the **treatment** for your skin been, for A lot 

example by making your home messy, or by A little

taking up time? Not much at all Not relevant

 

## Protocol ACD2058g

### Study Title

"A Phase III, Randomized, Double-Blind, Parallel-Group,
Placebo-Controlled, Multicenter, Multidose Study to Evaluate the
Efficacy and Safety of Subcutaneously Administered Anti-CD11a in Adults
with Moderate to Severe Plaque Psoriasis"

### Study Objectives

-   To investigate the efficacy of weekly subcutaneous (SC) dosing with
    either 1.0 mg/kg or 2.0 mg/kg efalizumab relative to placebo as
    measured by the proportion of subjects achieving a ≥75% decrease
    from baseline in PASI at the end of the initial 12-week treatment
    period (First Treatment, or FT Day 84)

-   To evaluate the safety and tolerability of 12 weekly SC doses of 1.0
    mg/kg or 2.0 mg/kg efalizumab relative to placebo

The primary objective of the study was to assess the safety and efficacy
of a 12-week treatment of efalizumab. The study was also designed to
explore a number of secondary safety and efficacy questions with special
emphasis on issues relevant to patients with psoriasis. These questions
included:

-   optimization of dose

-   duration of treatment-free response

-   potential for treatment-withdrawal phenomena (e.g. flaring,
    psoriasis variants)

-   safety and efficacy of retreatment following relapse

-   safety and activity of extended treatment for partial responders and
    non-responders

### Study Design

Study ACD2058g was a randomized, double-blind, placebo-controlled trial
to evaluate the efficacy and safety of efalizumab in subjects with
moderate to severe psoriasis. Following the initial 84-day blinded
placebo-controlled treatment period, responders were observed on no
treatment until they relapsed or until 168 days (OB period). Upon
relapse, patients who had initially received efalizumab were
rerandomized to receive placebo or efalizumab at the same dose
previously received. Responding patients in the placebo arm who relapsed
during the OB period were treated with efalizumab during retreatment.
Patients who were initially randomized to receive efalizumab who had no
response or a partial response at Day 84 were rerandomized to continue
efalizumab at the same dose they had received previously or to receive
placebo in the extended treatment regimen (ET) protocol for an
additional contiguous 84 days. Partial responders and non-responders who
received placebo initially went on to receive efalizumab in the ET
period. The study also included a follow-up period (FU) and an extended
follow-up period (EFU), for people who had not relapsed by the FU Day
84, to assess duration of effect and safety. Figure 1 below shows the
study schema.

> Figure 1 Design of Study ACD2058g
>
> ![](media/image1.png){width="5.299305555555556in"
> height="5.902083333333334in"}

![](media/image2.png){width="5.53125in" height="6.947916666666667in"}

#### Open Label Extension Study

Protocol ACD2062g served as the open-label extension for Study ACD2058g.
Subjects who did not experience a ≥50% improvement in PASI by ET day 56
(as compared to FT day 0) could transfer to open-label treatment.

#### Study Drug

Subjects in the active group received XOMA-manufactured efalizumab.
Dosing volumes and schedules were identical during the FT, RT, and ET
periods. Subjects received an initial conditioning dose of 0.7 mg/kg
study drug followed by 11 weekly doses of 1.0 or 2.0 mg/kg SC study drug
(efalizumab or placebo).

#### Randomization

During the FT period, subjects were randomized to low-dose (1.0 mg/kg)
efalizumab, high dose (2.0 mg/kg) efalizumab or low dose or high dose
placebo in a 2:2:1:1 ratio. Randomization was stratified by FT Day 0
PASI (≤ 16, ≥ 16.1), by prior treatment for psoriasis (naïve to systemic
treatment vs. history of prior systemic therapy) and by study site
through an IVRS. The random assignment to efalizumab or placebo was
blinded to subjects, investigators and the sponsor.

At the start of the ET period, subjects who previously received
efalizumab were rerandomized within the low- or high- dose group to
active therapy or placebo in a 2:1 ratio. Randomization was balanced for
subjects who were partial responders and non-responders.

All patients assigned to placebo in the FT period were reassigned to
receive efalizumab, whether they participated in the RT or ET periods
and regardless of response status during the first treatment period.

#### Withholding Treatment

Subjects were discontinued from efalizumab treatment if they met any of
the following criteria: diagnosis of any cancer; anaphylaxis;
opportunistic infection; or any medical condition that the investigator
determined could jeopardize the subject's safety if he or she continued
in the study. Other reasons for discontinuation included pregnancy,
administration of live virus or bacteria vaccine, or concurrent
treatment with an excluded systemic or topical therapy.

If a subject had an atypical severe relapse or emergence of a new
psoriatic morphology (e.g., pustular, rupioid, guttate), the
investigator was to contact the Medical Monitor. If, in the judgment of
the investigator, this flare required treatment, the subject had to
discontinue from the study.

Treatment options for these subjects included the following:

-   Immediate transfer to the open-label study, ACD2062g, for treatment
    with efalizumab upon approval from the Medical Monitor

-   Early discontinuation from the study to begin excluded psoriasis
    medications. Subjects were to undergo end-of-treatment-period
    evaluations and immediately enter the follow-up period.

Concomitant Medications

The only concomitant psoriasis treatments that could be used until study
Day 84 were Eucerin cream and tar or salicylic acid preparations (for
scalp psoriasis only). Potency Group VII topical corticosteroids could
be used in small amounts on psoriatic lesions on the face, hands, feet,
groin, or axillae, if required (except for the day of the scheduled
visit).

After FU Day 84, any topical or systemic psoriasis therapies could be
used at the investigator's discretion, even for subjects continuing in
the extended follow-up EFU period through FU Day 252.

#### Disallowed treatments

The following were not allowed: Systemic treatments for psoriasis (e.g.,
PUVA, cyclosporine, corticosteroids, methotrexate, oral retinoids, MMF,
thioguanine, hydroxyurea, sirolimus, azathioprine, 6-MP, etanercept) and
immunosuppressive medications for any indication other than psoriasis.

Treatment with UVB phototherapy and all other topical treatments for
psoriasis (e.g., topical corticosteroids, calcipotriene, tazarotene,
anthralin, tar) were excluded from Day --14 through Day 84, with the
exceptions noted previously*.* Tanning booths or nonprescription UV
light sources were not to be used.

Use of live virus or bacteria vaccines were prohibited.

#### Eligibility

Inclusion

-   Plaque psoriasis covering ≥ 10% of total BSA

-   A minimum PASI score of 12.0 at screening

-   Plaque psoriasis diagnosed for at least 6 months

-   Plaque psoriasis clinically stable for at least 3 months prior to
    screening

```{=html}
<!-- -->
```
-   Candidate for systemic therapy for psoriasis who had not been
    previously treated or history of prior treatment with systemic
    therapy for psoriasis (e.g., PUVA, cyclosporine, corticosteroids,
    methotrexate, oral retinoids

-   Body weight ≤ 140 kg

-   18 to 70 years old

-   Women of childbearing potential had to use an acceptable method of
    contraception to prevent pregnancy and agree to continue to practice
    an acceptable method of contraception for the duration of their
    participation in the study.

-   Willingness to hold sun exposure reasonably constant and to avoid
    use of tanning booths or other UV light sources for the duration of
    the trial

Exclusion

Subjects who met any of the following exclusion criteria were ineligible
for

study entry:

-   Guttate, erythrodermic, or pustular psoriasis as sole or predominant
    form of psoriasis

-   History of severe allergic or anaphylactic reactions to humanized
    monoclonal antibodies

-   Clinically significant psoriasis flare during screening or at the
    time of enrollment

-   History of or ongoing uncontrolled bacterial, viral, fungal, or
    atypical mycobacterial infection

-   History of opportunistic infections (e.g., systemic fungal
    infections, parasites)

-   History of hepatitis B or C infection

-   Hepatic enzymes 3× the upper limits of normal (ULN) Subjects with
    hepatic enzymes elevated above the ULN but \<3× the ULN had to be
    tested for hepatitis B and C. Only subjects with negative viral
    tests could be enrolled.

-   Active tuberculosis (TB) or currently undergoing treatment for TB.
    Purified protein derivative (PPD) testing and/or a chest X-ray were
    required for high-risk subjects.

Presence or history of malignancy within the past 5 years, including
lymphoproliferative disorders. Subjects with a history of fully resolved
basal cell or squamous cell skin cancer could be enrolled.

-   Previous treatment with efalizumab

-   Initiation or change in treatment regimen of β-blockers,
    angiotensin-converting enzyme (ACE) inhibitors, interferons,
    quinidine, antimalarial drugs, or lithium within the past month

-   Seropositivity for human immunodeficiency virus (HIV). Subjects
    underwent mandatory testing at screening.

-   Pregnancy or lactation

-   White blood cell (WBC) count \<4000/µL or \>14,000/µL

-   Serum creatinine ≥ 2× the ULN

-   Progressive hearing loss

-   Any medical condition that, in the judgment of the investigator,
    could have jeopardized the subject's safety following exposure to
    study drug

#### Efficacy Outcomes

The primary efficacy outcome measure was the proportion of subjects with
a ≥ 75% improvement in PASI score between FT Day 0 and FT Day 84 (the
end of the FT period).

The principal secondary efficacy outcome measure was the proportion of
subjects who achieved an OLS rating of Minimal or Clear at FT Day 84.

#### Assessment of Safety

The following were performed: physical examinations (including vital
signs and body weight); monitoring for adverse events; blood chemistry,
hematology (CBC, platelet, differential); urinalysis; antibodies to
efalizumab (HAHA) and urine pregnancy test (females of childbearing
potential). TB skin testing was done for high risk subjects only at day
84. Audiograms were also performed in this study prior to the first
study drug administration and at the end of FT (FT Day 84) ET and RT.
(See appendix 1)

Drug concentration measurements, steady-state trough concentration, were
performed on samples collected on FT Day 84 for HAHA analysis. Patients
who were positive for anti-efalizumab antibodies were excluded from the
summary.

Adverse events and concomitant medications were recorded. Adverse events
were defined as any sign, symptom, data or medical diagnosis, regardless
of relationship to study drug, that began or worsened after the start of
study drug treatment and were recorded in the subject's adverse event
case report form. Definitions of seriousness, severity and causality
were included in the protocol. Provisions were made for reporting
serious adverse events to sponsor, to IRB, and to FDA.

#### Statistical Considerations

Two treatment comparisons were of interest during the FT period of this
study: 1.0 mg/kg efalizumab versus placebo and 2.0 mg/kg efalizumab
versus placebo. The placebo groups for each of the two dose levels were
combined for all statistical comparisons following investigation of
baseline comparability of the two placebo groups.

Analysis of Treatment Group Comparability:

Treatment groups were assessed for comparability at the beginning of the
FT, RT and ET periods with respect to demographic (i.e., age, sex,
race/ethnicity) and baseline characteristics. The baseline value of any
variable was defined as the last available value prior to the first
administration of study drug. Continuous variables were analyzed using
ANOVA, and categorical variables were assessed using appropriate
contingency table methodology.

Efficacy Analyses: First Treatment Period

Analysis Population:

The intent-to-treat (ITT) population consisted of all subjects who were
randomized, whether or not they received any study drug or completed the
full course of treatment. The ITT population was the primary analysis
population for the primary and secondary endpoints.

Primary Endpoint:

Response status at the end of the FT period was determined as follows:

-   Responder: Any subject whose PASI score decreased ≥ 75% from FT Day
    0 to FT Day 84

-   Partial responder: Any subject whose PASI score decreased ≥ 50% but
    \<75% from FT Day 0 to FT Day 84

-   Non-responder: Any subject whose PASI score decreased \<50% from FT
    Day 0 to FT Day 84

The evaluation of the primary endpoint consisted of the pairwise
comparison of the proportion of responders in each efalizumab dose group
(1.0 mg/kg efalizumab and 2.0 mg/kg efalizumab) versus placebo by
Fisher's exact test for the ITT population. Partial responder and
non-responder categories were combined for the primary analysis. The
placebo groups from the FT period for each of the two dose levels were
also combined for all statistical comparisons.

Conventions for missing data imputation were as follows:

For all study endpoints, if a subject discontinued from the study prior
to FT Day 84 but after receiving the final scheduled dose of study drug
on FT Day 77, data from the early termination visit were to be used for
analysis, i.e., the Day 84 data was not considered to be missing in this
case.

A formal interim analysis of the primary efficacy endpoint was performed
by an independent data monitoring committee (DMC) once approximately
half (\~225) of the projected 450 subjects completed the FT period. The
stopping rules established prior to review of the results by the DMC
allowed the trial to be stopped for futility only; stopping for efficacy
was not allowed. Nonetheless, a penalty rule adjusting the critical
value for the final analysis was established. Therefore, the analysis of
the primary efficacy endpoint was carried out at the 0.049 level rather
than at the 0.05 level. To maintain a type I error rate for the primary
analysis of α=0.049 (two sided), the Hochberg-Bonferroni multiple
comparisons procedure was used to adjust for the two comparisons. If
both comparisons had p\<0.049 in favor of efalizumab over placebo, both
active treatment groups were considered significantly different from
placebo. If one comparison had a

p\>0.049, the other active treatment was considered statistically
significantly different from placebo only if its associated p-value was
\<0.0245 in favor of efalizumab over placebo.

#### Protocol Amendments

The protocol was amended twice. The first amendment was to ensure that
only patients who were clinically stable could enroll. The principal
secondary objective was changed from the dynamic physician's global
assessment to the static physician's global assessment scale based on
discussions with the FDA. This change was also reflected in the
secondary and other endpoints. In the second protocol amendment, the
unblinding of treatment assignment was allowed to be performed
separately for the FT period and the RT and ET periods because the
availability of the primary efficacy results at the earliest possible
time was necessary to justify the continued exposure to efalizumab in
the ongoing open-label studies.

### Study Results 

#### Patient Disposition

The first subject was enrolled into the study on January 4, 2000, and
the last subject completed the study on October 15, 2001. Twenty nine
sites in the United States and Canada participated. A total of 498
patients were enrolled into this study (planned enrollment 450). The
disposition of the patients who enrolled is shown in Table 3.

Table 3 Disposition of Subjects and Reasons for Discontinuation during
the FT Period

  -------------------------------- ------------ ------------ -------------
                                                Efalizumab   

                                   Placebo      1.0 mg/kg    2.0 mg/kg

  Subject Status                   (n=170)      (n=162)      (n=166)

  Completed FT, n                  151 (89%)    149 (92%)    145 (87%)

  Entered ET                       144          83           99

  Entered OB                       4            63           44

  Entered FU                       1            2            2

  Discontinued from study          2            1            0

  Discontinued FT, n               19 (13%)     13 (8%)      21 (13%)

  Entered FU                       7            5            8

  Discontinued from study          12           8            13

  Reason for discontinuation from  (n=19)       (n=13)       (n=21)
  FT                                                         

  Adverse event                    5            5            8

  Lost to follow-up                3            3            5

  Subject's decision               8            2            5

  Investigator's decision          2            3            2

  Use of excluded medication       1            0            1
  -------------------------------- ------------ ------------ -------------

During the first treatment period, the most common reason for
discontinuation in the efalizumab treatment arm was for adverse events.
In the placebo treatment arm, the most common reason for discontinuation
was "subject's decision." Several, but not all, of the patients who
discontinued the study due to "subject's decision" were noted to have
worsening of both the PASI score and the dynamic physician's global
assessment including some of the patients who were randomized to study
drug and others to placebo (data not shown).

#### Demographics

Table 4 below depicts the demographics of subjects during the first
treatment period of the study.

Table 4 Demographic Characteristics of Subjects in the FT Period

  ----------------------- ------------ --------------- ------------ --------------- ------------ ----------------
                                                                    FT Efalizumab                

                                       FT Placebo                   1.0 mg/kg/wk                 2.0 mg/kg/wk

  Characteristic, n                    (n=170)                      (n=162)                      (n=166)

  Age (yr)                                                                                       

  Mean                                 42                           45                           46

  Median                               43                           45                           44

  Range                                18--68                       18--75                       20--74

  Age group (yr)                                                                                 

  18--40                               73 (42.9%)                   53 (32.7%)                   63 (38.0%)

  41--64                               94 (55.3%)                   98 (60.5%)                   87 (52.4%)

  ≥ 65                                 3 (1.8%)                     11 (6.8%)                    16 (9.6%)

  Sex                                                                                            

  Male                                 124 (73%)                    118 (73%)                    118 (71%)

  Female                               46 (27%)                     44 (27%)                     48 (29%)

  Race/ethnicity                                                                                 

  White                                157 (92.4%)                  147 (90.7%)                  152 (91.6%)

  Black                                3 (1.8%)                     5 (3.1%)                     1 (0.6%)

  Asian/ Pacific Islander              6 (3.5%)                     6 (3.7%)                     3 (1.8%)

  Hispanic                             4 (2.4%)                     2 (1.2%)                     8 (4.8%)

  Other                                0                            2 (1.2%)                     2(1.2%)

  Weight (kg)                                                                                    

  Mean                                 93                           92                           94

  Median                               91                           90                           91

  Range                                45--144                      50--138                      53--144

  BMI (kg/m^2^)                                                                                  

  Mean                    31                           31                           31           

  Median                  30                           30                           30           

  Range                   14.8--60.2                   18.7--52.0                   18.5--53.6   
  ----------------------- ------------ --------------- ------------ --------------- ------------ ----------------

#  {#section .unnumbered}

More male than female patients participated in the study, whereas, in
the general psoriasis population, men and women are equally affected.
The population tends to have higher than average median weight and body
mass index probably reflecting the overall U.S. psoriatic population.

Other than the gender distribution, the characteristics are reflective
of the general psoriasis population in the United States. A higher
proportion of patients were age 65 or older in the active treatment arms
than in placebo. The numbers of patients older than 70 years of age are
limited because this age group was excluded per the eligibility criteria
(data not shown). The other baseline characteristics were well-balanced
among the treatment groups.

#### Disease Characteristics at Baseline

Table 5 below contains the baseline disease characteristics for the
study population.

Table 5 Baseline Psoriasis Characteristics of Subjects in the FT Period

+-------------------------+-------------+--------------+--------------+
|                         |             | FT           |              |
|                         |             | Efalizumab   |              |
+-------------------------+-------------+--------------+--------------+
|                         | FT Placebo  | 1.0 mg/kg/wk | 2.0 mg/kg/wk |
+-------------------------+-------------+--------------+--------------+
| Characteristic          | (n=170)     | (n=162)      | (n=166)      |
+-------------------------+-------------+--------------+--------------+
|                         |             |              |              |
+-------------------------+-------------+--------------+--------------+
| Duration of psoriasis   |             |              |              |
| (yr)                    |             |              |              |
+-------------------------+-------------+--------------+--------------+
| Mean                    | 18.5        | 19.1         | 16.7         |
+-------------------------+-------------+--------------+--------------+
| Median                  | 17          | 19           | 15           |
+-------------------------+-------------+--------------+--------------+
| Range                   | 1--56       | 1--58        | 1--60        |
+-------------------------+-------------+--------------+--------------+
| Prior systemic therapy  |             |              |              |
+-------------------------+-------------+--------------+--------------+
| Yes                     | 91 (53.5%)  | 89 (54.9%)   | 93 (56.0%)   |
+-------------------------+-------------+--------------+--------------+
| No                      | 79 (46.5%)  | 73 (45.1%)   | 73 (44.0%)   |
+-------------------------+-------------+--------------+--------------+
| PASI                    |             |              |              |
+-------------------------+-------------+--------------+--------------+
| Mean                    | 19.02       | 18.63        | 18.86        |
+-------------------------+-------------+--------------+--------------+
| Median                  | 16.5        | 16.9         | 16.8         |
+-------------------------+-------------+--------------+--------------+
| Range                   | 9.6--57.6   | 11.9--50.1   | 10.0--55.6   |
+-------------------------+-------------+--------------+--------------+
| PASI category           |             |              |              |
+-------------------------+-------------+--------------+--------------+
| ≤ 16.0                  | 79 (46.5%)  | 74 (45.7%)   | 74 (44.6%)   |
+-------------------------+-------------+--------------+--------------+
| 16.1--30.0              | 78 (45.9%)  | 77 (47.5%)   | 79 (47.6%)   |
+-------------------------+-------------+--------------+--------------+
| \>30                    | 13 (7.6%)   | 11 (6.8%)    | 13 (7.8%)    |
+-------------------------+-------------+--------------+--------------+
| PASI thickness          |             |              |              |
| component               |             |              |              |
+-------------------------+-------------+--------------+--------------+
| Mean                    | 6.26        | 6.07         | 6.08         |
+-------------------------+-------------+--------------+--------------+
| Median                  | 5.6         | 5.5          | 5.5          |
+-------------------------+-------------+--------------+--------------+
| Range                   | 2.4--19.2   | 2.1--18.2    | 3.0--18.6    |
+-------------------------+-------------+--------------+--------------+
| Physician's Global      |             |              |              |
| Assessment              |             |              |              |
+-------------------------+-------------+--------------+--------------+
| Mild                    | 6 (3.5%)    | 4 (2.5%)     | 4 (2.4%)     |
+-------------------------+-------------+--------------+--------------+
| Moderate                | 86 (50.6%)  | 90 (56.3%)   | 86 (51.8%)   |
+-------------------------+-------------+--------------+--------------+
| Severe                  | 67 (39.4%)  | 61 (38.1%)   | 70 (42.2%)   |
+-------------------------+-------------+--------------+--------------+
| Very severe             | 11 (6.5%)   | 5 (3.1%)     | 6 (3.6%)     |
+-------------------------+-------------+--------------+--------------+
| \% BSA of psoriasis     |             |              |              |
+-------------------------+-------------+--------------+--------------+
| Mean                    | 29.4        | 29.6         | 29.9         |
|                         |             |              |              |
| Median                  | 25.6        | 24.3         | 24.2         |
+-------------------------+-------------+--------------+--------------+
| Range                   | 10-85       | 10-72        | 10-83        |
+-------------------------+-------------+--------------+--------------+
| Itching Scale           |             |              |              |
+-------------------------+-------------+--------------+--------------+
| Mean                    | 5.9         | 5.8          | 6.1          |
+-------------------------+-------------+--------------+--------------+
| Median                  | 6           | 6            | 7            |
+-------------------------+-------------+--------------+--------------+
| Range                   | 0-10        | 0-10         | 0-10         |
+-------------------------+-------------+--------------+--------------+

The median duration of disease was 17 years (range 1-60 years).
Approximately 55% of all subjects had a history of prior systemic
therapy; however, for a substantial proportion of the study stubjects,
efalizumab was the first systemic therapy received. The median baseline
PASI score was approximately 16.7. The treatment groups were
well-balanced in all the measures of baseline disease activity. Overall,
the baseline psoriasis characteristics indicate the study population had
moderate-to-severe psoriasis.

Table 6 below contains information with regard to treatment compliance
with study drug by treatment group.

Table 6 Treatment Compliance for Subjects during the FT Period

  -------------------- ----------------- ----------------- ---------------
                                         Efalizumab        

  No. of Doses         Placebo           1.0 mg/kg/wk      2.0 mg/kg/wk

  Received             (n=170)           (n=162)           (n=166)

  All 12               122 (72%)         129 (80%)         119 (72%)

  10--11               27 (16%)          20 (12%)          29 (18%)

  \<10                 21 (12%)          13 (8%)           18 (11%)
  -------------------- ----------------- ----------------- ---------------

Twenty-one subjects (4.2%) received two or more conditioning doses: 5.9%
of subjects in the placebo group, 3.1% in the 1.0 mg/kg/wk efalizumab
group, and 3.6% in the 2.0 mg/kg/wk efalizumab group.

The proportion of patients who received ≤ 10 doses, in part, reflects
the proportion of patients discontinuing the first treatment period.

#### Use of Concomitant Medications

A total of 30 subjects, 6.0% of all patients, received an excluded
medication or phototherapy during the first treatment period. Eight of
these patients were in the placebo group, 14 in the 1.0 mg/kg dose
efalizumab group, and 8 were in the 2.0 mg/kg efalizumab group.

#### Primary Efficacy Outcomes

Table 7 PASI Response to Treatment during the FT Period: All Randomized
Subjects

  ----------------------- ----------------- ------------ -----------------
                                            Efalizumab   

  PASI Response at FT Day Placebo           1.0 mg/kg/wk 2.0 mg/kg/wk
  84                                                     

                          (n=170)           (n=162)      (n=166)

  Responders, n           4 (2%)            63 (39%)     44 (26%)

                                                         

  Partial and             166 (98%)         99 (61%)     122 (74%)
  non-responders, n \*                                   

  Fisher's exact p-value                                 

  efalizumab vs. placebo  ---               \<0.001      \<0.001
  ----------------------- ----------------- ------------ -----------------

\* Included subjects who discontinued.

The proportion of responders was statistically higher in the treatment
groups than in placebo. The absolute difference was 37% for the 1.0
mg/kg/wk group and 24% for the 2 mg/kg/wk group. The response rate was
not higher with the 2.0 mg/kg/wk vs. the 1.0 mg/kg/wk dose of
efalizumab.

*Reviewer's comment:* *CD11a receptors of circulating lymphocytes are
saturated at the 1.0 mg/kg/wk dose and would probably explain the lack
of dose response.*

Last observation carried forward and other sensitivity analyses for
missing data did not change the estimate of the treatment effect.

Table 8 Mean Percent Improvement in PASI Thickness, Erythema, and
Scaling Components during the FT Period

  ------------------------- -------------- --------------- ----------------
                                           FT Efalizumab   

                            FT Placebo     1.0 mg/kg/wk    2.0 mg/kg/wk

  PASI Component            (n=170)        (n=162)         (n=166)

  Thickness ^a^             17.4           55.9            45.4

  Erythema ^a^              16.4           50.9            43.0

  Scaling ^a^               17.4           58.6            51.2

  PASI total ^b^            19.8           60.1            50.5
  ------------------------- -------------- --------------- ----------------

Note: Improvement in each component was reflected by a decrease in
score.

a The last observation carried was used to impute missing FT Day 84 PASI
data.

b Values from the early termination visits were assigned to the next
scheduled visit for PASI evaluation.

The components of the PASI - thickness, erythema, scaling- each show
higher mean percentage improvement in the efalizumab-treated patients as
compared to placebo-treated patients. Therefore, the all of the
components appear to contribute similarly to improvement in the overall
score.

The effect on affected body surface area is shown below.

Table 9 Mean Improvement in Percent BSA of Psoriasis during the FT
Period

  --------------------------- -------------- -------------- --------------
                                             FT Efalizumab  

                              FT Placebo     1.0 mg/kg/wk   2.0 mg/kg/wk

                              (n=170)        (n=162)        (n=166)

  Percent BSA affected at FT  29.4           29.6           29.9
  Day 0                                                     

  Percent BSA affected FT Day 27.6           15.8           19.9
  84                                                        

  Improvement ^a^ from        1.8            13.8           10.0
  baseline                                                  
  --------------------------- -------------- -------------- --------------

^a^ Improvement was reflected by a decrease in the percent BSA score.

The mean percentage body surface area affected at the end of the 84-day
treatment period improved more in the 1.0 mg/kg/wk group and 2.0
mg/kg/wk efalizumab groups than in in the placebo-treated patients.

Reviewer's comment: The mean percentage improvement in affected BSA is
smaller than that of the other measures of disease severity- erythema,
thickness and scale.

The response among various subsets of the studied population is show in
Table 10 below.

Table 10 PASI Responders by Subsets of Randomized Subjects: FT Period

  ---------------------------- -------------- ------------- ---------------
                                              Efalizumab    

                               Placebo        1.0 mg/kg     2.0 mg/kg

  Subject Subset               n=170          n=162         n=166

  Gender                                                    

  Men                          1/124 (0.8%)   43/118 (36%)  29/118 (25%)

  Women                        3/46 (6.5%)    20/44 (46%)   15/48 (31%)

  Age group (yr)                                            

  18--40                       3/73 (4.1%)    17/53 (32%)   17/63 (27%)

  41--64                       1/94 (1.1%)    40/98 (41%)   24/87 (27%)

  ≥ 65, n                      0/3 (0%)       6/11 (55%)    3/16 (19%)

  Baseline PASI category                                    

  ≤ 16.0                       1/79 (1.3%)    32/74 (43%)   20/74 (27%)

  16.1--30.0, n                2/78 (2.6%)    25/77 (33%)   20/79 (25%)

  \>30.0, n                    1/13 (7.7%)    6/11 (55%)    4/13 (31%)

  Prior systemic therapy                                    

  Yes, n                       1/91 (1.1%)    32/89 (36%)   27/93 (29%)

  No, n                        3/79 (3.8%)    31/73 (43%)   17/73 (23%)
  ---------------------------- -------------- ------------- ---------------

The results of the primary efficacy analysis are generalizable across
gender, age, baseline PASI and history of prior systemic therapy
subsets. There was a trend towards higher response rates in patients in
the low dose group than the high dose group of efalizumab.

The data below show the response rate by geographic latitude by
treatment group

(see Table 11). The Northern U.S. sites included those in the Northeast,
Northcentral, and Northwest regions (Washington, Oregon, Utah, Colorado,
and northern California).

The Southern U.S. sites included those in the south and southwest
regions (Arizona, New

Mexico, and southern California).

Table 11 PASI Response to Treatment by Latitude (FT Period)

  ------------- -------------------- ------------- ------------ ------------
                                                   Efalizumab   Efalizumab

                                     Placebo       1.0 mg/kg/wk 2.0 mg/kg/wk

  Latitude      FT Day 84 Response   (N=170)       (N=162)      (N=166)

                                                                

  Canada        N                    47            45           46

                Responder            2 (4.3%)      14 (31.1%)   11 (23.9%)

                95% Confidence       \[0.005,      \[0.182,     \[0.126,
                Interval             0.145\]       0.466\]      0.388\]

                                                                

  Northern      N                    76            77           74
  United States                                                 

                Responder            2 (2.6%)      34 (44.2%)   19 (25.7%)

                95% Confidence       \[0.003,      \[0.328,     \[0.162,
                Interval             0.092\]       0.559\]      0.372\]

                                                                

  Southern      N                    47            40           46
  United States                                                 

                Responder            (0.0%)        15 (37.5%)   14 (30.4%)

                95% Confidence       \[0.000,      \[0.227,     \[0.177,
                Interval             0.075\]       0.542\]      0.458\]
  ------------- -------------------- ------------- ------------ ------------

Clinical responses did not differ by geographic latitude.

Table 12 Covariates Potentially Predictive of PASI Response: FT Period

  -------------------------------------- ----------- --------------------
  Model Predictor                        Odds Ratio  95% CI

  Sex                                                

  Female vs. male                        1.725       1.021, 2.912

  Prior systemic therapy                             

  No vs. yes                             1.108       0.689, 1.779

  Geographic region                                  

  Canada vs. western United States       0.612       0.314, 1.186

  North central vs. western United       1.186       0.620, 2.276
  States                                             

  Northeastern vs. western United States 0.205       0.045, 0.676

  Southern vs. western United States     0.622       0.287, 1.312
  -------------------------------------- ----------- --------------------

The following covariates were examined in the model and did not have any
relationship to treatment response: baseline PASI score, age, history of
prior systemic therapy and season (spring vs. summer). There was a
suggestion of higher responses in women, but this was not supported in
subsequent studies. Also, a comparison of response by geographic region
suggested a higher response in the Western United States vs. that seen
in the Northeastern United States.

#### Secondary Efficacy Outcomes

Table 13 Principal Secondary Efficacy Endpoint: FT Period

  ----------------------------- ----------- ------------ -----------------
                                            FT           
                                            Efalizumab   

                                FT Placebo  1.0 mg/kg/wk 2.0 mg/kg/wk

  OLS Response at FT Day 84     (n=170)     (n=162)      (n=166)

  Minimal or Clear              5 (2.9%)    52 (32.1%)   37 (22.3%)

  Mild to Very Severe \*        165 (97.1%) 110 (67.9%)  129 (77.7%)

  Fisher's exact p-value        ---         \<0.001      \<0.001
  efalizumab vs. placebo                                 
  ----------------------------- ----------- ------------ -----------------

\* Included subjects who were classified as Mild, Moderate, Severe, and
Very

Severe and those who discontinued.

The secondary efficacy outcomes also showed that efalizumab was superior
to placebo.

![](media/image3.png){width="6.479166666666667in"
height="4.180555555555555in"}

From the figure, there is separation of the efalizumab curves from that
of placebo by day 14 days of treatment.

The PGA, a physician's global assessment, was used to measure the
dynamic response of patients as compared baseline (See Table 14 below).

Table 14 PGA Response for Subjects during the FT Period

  ---------------------------- ------------- ------------ -----------------
                                             FT           
                                             Efalizumab   

                               Placebo       1.0 mg/kg/wk 2.0 mg/kg/wk

  PGA Response at FT Day 84    (n=170)       (n=162)      (n=166)

  Excellent or Cleared         7 (4.1%)      63 (38.9%)   50 (30.1%)

  Good to Worse ^a^            163 (95.9%)   99 (61.1%)   116 (69.9%)

  Fisher's exact p-value                                  

  efalizumab vs. placebo       ---           \<0.001      \<0.001

  ^a^ Included subjects who                               
  were classified as Good,                                
  Fair, Slight, Poor,                                     
  Unchanged, or Worse and                                 
  those who discontinued.                                 
  ---------------------------- ------------- ------------ -----------------

A greater proportion of patients achieved excellent or cleared in both
efalizumab treatment groups compared to placebo using the dynamic
physician's global assessment. The differences reached statistical
significance.

#### Time-to-response and duration of treatment response

Time-to-onset of PASI-75 response was analyzed and the results are shown
in Table 15 below.

Table 15 Time (days) to PASI-75 Response, Using Kaplan Meier Estimates
Study ACD2058g (FT Period): Subjects Who Achieved a PASI-75 Response at
Any Time

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

                                          Efalizumab      Efalizumab

  Characteristic            Placebo       1.0 mg/kg/wk    2.0 mg/kg/wk

                                                          

                                                          

  Subjects Who Achieved     9             74              52
  PASI-75 at Any Time                                     

  Median                    43.0          57.0            57.0

  95% C.I. for Median       (41.0, 71.0)  (56.0, 59.0)    (55.0, 71.0)

  25-75 %ile                41.0 - 71.0   43.0 - 72.0     45.5 - 79.5

  Minimum - Maximum         29.0 - 74.0   28.0 - 89.0     28.0 - 92.0
  ------------------------- ------------- --------------- ---------------

Median time to achieve PASI 75 in patients who achieved PASI 75 at any
time was approximately 2 months.

#### Duration

Time-to-relapse defined as a loss of ≥ 50% improvement in PASI score
achieved between baseline and the end of the 84-day treatment period was
summarized by treatment group for treatment responders (≥ PASI 75 at day
84). The results are shown in Table 16 below.

Table 16 Time (days) to Relapse during the OB Period, Using Kaplan-Meier
Estimates: Subjects Treated with Efalizumab during the FT Period

  ---------------------------------- ------------------ ------------------
                                     Efalizumab         

                                     1.0 mg/kg          2.0 mg/kg

  Characteristic                     n=63               n=44

  Events                             55                 37

  Censored observations ^a^          8                  7

  Median (95% CI)                    60.0 (57, 66)      59.0( 57, 82)

  25th--75th Percentile              43.0--85.0         49.0--87.0
  ---------------------------------- ------------------ ------------------

^a^Data from subjects who discontinued prior to relapse or who did not
relapse

during the OB period were censored.

The median time to relapse during the observation period was 60 days (67
days after the last dose of efalizumab) for the 1.0- mg/kg/wk group and
59 days for the 2-mg/kg/wk group.

An analysis of the distribution of percent improvement in PASI achieved
during the first 84 days of treatment is shown in Table 17 below.

Table 17 PASI Response by Percent Improvement from Baseline for Subjects
during the FT Period (% of total)

  --------------------------- --------------- ------------ --------------
                                              Efalizumab   

  Percent Improvement from    Placebo         1.0 mg/kg/wk 2.0 mg/kg/wk
  Baseline                                                 

                              (n=170)         (n=162)      (n=166)

  ≥ 90%                       1.2             12.3         4.8

       ≥75% to \< 90%         1.2             26.5         21.7

       ≥ 50% to \< 75%        12.4            22.2         24.7

       ≥ 25% to \< 50%        20.0            16.7         21.1

  \< 25%                      54.1            14.2         15.7

  Missing ^a^                 11.2            8.0          12.0
  --------------------------- --------------- ------------ --------------

^a^Subjects who were missing the FT Day 84 score were classified as
non-responders for the analysis of the primary efficacy endpoint.

This analysis demonstrates a general shift toward improvement in the
efalizumab groups compared with the placebo group. Additionally, a trend
toward higher percentage improvements in PASI in the low dose group than
in the high dose group exists.

#### The OB Period

Patients who achieved PASI 75 at the end of the first treatment period
could enter the observation period. A total of 111 patients entered the
OB Period. Of these, 4 received placebo in the first treatment period
and the remainder received treatment with efalizumab. Overall, 83% of
the patients who discontiued the observation period met the endpoint of
relapse during the observation period and entered retreatment. Overall,
9.9% of patients did not experience relapse during the 84-day
observation period.

Table 18 Disposition of Subjects and Reasons for Discontinuation during
the OB Period

  ------------------------- --------- ------------ ---------- --------------
                                      FT                      
                                      Efalizumab              

                                                              

                            FT        1.0 mg/kg/wk 2.0        All Subjects
                            Placebo                mg/kg/wk   

  Subject Status            (n=4)     (n=63)       (n=44)     (n=111)

  Completed OB, n           1 (25.0%) 5 (7.9%)     5 (11.4%)  11 (9.9%)

  Enrolled in Study         0         0            1          1
  ACD2062g                                                    

  Entered RT                0         1            1          2

  Entered FU                1         3            3          7

  Discontinued from study   0         1            0          1

  Discontinued OB, n        3 (75.0%) 58 (92.1%)   39 (88.6%) 100 (90.1%)

  Enrolled in Study         0         1            2          3
  ACD2062g                                                    

  Entered RT                3         49           31         83

  Entered FU                0         2            2          4

  Discontinued from study   0         6            4          10

  Reason for                                                  
  discontinuation from OB                                     

  Adverse event             0         1            1          2

  Lost to follow-up         0         1            1          2

  Subject's decision        0         2            1          3

  Investigator's decision   0         1            4          5

  Pregnancy                 0         1            1          2

  Relapse of psoriasis      3         52           31         86
  ------------------------- --------- ------------ ---------- --------------

A protocol amendment made it possible for patients experiencing severe
psoriasis upon relapse to enter Study ACD2062g. Of the 100 patients who
discontinued the observation period, 86 patients experienced a relapse
of psoriasis. Of these patients, 83 entered the retreatment period and 3
entered Study ACD2062g. Among the 14 patients listed as having
discontinued for reasons other than relapse of psoriasis, several
discontinued for psoriasis variants and worsening of psoriasis.

Table 19 Psoriasis-Related Concomitant Medications Initiated during the
OB Period:

+-------------+---------------+---------+---+----+---+----+---+-------+
|             |               | FT      |   |    |   |    |   |       |
|             |               | Period  |   |    |   |    |   |       |
|             |               | Res     |   |    |   |    |   |       |
|             |               | ponders |   |    |   |    |   |       |
+-------------+---------------+---------+---+----+---+----+---+-------+
|             |               | Placebo | D |    | D |    | A |       |
|             |               |         | r |    | r |    | l |       |
|             |               |         | u |    | u |    | l |       |
|             |               |         | g |    | g |    | S |       |
|             |               |         |   |    |   |    | u |       |
|             |               |         | 1 |    | 2 |    | b |       |
|             |               |         | . |    | . |    | j |       |
|             |               |         | 0 |    | 0 |    | e |       |
|             |               |         | m |    | m |    | c |       |
|             |               |         | g |    | g |    | t |       |
|             |               |         | / |    | / |    | s |       |
|             |               |         | k |    | k |    |   |       |
|             |               |         | g |    | g |    |   |       |
|             |               |         | / |    | / |    |   |       |
|             |               |         | w |    | w |    |   |       |
|             |               |         | k |    | k |    |   |       |
+-------------+---------------+---------+---+----+---+----+---+-------+
| USAN Class  | Generic Name  | (N=4)   | ( |    | ( |    | ( |       |
|             |               |         | N |    | N |    | N |       |
|             |               |         | = |    | = |    | = |       |
|             |               |         | 6 |    | 4 |    | 1 |       |
|             |               |         | 3 |    | 4 |    | 1 |       |
|             |               |         | ) |    | ) |    | 1 |       |
|             |               |         |   |    |   |    | ) |       |
+-------------+---------------+---------+---+----+---+----+---+-------+
|             |               |         |   |    |   |    |   |       |
+-------------+---------------+---------+---+----+---+----+---+-------+
| Subjects    |               | 4       |   | 63 |   | 44 | 1 |       |
| with        |               |         |   |    |   |    | 1 |       |
|             |               |         |   |    |   |    | 1 |       |
| completed   |               |         |   |    |   |    |   |       |
|             |               |         |   |    |   |    |   |       |
| medication  |               |         |   |    |   |    |   |       |
| forms       |               |         |   |    |   |    |   |       |
+-------------+---------------+---------+---+----+---+----+---+-------+
| Subjects    |               | 2       | 1 |    | 1 |    | 2 |       |
| initiated   |               | (50.0%) | 2 |    | 3 |    | 7 |       |
| at least    |               |         | ( |    | ( |    | ( |       |
| one         |               |         | 1 |    | 2 |    | 2 |       |
| psoriasis-  |               |         | 9 |    | 9 |    | 4 |       |
| related     |               |         | . |    | . |    | . |       |
| medication  |               |         | 0 |    | 5 |    | 3 |       |
|             |               |         | % |    | % |    | % |       |
|             |               |         | ) |    | ) |    | ) |       |
+-------------+---------------+---------+---+----+---+----+---+-------+
|             |               |         |   |    |   |    |   |       |
+-------------+---------------+---------+---+----+---+----+---+-------+
| D           | \- Total -    | (0.0%)  | 2 | (3 | 2 | (4 | 4 | (     |
| ermatologic |               |         |   | .2 |   | .5 |   | 3.6%) |
| agents      |               |         |   | %) |   | %) |   |       |
+-------------+---------------+---------+---+----+---+----+---+-------+
|             | Acitretin     | (0.0%)  |   | (0 | 1 | (2 | 1 | (     |
|             |               |         |   | .0 |   | .3 |   | 0.9%) |
|             |               |         |   | %) |   | %) |   |       |
+-------------+---------------+---------+---+----+---+----+---+-------+
|             | Calcipotriene | (0.0%)  | 1 | (1 |   | (0 | 1 | (     |
|             |               |         |   | .6 |   | .0 |   | 0.9%) |
|             |               |         |   | %) |   | %) |   |       |
+-------------+---------------+---------+---+----+---+----+---+-------+
|             | Coal tar      | (0.0%)  | 1 | (1 | 1 | (2 | 2 | (     |
|             |               |         |   | .6 |   | .3 |   | 1.8%) |
|             |               |         |   | %) |   | %) |   |       |
+-------------+---------------+---------+---+----+---+----+---+-------+
|             |               |         |   |    |   |    |   |       |
+-------------+---------------+---------+---+----+---+----+---+-------+
| Steroids    | \- Total -    | 2       | 1 |    | 1 |    | 2 |       |
|             |               | (50.0%) | 1 |    | 2 |    | 5 |       |
|             |               |         | ( |    | ( |    | ( |       |
|             |               |         | 1 |    | 2 |    | 2 |       |
|             |               |         | 7 |    | 7 |    | 2 |       |
|             |               |         | . |    | . |    | . |       |
|             |               |         | 5 |    | 3 |    | 5 |       |
|             |               |         | % |    | % |    | % |       |
|             |               |         | ) |    | ) |    | ) |       |
+-------------+---------------+---------+---+----+---+----+---+-------+
|             | Betamethasone | (0.0%)  |   | (0 | 1 | (2 | 1 | (     |
|             | valerate      |         |   | .0 |   | .3 |   | 0.9%) |
|             |               |         |   | %) |   | %) |   |       |
+-------------+---------------+---------+---+----+---+----+---+-------+
|             | Cortisone     | (0.0%)  |   | (0 | 1 | (2 | 1 | (     |
|             | acetate       |         |   | .0 |   | .3 |   | 0.9%) |
|             |               |         |   | %) |   | %) |   |       |
+-------------+---------------+---------+---+----+---+----+---+-------+
|             | Dexamethasone | (0.0%)  |   | (0 | 1 | (2 | 1 | (     |
|             |               |         |   | .0 |   | .3 |   | 0.9%) |
|             |               |         |   | %) |   | %) |   |       |
+-------------+---------------+---------+---+----+---+----+---+-------+
|             | Fluocinolone  | (0.0%)  |   | (0 | 1 | (2 | 1 | (     |
|             | acetonide     |         |   | .0 |   | .3 |   | 0.9%) |
|             |               |         |   | %) |   | %) |   |       |
+-------------+---------------+---------+---+----+---+----+---+-------+
|             | Fluticasone   | (0.0%)  | 2 | (3 |   | (0 | 2 | (     |
|             | propionate    |         |   | .2 |   | .0 |   | 1.8%) |
|             |               |         |   | %) |   | %) |   |       |
+-------------+---------------+---------+---+----+---+----+---+-------+
|             | Halobetasol   | (0.0%)  | 1 | (1 |   | (0 | 1 | (     |
|             | propionate    |         |   | .6 |   | .0 |   | 0.9%) |
|             |               |         |   | %) |   | %) |   |       |
+-------------+---------------+---------+---+----+---+----+---+-------+
|             | H             | 1       | 5 | (7 | 5 |    | 1 | (     |
|             | ydrocortisone | (25.0%) |   | .9 | ( |    | 1 | 9.9%) |
|             |               |         |   | %) | 1 |    |   |       |
|             |               |         |   |    | 1 |    |   |       |
|             |               |         |   |    | . |    |   |       |
|             |               |         |   |    | 4 |    |   |       |
|             |               |         |   |    | % |    |   |       |
|             |               |         |   |    | ) |    |   |       |
+-------------+---------------+---------+---+----+---+----+---+-------+
|             | Mometasone    | (0.0%)  | 4 | (6 | 1 | (2 | 5 | (     |
|             | furoate       |         |   | .3 |   | .3 |   | 4.5%) |
|             |               |         |   | %) |   | %) |   |       |
+-------------+---------------+---------+---+----+---+----+---+-------+
|             | Prednisolone  | (0.0%)  |   | (0 | 1 | (2 | 1 | (     |
|             | acetate       |         |   | .0 |   | .3 |   | 0.9%) |
|             |               |         |   | %) |   | %) |   |       |
+-------------+---------------+---------+---+----+---+----+---+-------+
|             | Prednisone    | 1       |   | (0 | 2 | (4 | 3 | (     |
|             |               | (25.0%) |   | .0 |   | .5 |   | 2.7%) |
|             |               |         |   | %) |   | %) |   |       |
+-------------+---------------+---------+---+----+---+----+---+-------+
|             | Triamcinolone | (0.0%)  | 1 | (1 | 3 | (6 | 4 | (     |
|             | acetonide     |         |   | .6 |   | .8 |   | 3.6%) |
|             |               |         |   | %) |   | %) |   |       |
+-------------+---------------+---------+---+----+---+----+---+-------+

Overall, 24% of patients entering the observation period initiated at
least one psoriasis-related medication (See Table 19). The majority of
these patients initiated treatment with topical steroids. Three patients
initiated treatment with systemic steroids (prednisone).

*Reviewer's comment: It is possible that the use of the disallowed
concomitant medications during the observation period may have affected
the estimate of the duration of response. Analyses are ongoing to
evaluate.*

#### Response to Second Treatment Course in Patients who Responded to the First Treatment

The only study which examined the response to retreatment was Study
ACD2058. In this study, patients who were responders (achieved ≥ 75%
improvement in PASI) at day 84 were eligible to enter an observation
period, no treatment for up to 168 days during which they were followed
until relapse, and then rerandomized to a second treatment course. Upon
relapse, placebo patients received a second course of efalizumab, while
efalizumab-treated patients were rerandomized centrally to receive
either the same dosage of efalizumab or placebo in a 2:1 ratio.

Subjects not responding to the second course of treatment by RT Day 56
were eligible to transfer to the open label study, ACD2062g. As
discussed on page [33](#the-ob-period), the majority of both placebo-
and efalizumab- treated patients discontinued the observation period due
to relapse of their psoriasis.

Table 20 below reflects the disposition of the subset of patients who
responded to treatment with efalizumab (active drug) during the first 84
days of treatment and were rerandomized during the observation period to
retreatment.

Table 20 Disposition of RT-A Subjects and Reasons for Discontinuation

  --------------------------- ------------- ---------------- ---------------
                                            **Efalizumab**   

                              **Placebo**   **1.0 mg/kg**    **2.0 mg/kg**

  Subject Status              (n=27)        (n=32)           (n=23)

  Completed RT                8 (29.6%)     26 (81.2%)       16 (69.6%)

  Entered FU                  5             23               13

  Entered Study ACD2062g      2             3                1

  Discontinued from study     1             0                2

                                                             

  Discontinued RT             19 (70.4%)    6 (18.8%)        7 (30.4%)

  Entered FU                  1             0                2

  Entered Study ACD2062g      18            6                5

                                                             

  Reason for RT               (n=19)        (n=6)            (n=7)
  discontinuation                                            

  Subject's decision          1             0                1

  Investigator's decision     1             0                0

  Non-response to RT          16            6                6

  Non-response to ET ^a^      1             0                0
  --------------------------- ------------- ---------------- ---------------

^a^ One subject should have been classified as a non-responder to
retreatment, making the total number of non-responders 29 (90.6%).

Eighty-six subjects were eligible to enter RT. Of these, 82 were
rerandomized to RT.

Most of the patients who were rerandomized to receive efalizumab
completed the course of retreatment, while fewer than one-third (29.6%)
of the patients who were rerandomized to placebo completed the
retreatment period. Most of the latter patients discontinued due to
non-response to retreatment.

Table 21 below shows the psoriasis characteristics of the subset of
responders who entered retreatment upon relapse.

Table 21 Psoriasis Characteristics of RT-A Subjects

  ---------------------- ------------ ------------ ------------ -------------
                                      Efalizumab                All

                                                                Efalizumab-

                                      1.0          2.0          Treated

                         Placebo      mg/kg/wk     mg/kg/wk     Subjects

  Characteristic, n      (n=27)       (n=32)       (n=23)       (n=55)

                                                                

  Duration of psoriasis                                         
  (yr)                                                          

  Mean                   20.6         20.0         18.9         19.5

  Median                 21           20           18           20

  Range                  3--46        3--43        2--43        2--43

  Prior systemic therapy                                        

  Yes                    15 (55.6%)   19 (59.4%)   13 (56.5%)   32 (58.2%)

  No                     12 (44.4%)   13 (40.6%)   10 (43.5%)   23 (41.8%)

  Baseline PASI (FT Day                                         
  0)                                                            

  Mean                   18.7         17.7         19.2         18.3

  Median                 17.5         15.4         17.1         15.6

  Range                  11.9--29.7   12.0--35.3   12.1--36.0   12.0--36.0

  RT Day 0 PASI                                                 

  Mean                   14.8         13.2         13.7         13.4

  Median                 12.4         11.9         11.6         11.6

  Range                  7.5--39.0    7.4--29.2    8.5--28.7    7.4--29.2

  Baseline (FTDay 0)                                            
  PASI category                                                 

     ≤16.0               12 (44.4%)   19 (59.4%)   11 (47.8%)   30 (54.5%)

  16.1--30.0             15 (55.6%)   10 (31.3%)   8 (34.8%)    18 (32.7%)

  \>30                   0            3 (9.4%)     4 (17.4%)    7 (12.7%)

  Baseline (FT Day 0)                                           
  OLS                                                           

  Moderate               18 (66.7%)   21 (65.6%)   12 (52.2%)   33 (60.0%)

  Severe                 9 (33.3%)    10 (31.3%)   11 (47.8%)   21 (38.2%)

  Very severe            0            1 (3.1%)     0            1 (1.8%)
  ---------------------- ------------ ------------ ------------ -------------

The rerandomized patients were reasonably well balanced in terms of the
baseline disease severity. This subset had moderate-to-severe psoriasis
at Day 0 of the first treatment period according to the static
physician's global assessment and a median baseline PASI of 15.6. As
would be expected, the overall median PASI score at the beginning of
retreatment, 11.6, was lower than that at Day 0 of the first treatment
period.

Psoriasis Characteristics of RT-A Subjects (cont)

  ---------------------- ------------ ------------ ------------ -------------
                                      Efalizumab                All

                                                                Efalizumab-

                                      1.0          2.0          Treated

                         Placebo      mg/kg/wk     mg/kg/wk     Subjects

  Characteristic, n      (n=27)       (n=32)       (n=23)       (n=55)

  RT Day 0 OLS                                                  

  Mild                   0            1 (3.2%)     4 (17.4%)    5 (9.3%)

  Moderate               23 (85.2%)   25 (80.6%)   15 (65.2%)   40 (74.1%)

  Severe                 4 (14.8%)    4 (12.9%)    4 (17.4%)    8 (14.8%)

  Very severe            0            1 (3.2%)     0            1 (1.9%)

  \% BSA of psoriasis                                           

  Mean                   31.7         29.1         31.5         30.1

  Median                 32.0         24.6         28.0         24.8

  Range                  13.0--63.0   11.0--59.0   11.0--81.0   11.0--81.0

  RT Day 0 % BSA of                                             
  psoriasis                                                     

  Mean                   24.0         17.1         21.8         19.1

  Median                 20.0         14.0         15.5         14.8

  Range                  5.0--74.0    6.2--43.0    7.0--54.0    6.2--54.0

  FT Day 84 PGA                                                 

  Cleared                1 (3.7%)     2 (6.3%)     0            2 (3.6%)

  Excellent              23 (85.2%)   27 (84.4%)   20 (87.0%)   47 (85.5%)

  Good                   2 (7.4%)     2 (6.3%)     3 (13.0%)    5 (9.1%)

  Fair                   1 (3.7%)     0            0            0

  Missing                0            1 (3.1%)     0            1 (1.8%)

  RT Day 0 PGA                                                  

  Good                   1 (3.7%)     2 (6.3%)     0            2 (3.6%)

  Fair                   12 (44.4%)   17 (53.1%)   7 (30.4%)    24 (43.6%)

  Slight                 4 (14.8%)    5 (15.6%)    12 (52.2%)   17 (30.9%)

  Unchanged              2 (7.4%)     2 (6.3%)     1 (4.3%)     3 (5.5%)

  Worse                  8 (29.6%)    6 (18.8%)    3 (13.0%)    9 (16.4%)

  Unless otherwise                                              
  stated baseline was FT                                        
  Day 0.                                                        
  ---------------------- ------------ ------------ ------------ -------------

The subset of patients who subsequently received retreatment had
moderate to severe psoriasis at baseline (FT Day 0). The baseline
characteristics were comparable to the ITT population as a whole. The
patients' retreatment baseline were, as would be expected, better than
their original baseline in all measures of disease severity including
PASI and baseline BSA affected by psoriasis.

Treatment compliance in the patients randomized to retreatment is shown
in below.

Table 22 Treatment Compliance for RT-A Subjects

  -------------------- ---------------- --------------- --------------- --
                                        Efalizumab                      

  No. of Doses         Placebo          1.0 mg/kg/wk    2.0 mg/kg/wk    

  Received             (n=27)           (n=32)          (n=23)          

  All 12               8 (30%)          24 (75%)        16 (70%)        

  10--11               0                2 (6.3%)        1 (4.3%)        

  \<10                 19 (70%)         6 (19%)         6 (26%)         
  -------------------- ---------------- --------------- --------------- --

Whereas, the majority of patients in the efalizumab groups received all
12 doses in the RT period, less than one-third of the placebo patients
received all 12 doses. Again, the reasons for missed doses are probably
reflective of the reasons for discontinuing the retreatment period. In
the case of the placebo patients the most common reason was non-response
to treatment.

Response to retreatment is described below. These were patients who
responded to the first treatment period and then were rerandomized to
either efalizumab or placebo upon relapse (loss of 50% of improvement in
PASI). In this analysis, responses were compared to the original
baseline at FT Day 0.

Table 23 PASI Response to Retreatment (% Improvement

from FT Day 0)

  ------------------ ----------------------- -----------------------------
                     Placebo                 Efalizumab (Combined)

  Response Category  (N=27)                  (N=55)

  ≥ 75%              0                       17 ( 31%)

  ≥ 50% -\< 75%      5 (19%)                 20 ( 36%)

  0-50%              2 (7%)                  4 ( 7%)

  \<0%               1 (4%)                  1 (2 %)

  Missing            19 (70%)                13 ( 24%)
  ------------------ ----------------------- -----------------------------

Among patients who received retreatment with efalizumab, 34% of the 1
mg/kg group and 25% of the 2 mg/kg group responded at the PASI 75 level
at the end of the retreatment period. This was in contrast to patients
rerandomized to placebo who had no responders to retreatment. The
majority of the patients receiving efalizumab upon retreatment, 72% and
61% the 1 mg/kg group and 2 mg/kg group, respectively, responded at the
PASI 50 level.

While all patients had achieved a 75% improvement in PASI at Day 84 of
the first treatment period, less than one-third of the combined
efalizumab-treated patients achieved this level of response at Day 84 of
retreatment. The patients' state of active relapse at the beginning of
the retreatment period may have contributed to the lower response rate
to retreatment.

Figure 2 below depicts the PASI score at retreatment in relation to the
minimum relapse PASI defined as a loss of 50% of the improvement
achieved during the first treatment period.

Figure 2

![](media/image4.png){width="4.625in" height="4.46875in"}

Since PASI assessments were scheduled for OB Days 14, 28, 56, 84, 112,
140 and 168,

in most cases the retreatment baseline PASI score exceeded the minimum
retreatment score. The magnitude of the difference between retreatment
PASI and the minimum requirement ranged from 0 to nearly 25 points. In
most cases the difference did not exceed 10 PASI points. (Of note one
patient, entered retreatment with less than the minimum required PASI
score.)

*Reviewer's comment:* *It is not known whether the severity of relapse
may have played a role in inhibiting the ability of the drug to
recapture PASI responses comparable to those achieved during the first
treatment period.*

Of note, there was a considerable proportion of patients in each group
for whom these data are missing. The majority of the patients in the
placebo group had missing data. The high proportion of missing data
reflects the number of patients who transferred to Study ACD2062g with
our completing the retreatment period, due to non-response.

The responses to retreatment when compared to the new baseline are shown
in Table 24 below.

Table 24 PASI Response to Retreatment (% Improvement

from RT Day 0)

  ------------------ ----------------------- -----------------------------
                     Placebo                 Efalizumab (Combined)

  Response Category  (N=27)                  (N=55)

  ≥ 75%              0                       12 (22%)

  ≥ 55%              3 (11%)                 27 (49%)

  0-50               3 (11%)                 12 (22%)

  \< 0               2 (7.4%)                3 (5%)

  Missing            19 (70%)                13 (24%)
  ------------------ ----------------------- -----------------------------

By comparison to the most recent baseline, the proportions of patients
achieving PASI 50 and PASI 75 are fewer than when the comparison is to
the patient's own original baseline as would be expected.

The time course of response to retreatment is shown in Figure 3 below.
Separation of the efalizumab curves from that of placebo took place by
28 days of retreatment.

Figure 3

![](media/image5.png){width="5.0625in" height="3.1145833333333335in"}

The proportion of patients responding at retreatment day 84 by OLS
minimal to clear was approximately 23.6% higher in the combined
efalizumab group as compared to the placebo group. See Table 25 below.

Table 25 OLS Response to Treatment for RT-A Subjects

  ---------------- --------- ------------ ---------- ------------- --------------
                             Efalizumab                            

                             1.0          2.0        All           All
                                                     Efalizumab-   

  RT Day 84        Placebo   mg/kg/wk     mg/kg/wk   Treated       Efalizumab

  Characteristic   (n=27)    (n=32)       (n=23)     Subjects      vs. Placebo
                                                     (n=55)        

                                                                   

  Minimal or Clear 1 (3.7%)  9 (28.1%)    6 (26.1%)  15 (27.3%)    0.016
  ---------------- --------- ------------ ---------- ------------- --------------

#### Response to Extended Treatment in Patients who were Non-responders or Partial Responders to the First Treatment Period

The group of non-responders and partial responders from the first
treatment period who were re-randomized to extended treatment or placebo
for the extended treatment period was also analyzed.

The patient disposition of this group is shown below.

Table 26 Disposition of ET-A Subjects and Reasons for Discontinuation

  ---------------------------------- ------------- ------------ -----------
                                                   Efalizumab   

                                     Withdrawal/   1.0          2.0

                                     Placebo       mg/kg/wk     mg/kg/wk

  Subject Status                     (n=60) ^a^    (n=57)       (n=66)

  Completed ET, n                    24 (40.0%)    36 (63.2%)   48 (72.7%)

  Entered FU                         15            28           36

  Entered Study ACD2062g             8             8            12

  Discontinued from study            1             0            0

  Discontinued ET, n                 35 (58.3%)    21 (36.8%)   18 (27.3)

  Entered FU                         8             5            5

  Entered Study ACD2062g             26            13           11

  Discontinued from study            1             3            2

                                                                

  Reason for ET discontinuation                                 

  Adverse event                      6             2            4

  Lost to follow-up                  0             2            0

  Subject's decision                 3             3            2

  Investigator's decision            0             1            2

  Non-response to ET                 26            13           10

  ^a^ One subject (11010) was                                   
  randomized to the                                             
  withdrawal/placebo group, but                                 
  never received treatment                                      
  ---------------------------------- ------------- ------------ -----------

The demographics of the ET patients were similar to the ITT population
for first treatment. There were no significant differences among
treatment groups

(data not shown). Median age was 44 (range 19-72). As in the first
treatment group, there was a higher proportion of males than females
(73%: 27%).

Baseline psoriasis characteristics of ET patients were comparable across
treatment groups (Table 27).

Table 27 Baseline Psoriasis Characteristics of ET-A Subjects

  -------------------------- ------------ ------------ ------------ -------------
                                          Efalizumab                

                                                                    All

                                          1.0          2.0          Efalizumab-

                             Placebo      mg/kg/wk     mg/kg/wk     Treated

  Characteristic, ^a^ n      (n=60)       (n=57)       (n=66)       Subjects

  Duration of psoriasis (yr)                                        

  Mean                       17.3         20.0         15.0         17.3

  Median                     12           19           15           17

  Range                      1--60        2--58        1--42        1--58

  Prior systemic therapy                                            

  Yes                        31 (51.7%)   35 (61.4%)   40 (60.6%)   75 (61.0%)

  No                         29 (48.3%)   22 (38.6%)   26 (39.4%)   48 (39.0%)

  Baseline PASI                                                     

  Mean                       19.5         17.3         18.2         17.8

  Median                     18.1         16.6         15.9         16.3

  Range                      10.0--40.0   12.0--27.3   12.2--55.6   12.0--55.6

  FT Day 84 PASI                                                    

  Mean                       12.4         10.0         11.8         10.9

  Median                     9.8          9.8          9.3          9.3

  Range                      3.5--31.6    3.4--23.5    3.6--53.3    3.4--53.3

  Baseline PASI category                                            

     ≤16.0                   24 (40.0%)   25 (43.9%)   34 (51.5%)   59 (48.0%)

  16.1--30.0                 30 (50.0%)   32 (56.1%)   28 (42.4%)   60 (48.8%)

  \>30.0                     6 (10.0%)    0            4 (6.1%)     4 (3.3%)

  FT Day 84 PASI category                                           

     ≤16.0                   45 (75.0%)   50 (87.7%)   55 (83.3%)   105 (85.4%)

  16.1--30.0                 13 (21.7%)   7 (12.3%)    9 (13.6%)    16 (13.0%)

  \>30.0                     2 (3.3%)     0            2 (3.0%)     2 (1.6%)

  ^a^ The FT Day 84                                                 
  characteristics were based                                        
  on FT Day 84/ET Day 0                                             
  values.                                                           
  -------------------------- ------------ ------------ ------------ -------------

The efficacy results of extended treatment in non-responders and partial
responders to the first treatment period are shown below (Table 28).

Table 28 Proportion of ET-A Subjects Who Achieved PASI Response

  -------------------- --------- ------------ ---------- ------------- ------------
                                 Efalizumab                            

                                                         All           
                                                         Efalizumab-   

                                 1.0          2.0        Treated       All

                       Placebo   mg/kg/wk     mg/kg/wk   Subjects      Efalizumab

                       (n=60)    (n=57)       (n=66)     (n=123)       vs. Placebo

                                                                       

  ET Day 84 Responders 4 (6.7%)  12 (21.1%)   13 (19.7%) 25 (20.3%)    0.018
  -------------------- --------- ------------ ---------- ------------- ------------

These results demonstrate that an additional 13.6% of patients achieved
PASI 75% response in the combined efalizumab group compared to placebo
when treated with a three-month extended treatment beyond the first
treatment period.

*Reviewer\'s comment:*

*The use of intermittent treatment upon 50% relapse does not recapture
response in the majority of patients. Response was 31% at the PASI 75
level. However, the evidence suggests that extended treatment does
result in an additional 14% response in those patients who failed to
respond to the first course.*

### Summary of Efficacy: Study ACD2058g

-   After 3 months of efalizumab treatment (1 mg/kg/wk SC), a 37%
    treatment effect was observed (95% CI 28-46%) by PASI 75 response
    criteria.

-   The secondary endpoints confirmed the efalizumab treatment effect

    -   The principal secondary endpoint, "minimal or clear" by static
        physician's global assessment was achieved by 29% (absolute
        difference) of treated patients.

    -   A PASI 50 response was achieved by 46% (absolute difference) of
        treated patients.

-   The mean thickness, erythema and scaling components of the PASI
    score decreased by approximately 50%. All three components,
    thickness, erythema and scaling, changed to a similar extent. The
    mean affected surface area decreased by 14%.

-   Baseline variables and demographics including PASI score and history
    of previous systemic therapy did not influence response to
    treatment.

-   There was a general shift towards improvement in the entire
    efalizumab-treated group; however, a small proportion of patients
    developed clinically significant worsening of psoriasis (see safety
    assessments).

-   For efalizumab-treated patients who had a response, the time to PASI
    75 response was approximately 2 months.

-   Duration of response after treatment discontinuation was variable,
    but estimated as a median of 67 days until time to relapse, or loss
    of 50% of the improvement obtained in responders during the first
    treatment period.

-   Only one-third of patients who responded to the first treatment
    period and were followed until relapse responded to retreatment with
    efalizumab.

-   Among the patients who did not respond to the initial 12-week
    treatment period, an additional 14% achieved PASI 75% response in
    the combined efalizumab group compared to placebo when treated with
    an additional contiguous three-month extended treatment of
    efalizumab.

-   The 2 mg/kg/wk SC dose was not superior to the 1 mg/kg/wk SC dose.

## Protocol ACD2059g

### Study Title

"A Phase III, Randomized, Double-Blind, Parallel-Group,
Placebo-Controlled, Multicenter, Multidose Study to Evaluate the
Efficacy and Safety of Subcutaneously Administered Anti-CD11a in Adults
with Moderate to Severe Plaque Psoriasis Who Are Candidates for Systemic
Therapy"

### Study Objectives

[Primary]{.underline}

-   To investigate the efficacy of weekly SC dosing with either 1.0
    mg/kg or 2.0 mg/kg efalizumab relative to placebo as measured by the
    proportion of subjects achieving a ≥ 75% decrease from baseline in
    PASI at the end of the initial 12-week treatment period (First
    Treatment or FT Day 84)

-   To evaluate the safety and tolerability of 12 weekly SC doses of 1.0
    mg/kg or 2.0 mg/kg efalizumab relative to placebo

[Secondary]{.underline}

-   To evaluate the safety and tolerability of 24 weeks of continuous
    treatment with SC efalizumab FT responders

-   To investigate the efficacy of SC efalizumab as measured by the
    frequency of relapse during 12 weeks of "maintenance" treatment with
    one of two regimens of efalizumab compared with placebo

-   To investigate the efficacy of SC efalizumab administered for 24
    weeks compared with 12 weeks followed by placebo for 12 weeks as
    measured by PASI, Overall Lesion Severity (OLS), and Physician's
    Global Assessment, with particular attention to the proportion of
    subjects who became "cleared" or "almost cleared."

### Study Design

This was a Phase 3, randomized, double-blind, parallel-group,
placebo-controlled, multicenter, multidose study designed to evaluate
the efficacy and safety of efalizumab administered at weekly SC doses of
1.0 mg/kg or 2.0 mg/kg in subjects with moderate to severe plaque
psoriasis who were candidates for systemic therapy.

The study consisted of three periods, each of which lasted \~3 months
(84 days): FT, ET, and FU (see Figure 4).

Figure 4 Study ACD 2059 Schema

![](media/image6.png){width="5.4375in" height="6.010416666666667in"}

The treatment regimens in the three study periods were the following:

-   FT period: Day --28 through FT Day 84

> All subjects entered the FT period, which included a screening period
> and an initial 12- week course of 1.0 mg/kg/wk efalizumab, 2.0
> mg/kg/wk efalizumab, or placebo.

-   ET period: FT Day 84 (ET Day 0) through ET Day 84

> Responders and partial responders who received efalizumab during the
> first treatment period, received an additional 12 weeks of treatment
> with 2.0 mg/kg/wk efalizumab, 2.0 mg/kg/qow efalizumab, or placebo.
> Non-responders from the FT period received an additional 12 weeks of
> treatment with 4.0 mg/kg/wk efalizumab, 2.0 mg/kg/qow efalizumab, or
> placebo.

-   Patients who received placebo during the first treatment period were
    rerandomized differently from those who received efalizumab during
    the first treatment period. If a patient received placebo during the
    first treatment period and was classified as a responder, he/she
    continued to receive placebo during the extended treatment period.
    However, if a patient received placebo during the first treatment
    period and was considered a partial responder, he/she could be
    rerandomized to 2 mg/kg SC weekly or 2 mg/kg SC every other week.
    Finally, if a placebo patient was a nonresponder during the first
    treatment period, then he/she was rerandomized to 2 mg/kg SC weekly
    or 4 mg/kg SC weekly. Therefore, a partial responder or a
    nonresponder who received placebo during the first treatment period
    would receive active drug in the extended treatment period.

-   FU period: ET Day 84 (FU Day 0) to FU Day 84

> All subjects completed three monthly safety visits after the last dose
> of study drug.

#### Randomization

Subjects were randomized through an interactive voice response system in
a 4:4:1:1 ratio to high-dose (2.0 mg/kg) efalizumab, low-dose (1.0
mg/kg) efalizumab, high-dose placebo, or low-dose placebo.

Randomization was stratified by the FT Day 0 PASI score (≤ 16.0, ≥
16.1), by prior treatment for psoriasis (naive to systemic treatment vs.
prior systemic treatment), and by study site.

Re-randomization on ET Day 0 was dependent on response status at FT Day
84 and whether the subject received active drug or placebo in FT. For
subjects who received active drug, randomization was balanced within
categories defined by the FT dose (i.e., 1.0 mg/kg or 2.0 mg/kg SC
weekly) using static randomization tables.

Patients were assigned an ID number at screening. If the patient was
determined to be a candidate for therapy at screening, he/she was
randomized centrally as described. The patient was considered to be
enrolled at the time he/she was randomized.

#### Blinding

During both the FT and ET periods, subjects, investigators, and the
Sponsor were blinded to subject assignment to placebo or active study
drug. Dose level and dose frequency were not blinded during the FT and
ET periods.

Efalizumab produces an elevation of lymphocyte counts and total WBC
counts in most subjects. Therefore, only absolute neutrophil and
eosinophil counts from the leukocyte portion of the complete blood count
(CBC) were made available to investigators and monitors on samples drawn
after FT Day 0 until FU Day 84.

#### Open Label Extension study

No open label extension study existed.

#### Study Drug(s)

Actively treated subjects received either XOMA-manufactured efalizumab
or Genentech-manufactured efalizumab. Each subject received only one
product throughout the study. There was a matching placebo for each
product (manufactured by XOMA or Genentech).

FT: Each subject received an initial conditioning dose of 0.7 mg/kg
followed by 11 weekly doses of 1.0 mg/kg or 2.0 mg/kg study drug.

ET: On ET Day 0, all subjects received a conditioning dose of 0.7 mg/kg
study drug. Subjects assigned to receive 2.0 mg/kg weekly or every other
week received 2.0 mg/kg on ET Day 7. Subjects assigned to receive 4.0
mg/kg weekly, received a second conditioning dose of 2.0 mg/kg on ET Day
7 and their first full dose of 4.0 mg/kg on ET Day 14.

#### Withholding Treatment

Subjects were discontinued from efalizumab treatment if they met any of
the following criteria: diagnosis of any cancer, lymphoma, or leukemia;
anaphylaxis; opportunistic infection; or any medical condition that the
investigator determined could jeopardize the subject's safety if he or
she continued in the study.

Other reasons for discontinuation included pregnancy, administration of
live virus or bacteria vaccine, or concurrent treatment with excluded
systemic or topical therapy.

If a subject had an atypical severe relapse or emergence of a new
psoriatic morphology, the investigator was to contact the Medical
Monitor. If, in the judgment of the investigator, this flare required
treatment, the subject had to discontinue from study drug treatment and
enter the FU period.

#### Concomitant Medications

The only topical psoriasis treatments that could be used during the
screening, FT, ET, and FU periods were Eucerin cream and tar or
salicylic acid preparations (for scalp psoriasis only). Potency Group
VII topical corticosteroids could be used in small amounts on psoriatic
lesions on the face, groin, or axillae, if required.

Itching could be treated with oral, not topical, hydroxyzine
hydrochloride or diphenhydramine hydrochloride during the study.
However, these medications and other antihistamines were not to be used
within 24 hours prior to a clinic visit with a scheduled PASI
evaluation.

If a subject relapsed during the ET period (lost of ≥ 50% of the
improvement in the PASI score achieved between FT Day 0 and FT Day 84),
he/she could receive topical psoriasis therapies or UVB phototherapy.

If a subject relapsed during the FU period (lost ≥ 50% of the
improvement in the PASI score achieved between FT Day 0 and ET Day 84),
he/she could receive topical psoriasis therapies, UVB phototherapy, or
systemic psoriasis therapies (e.g., PUVA, cyclosporine, corticosteroids,
methotrexate, oral retinoids).

#### Disallowed treatments

Disallowed treatments were similar to those described in Study ACD2058g
(See page[19](#disallowed-treatments)).

#### Eligibility

The eligibility criteria of Protocol ACD2059g were similar to those of
Protocol ACD2058g. (Progressive hearing loss was no longer an exclusion
criterion in ACD 2059g as it was in ACD2058g.)

Efficacy Outcomes

The primary efficacy outcome measure for this study was the proportion
of subjects with a ≥ 75% improvement in PASI score between FT Day 0 and
FT Day 84.

The principal secondary efficacy outcome measure was the proportion of
subjects achieving an OLS rating of Minimal or better at FT Day 84.

Clinical and Laboratory Assessments

Assessments of Efficacy

The following were measured: PASI, OLS, psoriatic BSA, target lesion
assessment, PGA, DLQI, Itching scale. Patient photography was performed.

#### Safety Assessments

The following were performed: physical examinations (including vital
signs and body weight); monitoring for adverse events; blood chemistry,
hematology (CBC, platelet, differential); urinalysis; antibodies to
efalizumab and urine pregnancy test (females of childbearing potential),
RPR at baseline. PPD and/or chest X-ray were done at screening for high
risk subjects only. MHA-TP test was monitored in patients RPR+ at
baseline.

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

#### Protocol Amendments

The protocol was amended on 14 March 2001, to allow for the use of
topical psoriasis therapies and/or UVB phototherapy for subjects who
relapsed during the ET period the use of topical therapies, UVB
phototherapy and systemic therapies if a patient relapsed during the ET
period.

### Study Results

#### Patient Disposition

The study ACD2059g included 51 study centers in the United States and
Canada. A total of 597 patients were randomized and treated. The
following table shows the subject disposition (Table 29).

Table 29 Subject Disposition and Reasons for Discontinuation during the
FT Period

  ----------------------------- -------------- ------------- -------------
                                               FT Efalizumab 

                                FT Placebo     1.0 mg/kg/wk  2.0 mg/kg/wk

  Subject Status                (n=122)        (n=232)       (n=243)

  Completed FT                  111 (91.0%)    211 (90.9%)   227 (93.4%)

  Entered ET                    110 (90.2%)    210 (90.5%)   224 (92.2%)

  Entered FU                    0              1 (0.5%)      3 (1.3%)

  Discontinued from study       1 (0.9%)       0             0

  Discontinued from FT          11 (9.0%)      21 (9.1%)     16 (6.6%)

  Entered FU                    5              12            9

  Discontinued from study       6              9             7

  Reason for discontinuation                                 
  from FT                                                    

  Subject's decision            4              8             5

  Adverse event                 1              7             6

  Use of excluded medication    2              2             3

  Lost to follow-up             2              2             2

  Investigator's decision       2              2             0
  ----------------------------- -------------- ------------- -------------

A total of 597 subjects were enrolled and randomized, 122 in the placebo
group, 232 in the 1.0 mg/kg/wk group and 243 in the 2.0 mg/kg/wk group.
A total of 40 subjects (8.0 %) discontinued treatment during the first
treatment period. The proportions of patients completing the first
treatment course were comparable across treatment groups. The proportion
of patients who discontinued the FT for an adverse event was higher in
the active treatment arms than in placebo.

Demographics and baseline disease characteristics in this study were
similar to those in Study ACD2058g and are shown in Table 30 and in
Table 31 below.

Table 30 Demographic and Baseline Characteristics of Randomized Subjects
in the FT Period

  ----------------------------- --------------- ------------- ------------
                                                FT Efalizumab 

                                FT Placebo      1.0 mg/kg/wk  2.0 mg/kg/wk

  Characteristic                (n=122)         (n=232)       (n=243)

  Sex, n                                                      

  Male                          79 (64.8%)      151 (65.1%)   157 (64.6%)

  Female                        43 (35.2%)      81 (34.9%)    86 (35.4%)

  Race/ethnicity, n                                           

  White                         106 (86.9%)     197 (84.9%)   204 (84.0%)

  Hispanic                      7 (5.7%)        16 (6.9%)     22 (9.1%)

  Other a                       9 (7.4%)        19 (8.2%)     17 (7.0%)

  Age group (yr), n                                           

  18--40                        45 (36.9%)      75 (32.3%)    99 (40.7%)

  41--64                        68 (55.7%)      138 (59.5%)   123 (50.6 %)

     ≥65                        9 (7.4%)        19 (8.2%)     21 (8.6%)

  Age (yr)                                                    

  Mean                          45.4            46.3          44.9

  Range                         18--72          18--74        18--74

  Weight (kg)                                                 

  Mean                          93.0            91.6          93.3

  Range                         54--140         55--140       43--143

  BMI (kg/m^2^)                                               

  Mean                          31.25           31.44         31.50

  Range                         18.7--52.3      17.9--55.2    18.7--51.1

  Pacific Islander, Black,                                    
  American Indian or Alaskan                                  
  Native, or Other.                                           
  ----------------------------- --------------- ------------- ------------

Males constituted 65% of patients and Caucasians 85%. The median age was
46 with 8% of patients over age 65. Overall the treatment groups were
comparable with regard to demographic characteristics. The study
population's demographic characteristics are reflective of the general
population of patients with psoriasis, with the exception that more male
than female patients were enrolled. In general psoriatic population, the
sex ratio is one to one, male to female. Of note, the population is
heavier than the average US population and this probably reflects the
psoriasis population as a whole.

The range of ages shows that some patients were enrolled who were older
than the entry criteria allowed. In addition, some patients exceeded the
protocol specified weight limit of 140 kg.

*Table 31 Baseline Psoriasis Characteristics of Subjects in the FT
Period*

  ------------------------------ ------------- ------------- -------------
                                               FT Efalizumab 

                                 FT Placebo    1.0 mg/kg/wk  2.0 mg/kg/wk

  Characteristic                 (n=122)       (n=232)       (n=243)

  Duration of psoriasis (yr)                                 

  Mean (SD)                      19.6 (12.3)   19.3 (12.3)   18.2 (11.6)

  Range                          0--62         1--60         1--70

  Prior systemic therapy, n                                  

  Yes                            86 (70.5%)    160 (69.0%)   152 (62.6%)

  No                             36 (29.5%)    72 (31.0%)    91 (37.4%)

  PASI category, n                                           

      ≤16.0                      52 (42.6%)    95 (40.9%)    100 (41.2%)

  16.1--30.0                     54 (44.3%)    107 (46.1%)   120 (49.4%)

  \>30.0                         16 (13.1%)    30 (12.9%)    23 (9.5%)

  PASI score                                                 

  Mean (SD)                      20.43 (8.72)  19.98 (8.25)  19.83 (8.28)

  Range                          11.7--49.6    11.7--53.4    5.6--53.4

  OLS, n                                                     

  Minimal                        0             4 (1.7%)      0

  Mild                           5 (4.1%)      12 (5.2%)     23 (9.5%)

  Moderate                       59 (48.4%)    128 (55.2%)   127 (52.3%)

  Severe                         52 (42.6%)    76 (32.8%)    81 (33.3%)

  Very severe                    6 (4.9%)      12 (5.2%)     12 (4.9%)

  Percent BSA of psoriasis                                   

  Mean (SD)                      31.11 (18.87) 31.97 (18.12) 30.44 (17.75)

  Range                          10.0--90.0    10.0--98.0    7.0--94.0

  Patient's Assessment of Itch                               

  Mean (SD)                      3.1 (1.5)     3.0 (1.4)     3.1 (1.4)

  Range                          0--5          0--5          0--5
  ------------------------------ ------------- ------------- -------------

The overall baseline disease severity was moderate to severe plaque
psoriasis with a large percentage of subjects (66.7%) having a history
of prior systemic therapy. The mean duration of psoriasis was 19 years.
The mean PASI score upon entry was 20 and ranged from 5.6 to 53.

The proportion of placebo patients classified as moderate or higher by
the OLS score was 95.9% vs. 91.8% of the combined active treatment arm.
Overall baseline disease severity was comparable between treatment
groups.

STUDY CONDUCT

#### Adequacy of the blind

No instances were identified with regard to inadequate maintenance of
the study blind.

Protocol Deviations

A total of 33 subjects were treated with excluded medications for
psoriasis during the FT period. These consisted of 4 subjects in the
placebo arm (3.3%), 19 subjects in the 1.0 mg/kg/wk efalizumb arm
(8.2%), and 10 subjects in the 2.0 mg/kg group (4.1%). The most
frequently used excluded treatments were desonide followed by
fluocinolone acetonide, prednisone, and triamcinolone. No subjects used
phototherapy.

Table 32 Protocol Deviations during the FT Period

  ------------ ------------ ------------------------ ------------ ------------ -- --------------
                                                                  FT              
                                                                  Efalizumab      

                                                     FT Placebo   1.0 mg/kg/wk    2.0 mg/kg/wk

                            Protocol Deviation       (n=122)      (n=232)         (n=243)

  Total ^a^                                          34 (27.9%)   71 (30.6%)      58 (23.9%)

  Missing                                            20 (16.4%)   37 (15.9%)      29 (11.9%)
  laboratory                                                                      
  data                                                                            

  PASI                                                                            
  performed                                                                       
  outside of                                                                      
  the                                                                             

  FT Day 84                                          10 (8.2%)    17 (7.3%)       22 (9.1%)
  window ^b^                                                                      

                            \<82 Days                2 (1.6%)     6 (2.6%)        2 (0.8%)

                            \>86 Days                8 (6.6%)     11 (4.7%)       20 (8.2%)

  OLS                                                                             
  performed                                                                       
  outside of                                                                      
  the                                                                             

  FT Day 84                                          10 (8.2%)    17 (7.3%)       22 (9.1%)
  window ^b^                                                                      

                            \<82 Days                2 (1.6%)     6 (2.6%)        2 (0.8%)

                            \>86 Days                8 (6.6%)     11 (4.7%)       20 (8.2%)

  Use of                                             4 (3.3%)     19 (8.2%)       10 (4.1%)
  excluded                                                                        
  medication                                                                      

  Incorrect                                          2 (1.6%)     0               1 (0.4%) ^e^
  dosing level                                       ^c,\ d^                      

  Incorrect                                          2 (1.6%) ^f^ 0               1 (0.4%) ^g^
  study drug                                                                      

  ^a^          Represents                                                         
               the number                                                         
               of subjects                                                        
               with at                                                            
               least one                                                          
               protocol                                                           
               deviation.                                                         

  ^b^          For subjects                                                       
               who                                                                
               completed                                                          
               the FT                                                             
               period only.                                                       

  ^c^          Subject                                                            
               66801 was                                                          
               assigned to                                                        
               2.0 mg/kg/wk                                                       
               placebo and                                                        
               received                                                           

               1.0 mg/kg/wk                                                       
               placebo                                                            
               throughout                                                         
               the FT                                                             
               period.                                                            

  ^d^          Subject                                                            
               77604 was                                                          
               assigned to                                                        
               1.0 mg/kg/wk                                                       
               placebo and                                                        
               received 2.0                                                       
               mg/kg                                                              

               placebo on                                                         
               FT Days 7                                                          
               and 14.                                                            

  ^e^          Subject                                                            
               66809 was                                                          
               assigned to                                                        
               the 2.0                                                            
               mg/kg/wk                                                           
               efalizumab                                                         
               group and                                                          
               received 1.0                                                       
               mg/kg/wk                                                           
               efalizumab                                                         
               throughout                                                         
               the FT                                                             
               period.                                                            

  ^f^          Subject                                                            
               70410                                                              
               received 2.0                                                       
               mg/kg                                                              
               efalizumab                                                         
               on FT Day                                                          
               70, and                                                            

               Subject                                                            
               68843                                                              
               received 2.0                                                       
               mg/kg                                                              
               efalizumab                                                         
               on FT Day                                                          
               77.                                                                

  ^g^          Subject                                                            
               73207                                                              
               received                                                           
               placebo on                                                         
               FT Day 21.                                                         
  ------------ ------------ ------------------------ ------------ ------------ -- --------------

Comparable numbers of patients were noted to have protocol deviations in
each treatment group, 24-30% of patients depending on the treatment
group. The most common protocol violation noted was missing baseline
laboratory data. These protocol deviations were in general minor and
were judged to have not affected the outcome of the clinical study.

#### Primary Efficacy Outcomes

Response to first treatment course are shown in Table 33 below.

Table 33 PASI Response to Treatment for Randomized Subjects during the
FT Period

  ------------------------ ---------------- -------------- --------------
                                            FT Efalizumab  

  PASI Response            FT Placebo       1.0 mg/kg/wk   2.0 mg/kg/wk

  at FT Day 84             (n=122)          (n=232)        (n=243)

  Responders               6 (4.9%)         52 (22.4%)     69 (28.4%)

  Partial responders and                                   

  non-responders ^a^       116 (95.1%)      180 (77.6%)    174 (71.6%)

  Fisher's exact p-value                                   

  efalizumab vs. placebo   ---              \<0.001        \<0.001

  ^a^ Included subjects                                    
  who discontinued.                                        
  ------------------------ ---------------- -------------- --------------

The proportion of responders was higher in each of the treatment groups
than in placebo. The absolute differences were 17.5% for the 1.0
mg/kg/wk group and 23.5% in the 2.0 mg/kg/wk group. These results were
statistically significant. In study ACD2058g, the 2mg/kg/wk group had a
numerically lower response rate than the 1.0 mg/kg/wk group. In this
study the response rate was numerically higher in the 2 mg/kg/wk group.
However, there is no evidence that the 2 mg/kg/wk dose is superior to
the 1 mg/kg/wk dose.

The following table shows the mean improvement in the components of the
PASI score during the first treatment period (Table 34).

Table 34 Mean Percent Improvement in PASI Thickness, Erythema, and
Scaling Components during the FT Period

  -------------------------- -------------- ------------ -----------------
                                            FT           
                                            Efalizumab   

  PASI Component at FT Day   FT Placebo     1.0 mg/kg/wk 2.0 mg/kg/wk
  84                                                     

                             (n=122)        (n=232)      (n=243)

  Thickness ^a^              13.6           47.2         48.7

  Erythema ^a^               13.8           44.5         46.0

  Scaling ^a^                13.1           49.6         51.5

                                                         

  PASI total ^b^             (n=111)        (n=213)      (n=227)

                             17             51           51.7

  Note: Improvement in each                              
  component was reflected by                             
  a decrease in                                          

  score.                                                 

  ^a^ The last observation                               
  carried forward was used                               
  to impute missing Day 84                               

  PASI data.                                             

  ^b^ Values from the early                              
  termination visits were                                
  assigned to the next                                   

  scheduled visit for PASI                               
  evaluation.                                            
  -------------------------- -------------- ------------ -----------------

All of the components of the PASI -thickness, erythema and scaling-
showed improvement. Therefore, all of the components appear to
contribute similarly to improvement in the overall score.

Mean changes in percentage of body surface area during the first
treatment period are shown below (Table 35).

Table 35 Mean Improvement in Percent BSA of Psoriasis during the FT
Period

  ------------- ------------------- ---------------- ------------ ----------------
                                                     FT           
                                                     Efalizumab   

                                    FT Placebo       1.0 mg/kg    2.0 mg/kg

                Percent BSA         (n=122)          (n=232)      (n=243)

  FT Day 0                          31.1             32.0         30.4

  FT Day 84 ^a^                     30.8             22.1         19.1

  Improvement                       0.3              9.9          11.3
  ^b^                                                             

  Two-sample                                                      
  t-test                                                          
  p-value c                                                       

  efalizumab                        ---              \<0.001      \<0.001
  vs. placebo                                                     

  ^a^           The last                                          
                observation carried                               
                forward was used to                               
                impute missing Day                                
                84                                                

                PASI data.                                        

  ^b^           Improvement was                                   
                reflected by a                                    
                decrease in the                                   
                percent BSA score.                                

  ^c^           Using the pooled                                  
                error term from an                                
                ANOVA of all three                                
                treatment groups.                                 
  ------------- ------------------- ---------------- ------------ ----------------

The percent improvement in the percentage body surface area affected was
greater in both of the efalizumab-treated groups compared to placebo and
was approximately 9% higher in the 1.0 mg/kg dose group at than placebo
at the end of the first treatment period.

*Reviewer's comment:* *The percentage change in BSA is smaller than the
percentage improvements in the cardinal manifestations of
psoriasis-erythema, scale and elevation.*

The table below shows the distribution of improvement by treatment group
during the first treatment period (Table 36).

Table 36 PASI Response by Percent Improvement from Baseline for Subjects
in the FT Period

  ---------------------------- ------------- ------------ -----------------
                                             FT           
                                             Efalizumab   

  Percent Improvement          FT Placebo    1.0 mg/kg/wk 2.0 mg/kg/wk

  from Baseline                (n=122)       (n=232)      (n=243)

     ≥90%                      1 (0.8%)      10 (4.3%)    15 (6.2%)

     ≥75% to \<90%             5 (4.1%)      42 (18.1%)   54 (22.2%)

     ≥50% to \<75%             13 (10.7%)    68 (29.3%)   69 (28.4%)

     ≥25% to \<50%             21 (17.2%)    51 (22.0%)   48 (19.8%)

     \<25%                     71 (58.2%)    42 (18.1%)   41 (16.9%)

  Missing ^a^                  11 (9.0%)     19 (8.2%)    16 (6.6%)

  ^a^ Subjects who were                                   
  missing the FT Day 84 score                             
  were classified as                                      

  non-responders for analysis                             
  of the primary efficacy                                 
  endpoint.                                               
  ---------------------------- ------------- ------------ -----------------

The groups which received active treatment showed a general shift
towards improvement in PASI response from baseline. The treatment effect
by the PASI 50 criterion (efalizumab-placebo) was 36% for the 1.0
mg/kg/wk dose.

Figure 5 below depicts the distribution of the response to treatment by
percent change in PASI. A positive change is improvement and a negative
change indicates deterioration. The two efalizumab treatment groups (1
and 2 mg) were combined for this analysis.

Figure 5 Percent Change in PASI by Treatment Group

**Efalizumab (N=440) Placebo (N=111)**

![](media/image7.wmf){width="2.1458333333333335in"
height="2.7708333333333335in"}![](media/image8.wmf){width="2.1041666666666665in"
height="2.7708333333333335in"}

Percent Change in PASI by Treatment Group

  ------------------- ------------------------- -------------------------
                      Efalizumab                Placebo

  maximum             100.0                     96.97

  quartile            76.3                      36.70

  median              56.9                      15.36

  quartile            34.6                      -0.25

  minimum             -139.0                    -76.04
  ------------------- ------------------------- -------------------------

Of note, a few patients worsened by over 100% within the active
treatment group.

Table 37 PASI Responders by Subsets of Randomized Subjects during the FT
Period

  ------------------------ ---------------- -------------- ---------------
                                            FT Efalizumab  

                           FT Placebo       1.0 mg/kg/wk   2.0 mg/kg/wk

  Subject Subset           (n=122)          (n=232)        (n=243)

                                                           

  Sex                                                      

  Female, n                43               81             86

  Responders, n            3 (7.0%)         19 (23.5%)     30 (34.9%)

  95% CI                   0.015, 0.191     0.148, 0.342   0.249, 0.459

                                                           

  Male, n                  79               151            157

  Responders, n            3 (3.8%)         33 (21.9%)     39 (24.8%)

  95% CI                   0.008, 0.107     0.155, 0.293   0.183, 0.324

  Age group (yr)                                           

  18--40, n                45               75             99

  Responders, n            0                12 (16.0%)     25 (25.3%)

  95% CI                   0.000, 0.079     0.086, 0.263   0.171, 0.350

                                                           

  41--64, n                68               138            123

  Responders, n            3 (4.4%)         36 (26.1%)     36 (29.3%)

  95% CI                   0.009, 0.124     0.190, 0.342   0.214, 0.381

                                                           

     ≥65, n                9                19             21

  Responders, n            3 (33.3%)        4 (21.1%)      8 (38.1%)

  95% CI                   0.075, 0.701     0.061, 0.456   0.181, 0.616

  Baseline PASI score                                      

      ≤16.0, n             52               95             100

  Responders, n            2 (3.8%)         20 (21.1%)     25 (25.0%)

  95% CI                   0.005, 0.132     0.134, 0.306   0.169, 0.347

                                                           

  16.1--30.0, n            54               107            120

  Responders, n            3 (5.6%)         24 (22.4%)     35 (29.2%)

  95% CI                   0.012, 0.154     0.149, 0.315   0.212, 0.382

                                                           

  \>30.0, n                16               30             23

  Responders, n            1 (6.3%)         8 (26.7%)      9 (39.1%)

  95% CI                   0.002, 0.302     0.123, 0.459   0.197, 0.615

  Prior systemic therapy                                   

  Yes, n                   86               160            152

  Responders, n            4 (4.7%)         37 (23.1%)     47 (30.9%)

  95% CI                   0.013, 0.115     0.168, 0.304   0.237, 0.389

  No, n                    36               72             91

  Responders, n            2 (5.6%)         15 (20.8%)     22 (24.2%)

  95% CI                   0.007, 0.187     0.122, 0.320   0.158, 0.343
  ------------------------ ---------------- -------------- ---------------

The results for the primary endpoint in subsets defined by gender, age
group, baseline PASI score and history of prior systemic therapy are
consistent with the results of the ITT population as a whole. Treatment
effect was seen in each of the subgroups analyzed.

The median time to onset of PASI 75 response is shown below (Table 38).

Table 38 Time (days) to PASI-75 Response, Using Kaplan Meier Estimates
Study ACD2059g (FT Period)

  ------------------------------ ------------ ------------ ---------------
                                              Efalizumab   Efalizumab

  Characteristic                 Placebo      1.0 mg/kg/wk 2.0 mg/kg/wk

                                                           

  Subjects Who Achieved PASI-75  8            66           77
  at Any Time                                              

  Median                         63.0         57.5         58.0

  95% C.I. for Median            (42.0, 71.0) (57.0, 70.0) (57.0, 71.0)

  25-75 %ile                     42.5 - 70.5  45.0 - 72.0  57.0 - 77.0

  Minimum - Maximum              30.0 - 72.0  13.0 - 109.0 29.0 - 92.0
  ------------------------------ ------------ ------------ ---------------

As in study ACD2058g, the median time to onset of PASI 75 in patients
who responded at any time was approximately 2 months.

#### First Treatment Course: Secondary Outcomes 

The principal secondary endpoint, the static physician's global
assessment is shown below (Table 39).

**Table 39** Principal Secondary Efficacy Endpoint for the FT Period

  ---------------------------- -------------- ------------ ---------------
                                              FT           
                                              Efalizumab   

                               FT Placebo     1.0 mg/kg/wk 2.0 mg/kg/wk

  OLS Response at FT Day 84    (n=122)        (n=232)      (n=243)

  Minimal or Clear             4 (3.3%)       45 (19.4%)   55 (22.6%)

  Mild to Very Severe ^a^      118 (96.7%)    187 (80.6%)  188 (77.4%)

  Fisher's exact p-value                                   

  efalizumab vs. placebo       ---            \<0.001      \<0.001

  ^a^ Included subjects who                                
  were classified as Mild,                                 
  Moderate, Severe, and Very                               

  Severe and those who                                     
  discontinued.                                            
  ---------------------------- -------------- ------------ ---------------

Using the physician's static global assessment, the proportions of
responders, those achieving minimal or clear on the OLS scale was higher
in each of the active treatment arms than placebo. The absolute
difference was 16.1% in the 1.0 mg/kg/wk group and 19.3 in the 2.0
mg/kg/wk group. Therefore, the principal secondary outcome supports the
primary efficacy outcome. Of note, the percentages of responders by the
OLS are comparable to those by the PASI 75 criteria.

An additional secondary efficacy outcome was the proportion of patients
achieving excellent or cleared on the PGA, the physician's dynamic scale
(See Table 40).

Table 40 PGA Response of Subjects during the FT Period

  ---------------------------- -------------- ------------ -- --------------
                                              FT              
                                              Efalizumab      

                               FT Placebo     1.0 mg/kg/wk    2.0 mg/kg/wk

  PGA Response at FT Day 84    (n=122)        (n=232)         (n=243)

  Excellent or Cleared         5 (4.1%)       52 (22.4%)      69 (28.4%)

  Good to Worse ^a^            117 (95.9%)    180 (77.6%)     174 (71.6%)

  Fisher's exact p-value                                      

  efalizumab vs. placebo       ---            \<0.001         \<0.001

  ^a^ Included subjects who                                   
  were classified as Good,                                    
  Fair, Slight, Unchanged, or                                 

  Worse and those who                                         
  discontinued.                                               
  ---------------------------- -------------- ------------ -- --------------

The proportions of responders, those achieving excellent or cleared on
the PGA scale was higher in each of the active treatment arms than
placebo. The absolute differences were 18% for the 1 mg/kg/wk group and
24% for the 2.0 mg/kg/wk group. Therefore, the response by physician's
dynamic scale also supports the primary analysis.

#### Response to Second Treatment Course

The outcome of patients who responded to the first treatment period to a
subsequent contiguous treatment period was evaluated. Comparisons of the
proportion of subjects who experienced relapse of psoriasis in the
withdrawal/placebo group versus the 2.0 mg/kg/qow efalizumab group and
the 2.0 mg/kg/wk efalizumab group is shown in Table 41 below.

Table 41 Proportion of ET-AR Subjects Experiencing Psoriasis Relapse

  ------------------------ ---------------- ------------- ----------------
                                            ET-AR         
                                            Efalizumab    

                           ET-AR            2.0 mg/kg/qow 2.0 mg/kg/wk
                           Withdrawal/                    

  Response                 Placebo (n=40)   (n=40)        (n=39)

  Subjects who relapsed    27 (67.5%)       3 (7.5%)      3 (7.7%)
  ^a^                                                     

  Subjects who did not     13 (32.5%)       37 (92.5%)    36 (92.3%)
  relapse                                                 

  Fisher's exact p-value                                  

  efalizumab vs. placebo   ---              \<0.001       \<0.001

  Note: Relapse during the                                
  FU period was defined as                                
  the loss of ≥50% of the                                 
  improvement                                             

  in the PASI score                                       
  achieved between FT Day                                 
  0 and ET Day 84.                                        

  ^a^ Included subjects                                   
  who discontinued early                                  
  during the ET period.                                   
  ------------------------ ---------------- ------------- ----------------

Of the patients who remained on active treatment, 92% did not relapse;
whereas, the majority of patients who received placebo for the second 12
weeks of therapy, 67%, experienced loss of 50% of the improvement that
they achieved in the first treatment period of efalizumab therapy.

The proportion of patients who maintained a ≥ 75% improvement in PASI at
the end of the extended treatment period is shown in Table 42 below.

Table 42 Proportion of ET-AR Subjects Who Maintained PASI Response at ET
Day 84

  ----------------------- ---------------- ------------- ----------------
                                           ET-AR         
                                           Efalizumab    

                          ET-AR            2.0 mg/kg/qow 2.0 mg/kg/wk
                          Withdrawal/                    

  Response                Placebo (n=40)   (n=40)        (n=39)

  Responders              8 (20.0%)        31 (77.5%)    30 (76.9%)

  Partial responders and                                 

  non-responders a        32 (80.0%)       9 (22.5%)     9 (23.1%)

  Fisher's exact p-value                                 

  efalizumab vs. placebo  ---              \<0.001       \<0.001

  ^a^ Included subjects                                  
  who discontinued early                                 
  during the ET period.                                  
  ----------------------- ---------------- ------------- ----------------

Approximately 77% of responders to the first treatment period maintained
at least a PASI 75 level of improvement during the second 12 weeks of
continuous blinded therapy; whereas, 20% of patients who received
placebo during this period maintained responder status. Of the subjects
in the 2.0 mg/kg/qow and 2.0 mg/kg/wk efalizumab groups, 95.0% and
89.8%, respectively, maintained a ≥50% improvement in PASI at ET Day 84
compared with FT Day 0, whereas 40% of subjects in the
withdrawal/placebo group maintained this level of response (data not
shown). Therefore, the ability of efalizumab to maintain treatment
response in responders is better than its ability to recapture response
in patients in a state of active relapse (See Study ACD2058g, Response
to Second Treatment Course in Patients who Responded to the First
Treatment, p.
[34](#response-to-second-treatment-course-in-patients-who-responded-to-the-first-treatment)).

*Reviewer's comments*

*It is noteworthy that following discontinuation of efalizumab,
treatment response is maintained for [\>]{.underline} 3 months in some
patients (20%). Moreover, a small proportion of patients (7%)
experiences relapse of psoriasis (loss of 50% of response) despite
continued efalizumab therapy.*

#### Response to an additional 12-week treatment course in patients who were non-responders during the first treatment course

The response status by treatment group during extended treatment with
either efalizumab or placebo in the group of patients who were
non-responders to active drug in the first treatment period is shown
below.

Table 43 Proportion of ET-AN Subjects Who Achieved PASI Response at ET
Day 84

  ------------------------ ----------------------- -----------------------
                           ET-AN                   ET-AN Efalizumab
                           Withdrawal/Placebo      

  Response                 (n=59)                  4.0 mg/kg/wk (n=118)

  Responders               1 (1.7%)                15 (12.7%)

  Partial responders and                           

  non-responders a         58 (98.3%)              103 (87.3%)

  Fisher's exact p-value                           

  efalizumab vs. placebo   ---                     0.023

  ^a^ Included subjects                            
  who were missing ET Day                          
  84 evaluations.                                  
  ------------------------ ----------------------- -----------------------

These results show that treatment with a second contiguous 12 week
period of therapy can result in 11% of patients achieving response
status at the end of the extended treatment period. This result is
consistent with the finding in study ACD2058g. Of note, the dose used in
the extended treatment group is higher than the one for which the
sponsor is seeking approval.

#### Duration of Response

The median time to relapse for the withdrawal/placebo group was 64 days
after the last dose for subjects who received 1.0 mg/kg/wk during the
first treatment period. These results are consistent with those obtained
in Study ACD2058g (see page [31](#duration)).

#### Quality of Life

DLQI was designated as an exploratory outcome measure in Study ACD2059g.
Results of change in DLQI during the first treatment period are shown
below.

Table 44 DLQI, Mean Improvement from Baseline(FT Period): Randomized
Subjects

  ----------------------- ---------- -------------- ------------ --- ---- ------------ --- ---
                                                    Efalizumab            Efalizumab       

                                     Placebo        1.0 mg/kg/wk          2.0 mg/kg/wk     

                                     (N=122)        (N=232)               (N=243)          

  Baseline                N          120            228                   238              

                          Mean       12.2           11.9                  12.4             

                          Median     10.0           11.0                  11.0             

                          25-75 %ile 7.0 - 17.0     7.0 - 16.0            7.0 - 17.0       

                          Range      1 - 30         0 -30                 0 -30            

                                                                                           

  Improvement from        N          120            228                   238              
  Baseline                                                                                 

                          Mean       1.7            5.5                   6.0              

                          Median     1.0            5.0                   5.0              

                          25-75 %ile -1.0 -4.0      2.0 -9.0              1.0 - 10.0       

                          Range      -13 -19        -12 -24               -15 -30          

  Pairwise p values for                                                                    
  improvement from                                                                         
  baseline are ≤ 0.001                                                                     
  for both efalizumab                                                                      
  dose levels vs.                                                                          
  placebo.                                                                                 
  ----------------------- ---------- -------------- ------------ --- ---- ------------ --- ---

Efalizumab-treated patients demonstrated a mean change in DLQI of 5.5
and 6.0 in the 1.0 mg/kg/wk and 2.0 mg/kg/wk treatment groups vs. 1.7 in
the placebo--treated patients. These changes represented a significant
difference in favor of the efalizumab-treated patients vs. placebo and
are consistent with the results seen in Study ACD2390g (see page
[75](#quality-of-life-measures)).

*Reviewer's comment*

*The DLQI self-assessment questionnaire attempts to determine how much a
skin condition affects a patient's quality of life. A response of "not
at all" for all 10 questions yields a score of 0, and a response of "a
little" yields a score of 10. The median score across the study arms was
11 at baseline. The clinical significance of the shift in score from 11
to approximately 6 is not clear.*

### Summary of Efficacy: Study ACD2059g

-   Study ACD 2059g confirmed the efficacy of efalizumab in plaque
    psoriasis. In the 1.0 mg/kg/wk treatment group, the proportion of
    patients achieving a PASI 75 was 18% higher than that of the placebo
    group.

-   The numbers of responders in the 2.0mg/kg/wk group tended to be
    higher than that of the 1.0 mg/kg/wk, although the differences were
    not statistically significant. In both treatment groups the numbers
    of responders were statistically higher than placebo. Considering
    the results of Study ACD2058g and Study ACD2059g together, there is
    no evidence that the 2 mg/kg/wk dose is superior to the 1 mg/kg/wk
    dose.

-   The secondary efficacy outcomes also showed evidence of treatment
    response (absolute increase in proportion of responders) including
    the physician's static global assessment of "minimal or clear"
    (16%), PASI 50 (36%), physician's dynamic global assessment of
    "excellent or cleared" (18%).

-   A small proportion of patients experienced worsening of psoriasis
    during efalizumab treatment (see also safety assessment).

-   In patients treated with 1mg/kg efalizumab the duration of response
    off-treatment (64 days) and time to onset of response (58 days) were
    similar to those observed in study ACD2058 g.

-   Continuous treatment with efalizumab beyond the initial twelve-week
    treatment period maintained clinical response in 77% of patients;
    whereas, among patients who responded to the first treatment period
    with efalizumab and who received placebo during the extended
    treatment period a substantially lower proportion, 20%, maintained
    their treatment response.

-   Treatment with a second contiguous 12- week period of therapy can
    result in additional patients achieving response status, e.g. 11% in
    this study. This result is consistent with the findings in study
    ACD2058g

## Protocol ACD2390g

### Study Title

"A Phase IIIb, Randomized, Double-Blind, Parallel-Group,
Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and
Safety of 1.0 mg/kg Subcutaneously Administered Efalizumab in Adults
with Moderate to Severe Plaque Psoriasis"

### Study Objectives

To evaluate the efficacy of a 12-week course of 1.0 mg/kg/wk
subcutaneous (SC) efalizumab relative to placebo as measured by the
proportion of subjects achieving a ≥ 75% improvement in Psoriasis Area
and Severity Index (PASI) on Day 84 relative to

Day 0.

To evaluate the safety and tolerability of a 12-week course of 1.0
mg/kg/wk SC efalizumab relative to placebo.

*Reviewer's comment*

*The main objective of Study ACD2390g was to show the safety and
efficacy of Genentech-manufactured efalizumab. Previous studies had
shown that the 2 mg/kg/wk dose was not superior to the 1 mg/kg/wk dose.
Given the potential for dose-dependent toxicity of efalizumab, the study
only evaluated the 1 mg/kg dose.*

### Study Design

This was a Phase 3, randomized, double-blind, parallel-group,
placebo-controlled, multicenter study (approximately 30 sites) designed
to evaluate the efficacy and safety of efalizumab administered at weekly
SC doses of 1.0 mg/kg in subjects with moderate to severe plaque
psoriasis who were candidates for systemic therapy.

#### Randomization

Subjects were randomized (centrally) in a 2:1 ratio to receive either 12
weeks of 1.0 mg/kg/wk SC efalizumab or placebo.

Randomization was stratified by the Day 0 PASI score (≤ 16.0, ≥ 16.1),
by prior treatment for psoriasis (naive to systemic treatment vs. prior
systemic treatment), and by study center. A random permuted block design
was used to obtain approximately a 2:1 ratio within categories defined
by the stratification variables.

#### Blinding

Efalizumab produces an elevation of lymphocyte counts and total WBC
counts in most subjects that could result in unblinding. Therefore, from
Day 0 to Day 84 only absolute neutrophil and eosinophil counts from the
leukocyte portion of the complete blood count (CBC) were made available
to investigators and monitors. An independent assessor monitored the
entire leukocyte panel and notified the investigator and Medical Monitor
of any findings relevant to subject safety.

The pharmacokinetic, pharmacodynamic, and HAHA test results also had the
potential to unblind investigators and monitors. These data were
available only to laboratory staff until all subjects had completed the
study through Day 84. These data were not shared with investigators or
clinical monitors until after the completion of Study ACD2390g and until
the data were cleaned and frozen.

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

#### Study Drug

Each subject received an initial conditioning dose of 0.7 mg/kg followed
by 11 weekly doses of 1.0 mg/kg study drug (efalizumab or placebo
equivalent). Study drug was administered by SC injection by a trained
member of the research team. Subjects randomized to the efalizumab group
received the to-be-marketed formulation of efalizumab.

#### Open Label Extension Study

Study ACD2391g served as the open-label extension study for Study
ACD2390g. This study allowed evaluation of response after an extended
treatment with efalizumab for up to 24 weeks. The incidence of psoriasis
relapse in patients receiving a tapering regimen of efalizumab was also
analyzed.

*Reviewer's comment:* *The results of Study ACD2391g were not available
at the time of the original BLA submission.*

#### Criteria for Discontinuation of Treatment

Subjects were discontinued from efalizumab treatment if they met any of
the following criteria: pregnancy, any medical condition that the
investigator determined could jeopardize the subject's safety if he or
she were to continue in the study, or diagnosis of severe or serious
arthritis with evidence of joint inflammation upon examination for any
subject without a history of arthritis.

Other reasons for discontinuation included initiation of any excluded
topical or systemic treatment for psoriasis or excluded medication or
vaccine. Subjects who required concomitant treatment with systemic
psoriasis therapies had to discontinue from study drug immediately. For
subjects who withdrew early, the Day 84 assessments were to be completed
and the subject entered Study ACD2391g for follow-up.

#### Concomitant treatments

The only concomitant psoriasis treatments that could be used during the
entire study (screening and treatment period) were Eucerin cream and tar
or salicylic acid preparations (for scalp psoriasis only). Potency Group
VI or VII topical corticosteroids could be used in small amounts on
psoriatic lesions on the face, hands, feet, groin, or axillae, if
required.

#### Disallowed treatments

The following were not allowed:

Systemic treatments for psoriasis (e.g., PUVA, cyclosporine,
corticosteroids, methotrexate, oral retinoids) and immunosuppressive
medications for any indication other than psoriasis.

Treatment with UVB phototherapy and all other topical treatments for
psoriasis (e.g., topical corticosteroids, calcipotriene, tazarotene,
anthralin, tar) were excluded from Day --14 through Day 84, with the
exceptions noted previously*.* Tanning booths or nonprescription UV
light sources were not to be used .

Use of live virus vaccines or live bacteria vaccines was prohibited.

#### Eligibility

Patients were required to have plaque psoriasis, diagnosed for at least
6 month, over at least 10% BSA and a PASI of at least 12 at screening.
The eligibility criteria were similar to Study ACD 2058g.

#### Efficacy Outcomes

Primary Efficacy Endpoint

The proportion of patients with [\>]{.underline}75% improvement in PASI
score at the end of the treatment period (Day 84) was the primary
efficacy endpoint.

[Principal Secondary Efficacy Endpoint]{.underline}

The proportion of subjects who achieved an OLS rating of "Minimal or
Clear" at Day 84

was compared between treatment groups.

#### Other Secondary Efficacy Outcome Measures

Secondary efficacy outcome measures in support of the primary efficacy
outcome measure are in order of importance:

-   Proportion of subjects with a ≥ 50% improvement in PASI score at Day
    84

relative to Day 0

-   Mean percentage improvement from baseline (Day 0) in PASI over time

-   Mean improvement from baseline (Day 0) in the DLQI at Day 84

-   Mean improvement from baseline (Day 0) in the Itching Scale at Day
    84

-   Mean improvement from baseline (Day 0) in the PSA at Day 84

-   Proportion of subjects attaining a PGA rating of Excellent or
    Cleared at

Day 84

-   Mean improvement from baseline (Day 0) in the thickness component of

the PASI at Day 84

-   Mean improvement from baseline (Day 0) in the percentage of body

surface area (BSA) affected by psoriasis at Day 84

#### Clinical and Laboratory Assessments

At baseline, physical examinations (including vital signs and body
weight) were performed. Concomitant medications and adverse events were
monitored weekly during the treatment period. Vital signs were monitored
pre-dose on days 0, 28, 56 and 84. Hematology, chemistries and
urinalysis were monitored on days 0, 56 and 84. Serum antibody and serum
PK were assessed and blood for PD (including lymphocyte subsets and
CD11a expression) was collected at selected treatment sites. In females
of childbearing potential, urine pregnancy testing was performed.

####   {#section-3 .unnumbered}

The following psoriasis assessments were done monthly: PASI, OLS,
psoriatic BSA, PGA, DLQI, Itching scale. Patient photography was
performed.

#### Planned Statistical Analyses

Sample size considerations

The sample size for this study was based primarily on safety
considerations. The planned accrual was up to 333 subjects in the active
treatment group (1.0 mg/kg efalizumab) and up to 167 subjects in the
placebo group for a total of up to 500 subjects. The probability of
observing one or more instances of an adverse event with a background
rate of 1% or 2% over the period of observation in a treatment group
containing 333 subjects was 0.965 and 0.999, respectively.

Missing Data

For the all study endpoints, if a subject discontinued from the study
prior to Day 84 but after receiving the final scheduled dose of study
drug on Day 77, data from the early termination visit were used for
analysis in place of Day 84.

For the primary and principal secondary efficacy endpoints (PASI 75,
OLS, and PASI 50) subjects with a missing data at Day 84 were classified
as non-responders for analysis of this endpoint (worst outcome
imputation).

*Baseline Data*

Data were summarized for each treatment group. Subjects were stratified
by baseline PASI, history of prior systemic therapy and center.

*Efficacy Analyses*

All statistical tests were two sided and were performed at the 5% level
of significance.

Primary Endpoint

Response status at the end of the study was determined as follows:

• Responder: any subject whose PASI score decreased by ≥ 75% on Day 84
relative to Day 0

• Partial responder: any subject whose PASI score decreased by ≥ 50% but
\<75% on Day 84 relative to Day 0

• Non-responder: any subject whose PASI score decreased by \<50% on Day
84 relative to Day 0

The treatment effect was defined as the difference in the proportion of
responders between the active group (1.0 mg/kg SC efalizumab) and the
placebo group. The primary endpoint was evaluated by comparing the
proportion of responders between the active group and the placebo group
using Fisher's exact test for the ITT population; the exact 95%
confidence interval (CI) for response rate within each treatment group
and the difference in response rate between the active and placebo group
were calculated. Partial responders and non-responders were combined for
the primary analysis.

### Study Results 

#### Disposition, Demographics and Baseline Disease Characteristics

The first subject was enrolled into the study on 25 January 2002, and
the last subject completed the study on 30 July 2002. Thirty
investigators in United States and Canada enrolled a total of 556
patients into this study.

Table 45 Subject Disposition and Reasons for Discontinuation

  --------------------------------------- ---------------- ---------------
                                          Placebo          Efalizumab

  Subject Status                          (n=187)          (n=369)

  Completed treatment                     175 (93.6%)      345 (93.5%)

  Entered Study ACD2391g ET               174              342

  Entered Study ACD2391g FU               1                2

  Discontinued study                      0                1

  Discontinued treatment                  12 (6.4%)        24 (6.5%)

  Entered Study ACD2391g FU               3                11

  Discontinued study                      9                13

  Reason for discontinuation                               

  Subject's decision                      3                7

  Adverse event                           2                7

  Lost to follow-up                       5                4

  Use of excluded medication              0                5

  Investigator's decision                 2                1

  ET=Extended Treatment period.           FU=Follow-Up     
                                          period.          
  --------------------------------------- ---------------- ---------------

A total of 556 subjects were randomized, 187 in the placebo group and
369 in the 1.0 mg/kg/wk group. One subject (33602) who was randomized
into the efalizumab group never received any drug. Data from this
subject were included in the efficacy analysis, but excluded from the
safety analysis. The proportion of patients who discontinued due to use
of an excluded medication was higher in the efalizumab group than
placebo.

[Demographics: Populations Enrolled and Analyzed]{.underline}

Demographic characteristics were balanced among the treatment groups

Table 46 Demographic and Baseline Characteristics of Randomized Subjects

  ----------------- ------------------- -------------------- ----------------------
                                        Placebo              Efalizumab

                    Characteristic      (n=187)              (n=369)

  Sex, n                                                     

                    Male                132 (71%)            251 (68%)

                    Female              55 (29%)             118 (32%)

  Race/ethnicity, n                                          

                    White               167 (89%)            331 (89.7%)

                    Hispanic            7 (4%)               17 (4.6%)

                    Other ^a^           13 (7%)              21 (5.7%)

  Age group (yr), n                                          

                    18--40              68 (36%)             140 (38%)

                    41--64              106 (57%)            206 (56%)

                    ≥ 65                13 (7%)              23 (6%)

  Age (yr)                                                   

                    Mean                45                   45

                    Range               20--75               18--75

  Weight (kg)                                                

                    Mean                94                   94

                    Range               50--143              45--160

  Height (cm) ^b^                                            

                    Mean                173                  173

                    Range               147--196             123--198

  BMI (kg/m^2^) ^b^                                          

                    Mean                32                   31

                    Range               30--48               19--56
  ----------------- ------------------- -------------------- ----------------------

^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 available for 551 subjects: 185 in the placebo group and 366 in
the efalizumab group.

Overall, the treatment groups were comparable with regard to demographic
characteristics. The study population's demographic characteristics are
reflective of the general population of patients with psoriasis, with
the exception that more male than female patients were enrolled.
Psoriasis is estimated to affect males and females in a one to one
ratio. Of note, the population is heavier than the average US
population.

Randomization stratified by baseline PASI score (≤16.0, ≥16.1) and by
history of prior systemic treatment for psoriasis, was performed to
allow for a comparable baseline level of disease severity in each
treatment group. Characteristics of psoriasis at baseline are shown in
Table 47.

Table 47 Baseline Psoriasis Characteristics of Treated Subjects

  ------------------------------------- ----------------- ---------------
                                        Placebo           Efalizumab

  Characteristic                        (n=187)           (n=369)

  Duration of psoriasis (yr)                              

  Mean                                  19                19

  Range                                 1--53             1--62

  Prior systemic therapy, n                               

  Yes                                   139 (74%)         283 (77%)

  No                                    48 (26%)          86 (23%)

  PASI category, n                                        

     ≤16.0                              83 (44.4%)        155 (42.0%)

  16.1--30.0                            88 (47.1%)        181 (49.1%)

  \>30.0                                16 (8.6%)         33 (8.9%)

  PASI score                                              

  Mean                                  19                19

  Range                                 11--50            10--59

  PASI thickness component                                

  Mean                                  6.2               6.2

  Range                                 3--15             2.4--19

  OLS, n                                                  

  Minimal                               1 (0.5%)          1 (0.3%)

  Mild                                  12 (6.4%)         23 (6.2%)

  Moderate                              96 (51.3%)        206 (55.8%)

  Severe                                69 (36.9%)        121 (32.8%)

  Very severe                           9 (4.8%)          18 (4.9%)

  DLQI                                                    

  Mean                                  12                12

  Range                                 0--30             0--30

  Itching Scale                                           

  Mean                                  6.2               6.4

  Range                                 0--10             0--10

  PSA frequency                                           

  Mean                                  14                14

  Range                                 2--24             2--24

  PSA severity                                            

  Mean                                  15                15

  Range                                 2--24             0--24

  Percent BSA of psoriasis                                

  Mean                                  27                28\.

  Range                                 10--90            10--95
  ------------------------------------- ----------------- ---------------

The baseline disease severity is moderate to severe with the mean
disease duration 19 years and the mean PASI score 19. The majority
(approximately 3 out of 4) of patients enrolled with a history of prior
systemic therapy.

The two treatment groups were well-balanced with respect to the baseline
disease characteristics, including PASI, OLS, and BSA.

#### Study Conduct

Table 48 below shows protocol deviations noted in Study ACD2390g.

Table 48 Protocol Deviations Study 2390

  ---------------- ----------------------------- --------------- ------------------
                                                 Placebo         Efalizumab

                   Protocol Deviation            (n=187)         (n=369)

  Total a                                        38 (20.3%)      84 (22.8%)

  Missing                                        16 (8.6%)       38 (10.3%)
  laboratory data                                                
  b                                                              

  PASI performed                                 19 (10.2%)      32 (8.7%)
  outside of the                                                 

  Day 84 window                                                  
  ^c^                                                            

                   \<82 Days                     7 (3.7%)        11 (3.0%)

                   \>86 Days                     12 (6.4%)       21 (5.7%)

  OLS performed                                  19 (10.2%)      33 (8.9%)
  outside of the                                                 

  Day 84 window                                                  

                   \<82 Days                     7 (3.7%)        11 (3.0%)

                   \>86 Days                     12 (6.4%)       22 (6.0%)

  Use of excluded                                6 (3.2%)        18 (4.9%)
  medication                                                     

  Incorrect study                                1 (0.5%)        3 (0.8%)
  drug                                                           

  administration                                                 

  Incorrect dosing                               0               2 (0.5%)
  level                                                          

  ^a^              Represents the number of                      
                   subjects with at least one                    
                   protocol deviation.                           

  ^b^              Missing laboratories                          
                   (hematologic assessments,                     
                   chemistries,                                  

                   urinalysis, HIV serology,                     
                   serum antibody, pregnancy).                   

  ^c^              For subjects who completed                    
                   the treatment period.                         
  ---------------- ----------------------------- --------------- ------------------

One subject (33602) who was randomized into the efalizumab group never
received any drug.

Twenty-four subjects were treated with an excluded medication for
psoriasis during the treatment period: 6 subjects (3%) in the placebo
group and 18 subjects (5%) in the efalizumab group. One
efalizumab-treated patient received UVB. Also, among the disallowed
therapies were systemic steroids. Systemic steroids were used for
different indications including nonpsoriasis-related indications. One
patient received systemic steroids for psoriatic erythroderma (34229)
and other patients received either systemic steroids or intralesional
steroid injections for worsening psoriatic arthritis (33424, 34415).
Therefore, the use of systemic steroids indicated worsening of psoriasis
and/or psoriatic arthritis in some, but not all patients.

Treatment compliance is shown in Table 49 below.

Table 49 Compliance for Subjects

  ------------------------------- ------------------- -------------------
  Number of Doses                 Placebo             Efalizumab

  Received                        (n=187)             (n=369)

  All 12                          146 (78.1%)         271 (73.4%)

  10--11                          29 (15.5%)          74 (20.1%)

  \<10                            12 (6.4%)           24 (6.5%)
  ------------------------------- ------------------- -------------------

Treatment compliance was comparable between the two treatment groups.
Approximately 3 of 4 patients in each group received all 12 treatments.

#### Primary Efficacy Outcome 

Table 50 PASI Response to Treatment for Randomized Subjects

  --------------------------------------- --------------- ---------------
                                          Placebo         Efalizumab

  PASI Response at Day 84                 (n=187)         (n=369)

  Responders                              8 (4.3%)        98 (26.6%)

  Partial responders and non- responders  179 (95.7%)     271 (73.4%)
  ^a^                                                     

  Fisher's exact p-value efalizumab vs.   ---             \<0.001
  placebo                                                 

  Treatment effect                        22.3%           

  95% CI for treatment effect             15.8%, 29.5%    

  ^a^ Included subjects whose Day 84 PASI                 
  score was missing.                                      
  --------------------------------------- --------------- ---------------

The proportion of responders was higher in the treatment group than in
placebo. The absolute difference was 22.3%. These results were
statistically significant. Therefore, Study ACD2390g was successful in
establishing the efficacy of Genentech-manufactured efalizumab.

A more detailed examination of the percentage change in PASI at the end
of the first treatment period is shown in Table 51 below.

Table 51 PASI Response by Percent Improvement from Baseline

  ---------------------------------- ---------------- -------------------
  Percent Improvement                Placebo          Efalizumab

  from Baseline at Day 84            (n=187)          (n=369)

    ≥90%                             1 (0.5%)         19 (5.1%)

    ≥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%)

    ≥ --25% to \<0%                  32 (17.1%)       15 (4.1%)

    ≥ --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^ Subjects with missing Day 84                    
  PASI scores were classified as                      
  non-responders.                                     
  ---------------------------------- ---------------- -------------------

The efalizumab-treated group showed a general shift towards improvement
in PASI response from baseline. Efalizumab treatment effect was 45%
using as criterion ≥ 50% improvement in PASI score. The proportion of
patients who experienced worsening of the PASI score was higher in the
placebo group (27.8%) than in the efalizumab group (12.5%).

Figure 6 below shows the distribution of the change in PASI score at day
84 by treatment group. The histograms reflect data from 347/369 patients
in the efalizumab group and 175/187 of the placebo group for whom the
data were available. A positive percentage change reflects improvement
from baseline and a negative score is deterioration.

Figure 6 Percent Change in PASI Score at Day 84 by Treatment Group

**Efalizumab (N=347) Placebo (N=175)**

![](media/image9.wmf){width="4.40625in" height="2.6979166666666665in"}

From this distribution, one can see that a small number of patients in
both treatment groups worsened during treatment.

depicts the percentage changes in PASI score by quantiles. The mean
percentage changes in PASI score were 52 and 19, respectively in the
efalizumab and placebo groups, while the median changes were 60 and 16.

Table 52 Percent Change in PASI by Treatment Group

  ------------------- ------------------------ --------------------------
                      Efalizumab               Placebo

  maximum             100                      92

  quartile            78                       38

  median              60                       16

  quartile            32                       0.0

  minimum             -79                      -107
  ------------------- ------------------------ --------------------------

There is a general shift towards higher PASI improvement within each
quartile in the efalizumab-treated group as compared to placebo.

#### Treatment Response in Patient Subgroups

Treatment responses were examined in various patient subgroups based on
demographic factors, baseline PASI and prior history of systemic therapy
( **Table 53** ).

Table 53 PASI Responders by Subsets of Randomized Subjects

  ---------------------------- ------------------- ----------------------
                               Placebo             Efalizumab

  Subject Subset               (n=187)             (n=369)

  Gender                                           

  Women                        2/55 (3.6%)         33 /118 (28%)

  Men, n                       6 /132 (4.5%)       65 /251 (26%)

                                                   

  Age group (yr)                                   

  18--40, n                    4 /68 (5.9%)        43 /140 (31%)

  41--64, n                    4 /106(3.8%)        51 /206 (25%)

   ≥ 65, n                  0 /13               4 /23(17%)

                                                   

  Baseline PASI score                              

   ≤ 16.0, n                4 /83 (5%)          40 /155 (26%)

  16.1--30.0, n                4 /88(4.5%)         48 /181 (27%)

  \>30.0, n                    0 /16               10 /33 (30%)

                                                   

  Prior systemic therapy                           

  Yes, n                       7 /139 (5%)         75 /283 (27%)

  No, n                        1 /48 (2.1%)        23 /86 (27%)
  ---------------------------- ------------------- ----------------------

The results for the primary endpoint in subsets defined by sex, age
group, baseline PASI score and history of prior systemic therapy are
consistent with the results of the ITT population as a whole.

A logistic regression analysis did not show baseline PASI score, age,
sex, and prior systemic therapy to be significantly predictive of
response.

Responses in the components of the PASI score are shown in Table 54
below.

Table 54 Mean Percent Improvement in PASI Thickness, Erythema, and
Scaling Components

  ------------- ------------------------- ----------------- ---------------------
                                          Placebo           Efalizumab

  PASI                                    (n=187)           (n=369)
  Component at                                              
  Day 84                                                    

  Thickness ^a^                           16.8              50.7

  Erythema ^a^                            16.8              45.6

  Scaling ^a^                             19.2              50.7

                                                            

  PASI total                              (n=175)           (n=347)
  ^b^                                                       

                                          19                52

  Note:                                                     
  Improvement                                               
  in each                                                   
  component was                                             
  reflected by                                              
  a decrease in                                             
  score.                                                    

  ^a^           The last observation                        
                carried forward was used                    
                to impute missing Day 84                    
                PASI data.                                  

  ^b^           Values from the early                       
                termination visits were                     
                assigned to the next                        

                scheduled visit for PASI                    
                evaluation.                                 
  ------------- ------------------------- ----------------- ---------------------

As in Studies ACD2058g and ACD2059g, each of the three components of the
PASI score appear to contribute similarly to improvement in the overall
score.

Table 55 Mean Improvement in Percentage of BSA of Psoriasis

  ------------------------------------ -------------- -------------------
                                       Placebo        Efalizumab

  Percentage of BSA                    (n=187)        (n=369)

  Day 0                                27             28

  Day 84 ^a^                           25             17

  Improvement ^b^                      2.6            11

  Two-sample t-test p-value                           

  efalizumab vs. placebo               ---            \<0.001

  ^a^ The last observation carried                    
  forward was used to impute missing                  
  Day 84 BSA value.                                   

  ^b^ Improvement was reflected by a                  
  decrease in the percent BSA value.                  
  ------------------------------------ -------------- -------------------

In addition to the improvements in each of the components of the PASI
score (thickness, erythema, scale), efalizumab-treated patients
demonstrated mean improvements in percentage body surface area affected
by psoriasis.

#### Secondary Efficacy Outcome

#### The principal secondary outcome results are shown in Table 56 below. {#the-principal-secondary-outcome-results-are-shown-in-table-56-below. .unnumbered}

Table 56 Principal Secondary Efficacy Endpoint

  ----------------------------------- ----------------- ------------------
                                      Placebo           Efalizumab

  OLS Response at Day 84              (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                                

  efalizumab vs. placebo              ---               \<0.001

  ^a^ Included subjects who were                        
  classified as Mild, Moderate,                         

  Severe, and Very Severe and those                     
  whose Day 84 OLS rating was                           
  missing.                                              
  ----------------------------------- ----------------- ------------------

The proportion of patients with an OLS rating of "Minimal or Clear" in
the efalizumab group was higher than in the placebo group. The absolute
difference from placebo was 22.5%. These results are supportive of the
primary efficacy analysis.

A more detailed examination of the distribution of Day 84 OLS categories
is presented in Table 57 below.

Table 57 OLS Response to Treatment at Day 84

  ----------------------------------- ----------------- ------------------
                                      Placebo           Efalizumab

  OLS Response at Day 84              (n=187)           (n=369)

  Clear                               0                 7 (1.9%)

  Minimal                             6 (3.2%)          88 (23.8%)

  Mild                                32 (17.1%)        125 (33.9%)

  Moderate                            92 (49.2%)        99 (26.8%)

  Severe                              40 (21.4%)        25 (6.8%)

  Very Severe                         6 (3.2%)          7 (1.9%)

  Missing                             11 (5.9%)         18 (4.9%)
  ----------------------------------- ----------------- ------------------

The distribution of the OLS scores shows a higher overall shift towards
milder scores in the efalizumab group than placebo. Higher numbers of
patients were classified as severe and very severe in the placebo group
as compared to the efalizumab-treated group. The proportions of patients
with missing data were comparable between treatment groups.

#### Onset of treatment effect

Figure 7 below shows the mean percentage improvement in PASI score over
time.

Figure 7

![](media/image10.png){width="5.99375in" height="4.217361111111111in"}

Statistically significant differences between treatment groups in favor
of efalizumab were noted by 28 days of therapy.

#### Quality of life measures

The Dermatology Life Quality Index (DLQI) mean change from baseline at
Day 84 was designated in a protocol amendment as a secondary efficacy
outcome measure. The DLQI, consists of a 10-item questionnaire and is
dermatology-specific measure of quality of life. The score ranges from
0-30. Decreases in the DLQI represent improvement in functionality and
subject well being.

Table 58 Improvement from Baseline in DLQI Overall Score

  ------------- ---------------------------- ----------------- -----------------
                                             Placebo           Efalizumab

                DLQI                         (n=187)           (n=369)

  Day 0                                                        

                n                            183               363

                Mean                         11.8              12.0

                Median                       11.0              11.0

                Range                        0 to 30           0 to 30

  Day 84 ^a^                                                   

                n                            187               368

                Mean                         10.2              6.4

                Median                       9.0               4.0

                Range                        0 to 30           0 to 30

  Improvement                                                  
  from baseline                                                
  ^b^                                                          

                n                            183               363

                Mean                         1.6               5.6

                Median                       1.0               5.0

                Range                        --13 to 25        --22 to 25

  Wilcoxon                                                     
  rank-sum test                                                
  p-value                                                      

  efalizumab                                 ---               \<0.001
  vs. placebo                                                  

  ^a^           The last observation carried                   
                forward was used to impute                     
                missing Day 84 DLQI values.                    

  ^b^           Improvement was reflected by                   
                a decrease in DLQI overall                     
                score.                                         
  ------------- ---------------------------- ----------------- -----------------

The baseline median score was 11 in both treatment groups, the baseline
mean score was 12, and the range was from 0-30. The mean improvement
from baseline was 5.6 in efalizumab-treated patients vs. 1.6 in
placebo-treated patients. This represents a statistically significant
difference between treatment groups in favor of the efalizumab-treated
group.

*Reviewer's comment*

*The clinical significance of a 4-point absolute improvement in score in
a scale ranging from 0-30 is not clear.*

### Summary of Efficacy: Study ACD2390g

This study demonstrated the efficacy of Genentech-manufactured
efalizumab

-   Approximately 22% more patients in the efalizumab-treated group had
    a 75% improvement in PASI score at the end of the first treatment
    period than placebo-treated patients.

-   Clinical responses as measured by the physician's static global
    assessment was consistent with those obtained by PASI 75 criteria.
    The absolute difference from placebo was 22.5%.

-   Onset to treatment effect was by 4 weeks.

-   Duration of response was not evaluated in this study.

## Protocol ACD2600g

### Study Title

"A phase IIIb, randomized, double- blind, parallel- group,
placebo-controlled, multicenter study to evaluate the safety of 1.0
mg/kg subcutaneously administered efalizumab in adults with moderate to
severe plaque psoriasis who are candidates for systemic therapy"

### Study Objectives

The primary objective of this study was to evaluate the safety and
tolerability of a 12-week course of 1.0 mg/kg SC Genetech-manufactured
efalizumab relative to placebo.

The secondary objectives of this study were to evaluate the efficacy of
a 12-week course of 1.0 mg/kg SC efalizumab relative to placebo as
measured by:

-   The proportion of subjects achieving a ≥75% improvement in Psoriasis

Area and Severity Index (PASI)

-   The Overall Lesion Severity (OLS) scale

-   The proportion of subjects achieving a ≥50% improvement in PASI

-   The Psoriasis Symptom Assessment (PSA)

### Study Design

#### Randomization

Subjects were randomized (centrally) in a 2:1 ratio to receive either 12
weeks of 1.0 mg/kg/ SC efalizumab or placebo. Randomization was
stratified within each study center by the Day 0 PASI score (≤16.0,
≥16.1) and by prior treatment for psoriasis (naive to systemic treatment
vs. prior systemic treatment). A random permuted block design was used
to obtain approximately a 2:1 ratio within categories defined by the
stratification variables.

#### Blinding

This was double-blind study. Subjects, investigators, and the Sponsor
were blinded regarding treatment assignment to placebo or active study
drug. Efalizumab produces elevations of lymphocyte and total white blood
cell counts. Therefore, to minimize the potential for unblinding, only
the absolute neutrophil count and the eosinophil count were to be made
available to the investigators and monitors from the CBC. Similarly,
anti-efalizumab antibody results were not to be shared with
investigators or the contract research organization until Study ACD2600g
has been unblinded.

#### Open-label extension

The open-label extension for this study was Study ACD2601g.

#### Study Drug

The study drug, route and dose was the same as Study ACD2390g.

#### Criteria for Discontinuation of Treatment

The criteria for discontinuation of treatment included the following:

-   Pregnancy

-   Administration of a live virus or bacteria vaccine

-   Initiation of excluded systemic treatment for psoriasis

-   Initiation of excluded immunosuppressive treatment for any
    indication

-   Initiation of excluded experimental medication or other treatment

-   Diagnosis of severe or serious arthritis with evidence of joint
    inflammation

(i.e., pain, swelling, stiffness, heat, and/or redness) upon examination
for

> any subject without a history of arthritis
>
> Subjects with a history of arthritis (such as, but not limited to,
> psoriatic arthritis) may have had variations in the severity of
> arthritis during the study; this did not require early discontinuation
> of study drug treatment.

-   Any medical condition (e.g., opportunistic infections, malignancies,
    immune complex disorders) that the investigator determined may
    jeopardize the subject's safety.

#### Concomitant Therapy

Allowed concomitant therapies were similar to those in study ACD2390g.
The concomitant therapies that were excluded were also similar to those
in study ACD2390g.

#### Elegibility Criteria

The eligibility criteria were similar to those in Studies ACD2390g and
ACD2058g.

#### Endpoints

#### Safety

The study's designated primary objective was to evaluate safety.

#### Efficacy

The principal secondary endpoint consisted of the comparison of the
proportion of subjects whose PASI score has decreased by ≥ 75% on Day 84
relative to Day 0 between the active group (1.0 mg/kg/wk efalizumab) and
the placebo group for the ITT population using Fisher's exact test.

#### Study Assessments

Analyses for anti-efalizumab antibody assessments were performed on
serum samples collected on Days 0 and 56. An unscheduled antibody sample
was to be obtained from subjects who discontinued prior to Day 56.

Dermatologic evaluation (PASI, psoriatic BSA, and static physicians
global assessment) and complete examination took place at baseline, Day
28, Day 56 and Day 84 of the study.

Screening laboratory evaluations consisted of hematology, chemistry
(electrolytes, glucose, creatinine, bilirubin, albumin, total protein,
liver function tests, creatine phosphokinase, and uric acid, urinalysis,
HIV serology, hepatitis B antigen, and hepatitis C serology.

In addition to urinalysis, hematology and chemistries, other tests were
performed at baseline and at day 84 of the study which were not
performed in prior phase 3 studies. These consisted of C-reactive
protein, fibrinogen, complement 3a and complement 5a.

### Study Results

A total of 686 subjects were enrolled and randomized, 236 in the placebo
group and 450 in the 1.0 mg/kg/wk group. The study was conducted at 58
study centers in the United States and Canada. The study was completed
February 19, 2003.

One subject randomized to efalizumab group was never dosed and was
removed from safety summaries

Table 59 ACD2600g: Subject Disposition and Reasons for Premature
Discontinuation in Randomized Subjects

  ------------------------------- -------------------- ------------------
                                  Placebo              Efalizumab

  Subject Status                  (N=236)              (N=450)

  Completed FT                    218 (92%)            421 (93%)

  Entered ACD2601g ET             218                  418

  Entered ACD2601g FU             0                    2

  Discontinued study              0                    1

                                                       

  Discontinued FT                 18 (7.6%)            29 ( 6.4%)

  Entered ACD2601g FU             5                    10

  Discontinued study              13                   19

                                                       

  Reasons for FT discontinuation                       

  Death                           1                    0

  Adverse event                   6                    11

  Lost to follow-up               3                    3

  Subject\'s decision             6                    9

  Physician\'s decision           2                    3

  Pregnancy                       0                    1

  Use of excluded rx              0                    2
  ------------------------------- -------------------- ------------------

The proportions of patients completing the first treatment course were
comparable across treatment groups. The proportion of patients who
discontinued the FT for an adverse event was similar in the active
treatment arms and in the placebo arm.

A total of 47 subjects (6.9%) discontinued treatment. One subject
assigned to placebo died during the study. Seventeen patients overall
discontinued due to adverse events, the most common reason given for
discontinuation. The proportions discontinuing for adverse events were
comparable between treatment groups. The second most common reason for
discontinuation was "subject's decision" accounting for 15 patients who
discontinued prematurely.

The demographic and other baseline characteristics of the studied
population are displayed in Table 60 below.

Table 60 ACD2600g: Demographic and Baseline Characteristics of
Randomized Subjects

  ------------------------------- ----------------- ----------------------
                                  Placebo           Efalizumab

  Characteristic                  (N=236)           (N=450)

  Sex                                               

  Male                            140 (59.3%)       303 (67.3%)

  Female                          96 (40.7%)        147 (32.7%)

  Race/ethnicity                                    

  White                           215 (91.1%)       412 (91.6%)

  Hispanic                        8 (3.4%)          18 (4.0%)

  Other ^a^                       13 (5.5%)         20 (4.4%)

  Age group (yr)                                    

  18--40                          74 (31.4%)        160 (35.6%)

  41--64                          149 (63.1%)       252 (56.0%)

  ≥ 65                            13 (5.5%)         38 (8.4%)

  Age (yr)                                          

  Mean                            46.4              45.6

  Range                           20 - 77           18 - 74

  Weight (kg)                                       

  Mean                            92.5              93.1

  Range                           46 - 159          51 - 159

  ^a^ The "Other" group included                    
  individuals who described their                   
  Asian or Pacific Islander,                        
  Black, American Indian or                         
  AlaskanNative, or                                 
  race/ethnicity as Other.                          
  ------------------------------- ----------------- ----------------------

Overall the two treatment groups were comparable in demographics and
baseline psoriasis characteristics, except that there was a higher ratio
of male to female patients in the efalizumab group than in placebo.
Aside from this gender imbalance, the patient population enrolled is
representative of the US population with moderate-to-severe chronic
plaque psoriasis.

Reviewer's comment: The range of ages shows that some patients were
enrolled who were older than the entry criteria allowed.

The baseline psoriasis characteristics of the study population are
displayed in Table 61 below.

Table 61 ACD2600g: Baseline Psoriasis Characteristics of Randomized
Subjects

  ------------------------------- ----------------- ----------------------
                                  Placebo           Efalizumab

  Characteristic                  (N=236)           (N=450)

  Prior systemic therapy, n                         

  Yes                             174 (73.7%)       328 (72.9%)

  No                              62 (26.3%)        122 (27.1%)

  PASI category, n                                  

  ≤ 16.0                          112 (47.5%)       201 (44.7%)

  16.1--30.0                      105 (44.5%)       210 (46.7%)

  \>30.0                          19 (8.1%)         39 (8.7%)

  PASI score                                        

  Mean (SD)                       18.69 (7.01)      19.14 (7.47)

  Range                           10.5 - 49.6       10.2 - 54.6

  Percent BSA of psoriasis                          

  Mean (SD)                       26.8(15.2)        27.7(15.8)

  Range                           10.0 - 83.0       10.0 - 85.0
  ------------------------------- ----------------- ----------------------

The overall baseline disease severity was moderate to severe plaque
psoriasis and was comparable between treatment groups. Most of the
patients, 73%, had a prior history of systemic therapy.

The tabulation of certain types of protocol deviations follows (Table
62).

Table 62 Study ACD2600g: Protocol Deviations

  ----------------------------- -- -------------- --- ------------ ------------ --
                                   Placebo            Efalizumab                

  Protocol Deviation               (n=236)            (n=450)                   

  Total a                          49 (20.8%)         91 (20.2%)                

  OLS performed outside of the     22 (9.3%)          44 (9.8%)                 

  Day 84 window ^b^                                                             

  \<82 Days                        10 (4.2%)          12 (2.7%)                 

  \>86 Days                        12 (5.1%)          32 (7.1%)                 

  PASI performed outside of the    22 (9.3%)          43 (9.6%)                 

  Day 84 window ^b^                                                             

  \<82 Days                        10 (4.2%)          11 (2.4%)                 

  \>86 Days                        12 (5.1%)          32 (7.1%)                 

  Missing laboratory data ^c^      19 (8.1%)          28 (6.2%)                 

  Use of excluded medication       10 (4.2%)          22 (4.9%)                 

  Incorrect study drug             2 (0.8%)           4 (0.9%)                  
  administration                                                                

  Incorrect dosing of study        1 (0.4%)           1 (0.2%)                  
  drug                                                                          

  Incorrect treatment              1 (0.4%)           1 (0.2%)                  
  assignment ^d^                                                                

  ^a^ Represents the number of                                                  
  subjects who had at least one                                                 
  protocol deviation.                                                           

  ^b^ For subjects who                                                          
  completed the treatment                                                       
  period.                                                                       

  ^c^ Missing laboratory                                                        
  results (hematologic                                                          
  assessments, chemistries,                                                     
  urinalysis,                                                                   

  C-reactive protein,                                                           
  fibrinogen, complement 3a,                                                    
  complement 5a, serum                                                          
  antibody,                                                                     

  pregnancy, HIV, hepatitis B                                                   
  antigen, and hepatitis C                                                      
  serology).                                                                    

  ^d^ Incorrect treatment                                                       
  assignment (subjects received                                                 
  incorrect study drug at the                                                   
  site).                                                                        
  ----------------------------- -- -------------- --- ------------ ------------ --

The most frequent protocol deviation was performance of the Day 84 OLS
and PASI assessments outside of the ±2 day visit window. Most of these
PASI assessments were performed within ±7 days of Day 84. The second
most common deviation was missing laboratory data. Six subjects were
administered study drug from the single-use vials on two consecutive
visits on one or two occasions; Subjects 42208 and 42209 were in the
placebo group, and Subjects 42202, 42204, 42206, and 42207 were in the
efalizumab group. One placebo-treated subject (41202) and one
efalizumab-treated subject (45408) were administered a 1.0 mg/kg dose
instead of the conditioning dose of 0.7 mg/kg on Day 0. Subject 40816
was randomized to receive placebo but was administered efalizumab on Day
77. Subject 41613 was randomized to receive efalizumab but was
administered placebo on Day 42.

*Reviewer's comment: These protocol deviations were not deemed to have
an effect on the study outcome.*

The efficacy results at the end of the 12-week treatment period are
summarized below (Table 63).

Table 63 ACD2600g: Efficacy Results of Randomized Subjects

  ------------------------- ---------------------- ----------------------
                            Placebo                Efalizumab

                            (N=236)                (N=450)

  PASI 75                   7 (3.0%)               106 (23.6%)

  PASI 50                   33 (14.0%)             234 (52.0%)

  OLS Clear/Minimal         10 (4.2%)              91 (20.3%)
  ------------------------- ---------------------- ----------------------

The Fisher's exact test p-value was \<0.001% for each comparison.

The proportion of PASI 75 responders was higher in the treatment group
than in placebo. The absolute difference was 20.6%. In addition, the
absolute difference in proportions of patients achieving PASI 50
response was 38% in favor of the efalizumab-treated group. Finally, the
efficacy outcome based on the response by physician's static global
assessment was also supportive of the response data as measure by PASI
outcomes.

These results were statistically significant.

### Summary of Efficacy: Study ACD2600g

-   The efficacy results of this study were consistent with those of the
    earlier phase 3 studies.

```{=html}
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```
-   The treatment effect was 21% by the PASI 75 criterion and 38% by the
    PASI 50 criterion.

-   Clinical responses as measured by the physician's static global
    assessment was consistent with those obtained by PASI 75 criteria.
    The absolute difference from placebo was 16%.

# EXPLORATORY EFFICACY ANALYSES

## Effect of Use of Excluded Therapies 

The possible influence of excluded concomitant medications on PASI
response during FT in Studies ACD2058g, ACD2059g, and ACD2390g was
assessed for each study, by material, by recomputing the proportion of
FT responders in each study after conservative re-categorization of each
user of excluded medication as a non-responder (\<PASI-75 response).
Accordingly, a list of all protocol-proscribed medications for FT was
compiled that included all topical high- and mid-potency
corticosteroids, systemic corticosteroids, and all other systemic agents
stated as prohibited by the protocols. This sensitivity exclusion list
included some medications conservatively considered potentially
efficacious but not proscribed previously in the protocols, including
two low-potency topical corticosteroids, alclometasone and desonide. All
of these excluded medications were flagged in the database such that for
the sensitivity analysis, a total of 24, 46, and 30 primary analysis
randomized subjects (total of 100) in Studies ACD2058g, ACD2059g, and
ACD2390g, respectively, were considered non-responders for the purpose
of this sensitivity exercise, based solely on the use of excluded
medications. Fourteen of these 100 subjects who had received excluded
medication had been FT responders in the primary analysis and were
re-categorized as non-responders in the sensitivity analysis.

The results of the sensitivity analysis are shown in Table 64 and are
compared with the results of the primary PASI-75 efficacy analysis. This
comparison of the primary and conservatively reclassified sensitivity
results revealed only minor differences in percent PASI response during
FT, and this result was ascribed to the very small number of subjects
who used prohibited medications.

Table 64 Sensitivity Analysis of FT PASI Response (Primary Endpoint) for
Usage of Excluded, Possibly Efficacious Concomitant Medications in the
Phase III Trials: Comparison to Results of Primary Analysis

  ----------------- --------- ------------- ------------ ------------- ------------ -------------
                                            Efalizumab                 Efalizumab   

                    Placebo                 (1.0                       (2.0         
                                            mg/kg/wk)                  mg/kg/wk)    

  Study             Primary   Sensitivity   Primary      Sensitivity   Primary      Sensitivity

  Genentech                                                                         
  Material                                                                          

  ACD2390g                                                                          

  n                 187       187           369          369           ---          ---

  Responder         8 (4.3%)  7 (3.7%)      98 (26.6%)   95 (25.7%)    ---          ---

  Treatment effect  ---       ---           22.3%        22.0%         ---          ---

  95% CI            ---       ---           15.8, 29.5   15.6, 29.1    ---          ---

  ACD2059g, (GNE)                                                                   

  n                 32        32            52           52            61           61

  Responder         0 (0.0%)  0 (0.0%)      5 (9.6%)     5 (9.6%)      13 (21.3%)   11 (18.0%)

  Treatment effect  ---       ---           9.6%         9.6%          21.3%        18.0%

  95% CI            ---       ---           --7.2, 29.7  --7.2, 29.7   3.5, 42.2    0.5, 38.4

  XOMA Material                                                                     

  ACD2059g (XOMA)                                                                   

  n                 90        90            180          180           182          182

  Responder         6 (6.7%)  6 (6.7%)      47 (26.1%)   46 (25.6%)    56 (30.8%)   55 (30.2%)

  Treatment effect  ---       ---           19.4%        18.9%         24.1%        23.6%

  95% CI            ---       ---           8.7, 31.0    8.2, 30.4     13.7, 35.9   13.1, 35.4

  ACD2058g                                                                          

  n                 170       170           162          162           166          166

  Responder         4 (2.4%)  4 (2.4%)      63 (38.9%)   60 (37.0%)    44 (26.5%)   41 (24.7%)

  Treatment effect  ---       ---           36.5%        34.7%         24.2%        22.3%

  95% CI            ---       ---           27.8, 46.2   26.0, 44.3    16.0, 33.4   14.3, 31.6
  ----------------- --------- ------------- ------------ ------------- ------------ -------------

The sensitivity analysis did not appreciably alter either the clinical
or statistical significance of the response rates in any dose group in
any studies, nor did it affect the magnitude of significance of the
treatment effects as corrected for placebo response.

[]{.mark}

[]{.mark}

[]{.mark}

# SUMMARY OF EFFICACY AND PATIENT POPULATION

-   The patient population was representative of the general population
    with chronic stable moderate to severe plaque psoriasis with the
    exception of the gender imbalance (fewer women than men were
    studied).

-   Primary efficacy outcome

    -   In patients receiving 1 mg/kg/wk SC, treatment effect ranged
        from 18% to 37% (depending on the study) by PASI 75 criteria.

    -   There was no meaningful difference in response by age, gender,
        race, baseline disease severity or history of previous systemic
        therapy for psoriasis.

```{=html}
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```
-   Secondary efficacy outcomes

    -   Other efficacy outcomes, including PASI 50 and static
        physician's global assessment showed statistically significant
        differences from placebo in favor of efalizumab-treated patients
        and were supportive of the primary efficacy outcome.

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-   Quality of life outcomes showed small degrees of improvement (3-4
    points on a scale from 0-30) in favor of the efalizumab-treated
    patients. The clinical significance of the degree of change is not
    known.

-   Median time to response in patients achieving PASI 75 was
    approximately 2 months (57 days). Statistically significant
    differences in the mean PASI scores between patients receiving
    efalizumab and those receiving placebo were seen by 2-4 weeks of
    therapy.

-   The median duration of treatment effect based on the time to loss of
    50% of improvement was 67 days following discontinuation of
    treatment.

-   A second 12-week course of treatment upon 50% relapse does not
    recapture response in the majority of patients who responded to the
    first 12 weeks of treatment. Response was 31% at the PASI 75 level,
    even though 100% of these patients responded to efalizumab during
    the first treatment period.

-   Among treatment responders during the initial 12 weeks of therapy,
    extended treatment for an additional 12 weeks can maintain treatment
    response in 77% of patients.

-   In patients who were nonresponders or partial responders during the
    first 12 weeks of efalizumab treatment, extended treatment with a
    contiguous 3 month treatment course can result in an additional
    11%-14% PASI 75 response (depending on the study).

# INTEGRATED SAFETY REVIEW

## Safety Database

Approximately 2400 patients received efalizumab weekly for 12 weeks of

continuous treatment, 939 for 24 weeks of continuous treatment, and 218
for

1 year of continuous treatment. In all, 1,620 patients received
efalizumab in the 12-week, placebo-controlled portion of the four phase
3 studies (ACD2058g, ACD2059g, ACD2390g and ACD2600g).

Of the 1115 subjects who entered the first extended treatment period
from 12--24 weeks (see Table 65 below), 939 completed 24 weeks of
treatment.

The population of patients who received the Genentech manufactured
product for the first time in controlled studies ranged in age from
18-75 years and included 67% men and 33% women. A high proportion of the
patients were Caucasian (88%) reflecting the general patient population
with psoriasis. The mean body weight was 93 kg. The disease severity at
baseline was moderate-to-severe psoriasis, with a mean PASI of 19 and
affected body surface area of 29%.

As stated previously, due to the differences in pharamcokinetics between
the XOMA and Genentech manufactured efalizumab, the FDA requested that
the safety data be analyzed separately according to manufacturer. No
differences in safety were found between the patients treated with
XOMA-manufactured vs. the Genentech-manufactured efalizumab (data not
shown). Therefore, for the purposes of this summary of the integrated
safety review, the databases will be pooled.

Table 65 Subjects with Moderate to Severe Plaque Psoriasis Receiving SC
Efalizumab Treatment beyond the Initial 12-Week Course (EE)

  ------------- ---------------------- --------- ------------ --------- -- --------- -- ----------
                                                 Efalizumab                             
                                                 Treatment                              
                                                 Segment                                

                                       EE-1                   EE-2         EE-3         EE-4

                Source (Manufacturer)  12--24 Wk              24--36 Wk    36--48 Wk    48--60 Wk

  Original BLA                                                                          

                XOMA                   360                    13           NA           NA

                Genentech              389                    292          243          149

                Original total         772 ^a^                318 ^b^      243          149

  BLA                                                                                   
  Amendment:                                                                            

  Study                                1                      0            4            79
  ACD2243g                                                                              
  (Genentech)                                                                           

  BLA                                                                                   
  Amendment:                                                                            

  Study                                342                    NA           NA           NA
  ACD2391g                                                                              
  (Genentech)                                                                           

  BLA Amendment                                                                         

                XOMA                   360                    13           NA           NA

                Genentech              732                    292          247          228

                **Current total**      **1115                 **318        **247**      **228**
                                       ^a^**                  ^b^**                     

  ^a^           Includes an additional                                                  
                23 subjects who                                                         
                received both XOMA and                                                  
                Genentech efalizumab                                                    
                during                                                                  

                EE-1 in Study                                                           
                ACD2062g.                                                               

  ^b^           Includes an additional                                                  
                13 subjects who                                                         
                received both XOMA and                                                  
                Genentech efalizumab                                                    
                in                                                                      

                Study ACD2062g during                                                   
                EE-2.                                                                   
  ------------- ---------------------- --------- ------------ --------- -- --------- -- ----------

**[Analyses of Adverse Events]{.underline}**

## Serious Adverse Events 

A serious adverse event is defined as: (1) Any death; (2) Any
life-threatening event (one which places the subject at immediate risk
of death); (3) Any event that requires or prolongs in-patient
hospitalization; (4) Any event that results in significant or persistent
disability/incapacity; (5) Any congenital anomaly/birth defect diagnosed
in the child of a subject who participated in this study and received
study drug; or (6) Other medically important event that, in the opinion
of the investigator, may jeopardize the subject or may require
intervention to prevent one of the other outcomes listed in the
definition above.

The overall incidence of serious adverse events during the first twelve
weeks of treatment for the placebo-controlled studies was 2.2% among
1,620 efalizumab-treated patients and 1.7% among 715 placebo-treated
patients.

#### Deaths in Clinical Trials for Psoriasis

Death was reported in 7 of 2762 efalizumab treated patients (0.3%) and 3
of the 715 (0.4%) placebo-treated patients. Two subjects died while
receiving efalizumab and 5 after completing treatment. None of the
deaths was attributed by the investigator to efalizumab treatment. A
description of the patients who died during the clinical trials is
provided in below.

Table 66 Deaths during the Clinical Trials of Efalizumab for Psoriasis

+---------+--------+------+---------+-------------+------------------+
| **      | **Tre  | *    | **D     | **          | **History and    |
| Subject | atment | *Age | uration | Diagnosis** | risk factors**   |
| no./    | g      | (yr  | study   |             |                  |
| Study** | roup** | )/** | drug    |             |                  |
|         |        |      | (w      |             |                  |
|         |        | **   | k)/time |             |                  |
|         |        | Gend | since   |             |                  |
|         |        | er** | last    |             |                  |
|         |        |      | dose    |             |                  |
|         |        |      | (wk)**  |             |                  |
+---------+--------+------+---------+-------------+------------------+
| 11520/  | Efal   | 60/  | 12/∼27  | Metastatic  | Noted to be      |
| A       | izumab | M    |         | rectal      | jaundiced during |
| CD2058g |        |      |         | cancer      | first treatment  |
|         | (XOMA) |      |         |             | period. Noted    |
|         |        |      |         |             | change in bowel  |
|         | 1.0    |      |         |             | habits, nausea   |
|         | mg     |      |         |             | and vomiting and |
|         | /kg/wk |      |         |             | 20 lb weight     |
|         |        |      |         |             | loss over the    |
|         |        |      |         |             | previous 2       |
|         |        |      |         |             | months. No       |
|         |        |      |         |             | mention of       |
|         |        |      |         |             | family history   |
|         |        |      |         |             | in the report.   |
|         |        |      |         |             | Died during the  |
|         |        |      |         |             | OB period.       |
+---------+--------+------+---------+-------------+------------------+
| 81601/  | Efal   | 58/  | ∼10     | Ath         | Event occurred   |
| A       | izumab | M    |         | ersclerotic | after the ninth  |
| CD2059g |        |      |         | car         | dose of          |
|         | (XOMA) |      |         | diovascular | efalizumab       |
|         |        |      |         | disease     | during the       |
|         | 4.0mg  |      |         |             | treatment        |
|         | /kg/wk |      |         |             | period.          |
|         |        |      |         |             |                  |
|         |        |      |         |             | Risk factors:    |
|         |        |      |         |             | Type 2 diabetes, |
|         |        |      |         |             | hypertension,    |
|         |        |      |         |             | Hyper            |
|         |        |      |         |             | cholesterolemia, |
|         |        |      |         |             | history of       |
|         |        |      |         |             | coronary artery  |
|         |        |      |         |             | bypass (1982 and |
|         |        |      |         |             | 1996)            |
+---------+--------+------+---------+-------------+------------------+
| 33007/  | Efal   | 52/  | 23/∼7   | Myocardial  | Hypertension and |
|         | izumab | M    |         | infarction  | smoking          |
| A       |        |      |         |             |                  |
| CD2391g | (Gene  |      |         |             |                  |
|         | ntech) |      |         |             |                  |
|         |        |      |         |             |                  |
|         | 1.0mg  |      |         |             |                  |
|         | /kg/wk |      |         |             |                  |
+---------+--------+------+---------+-------------+------------------+
| 68812/  | Efal   | 56/  | 12/∼72  | Accidental  | N/A              |
|         | izumab | M    |         | death       |                  |
| A       |        |      |         |             |                  |
| CD2059g | (XOMA) |      |         | (plane      |                  |
|         |        |      |         | crash)      |                  |
+---------+--------+------+---------+-------------+------------------+
| 17907/  | Efal   | 68/  | 12/∼41  | Athe        | Angina,          |
|         | izumab | F    | (       | rosclerotic | diabetes,        |
| A       |        |      | Patient | car         | hypertension,    |
| CD2062g | (XOMA) |      | died    | diovascular | peripheral       |
|         |        |      | after   | disease     | vascular         |
|         |        |      | com     |             | disease, chronic |
|         |        |      | pletion |             | anemia           |
|         |        |      | of      |             |                  |
|         |        |      | fo      |             |                  |
|         |        |      | llow-up |             |                  |
|         |        |      | period) |             |                  |
+---------+--------+------+---------+-------------+------------------+
| 28913/  | Efal   | 68/  | 11/∼27  | "M          | Elevated SGOT    |
|         | izumab | M    |         | icronodular | and total and    |
| A       |        |      |         | cirrhosis   | direct bilirubin |
| CD2243g | (Gen   |      |         | of the      |                  |
|         | etech) |      |         | liver"      |                  |
+---------+--------+------+---------+-------------+------------------+
| 12062/  | Efal   | 68/  | 20/∼38  | Unconfirmed | Stroke (1972),   |
| A       | izumab | F    |         |             | Hypertension and |
| CD2062g |        |      | (2.0    | report of   | depression       |
|         | (XOMA) |      | mg/kg/w | possible    | (1980),          |
|         |        |      | SC for  | diagnosis   | hyper            |
|         |        |      | total   | of          | cholesterolemia, |
|         |        |      | of 33   | pneumonia:  | diabetes         |
|         |        |      | doses)  | cause of    |                  |
|         |        |      |         | death       |                  |
|         |        |      | (       | classified  |                  |
|         |        |      | Patient | as unknown  |                  |
|         |        |      | died    |             |                  |
|         |        |      | after   |             |                  |
|         |        |      | com     |             |                  |
|         |        |      | pletion |             |                  |
|         |        |      | of      |             |                  |
|         |        |      | fo      |             |                  |
|         |        |      | llow-up |             |                  |
|         |        |      | period) |             |                  |
+---------+--------+------+---------+-------------+------------------+
| 81235/  | p      | 70/  | N/A     | Accidental  | N/A              |
|         | lacebo | M    |         | drowning    |                  |
| A       |        |      |         |             |                  |
| CD2059g |        |      |         |             |                  |
+---------+--------+------+---------+-------------+------------------+
| 41011/  | p      | 53/  | N/A     | Sudden      | Patient had      |
|         | lacebo | F    |         | cardiac     | right sided      |
| A       |        |      |         | death       | congestive heart |
| CD2600g |        |      |         |             | failure          |
|         |        |      |         |             | resulting from   |
|         |        |      |         |             | chronic          |
|         |        |      |         |             | obstructive      |
|         |        |      |         |             | pulmonary        |
|         |        |      |         |             | disease (COPD)   |
|         |        |      |         |             | and Pickwickian  |
|         |        |      |         |             | syndrome.        |
|         |        |      |         |             | (Subject was     |
|         |        |      |         |             | discontinued due |
|         |        |      |         |             | to exacerbation  |
|         |        |      |         |             | of COPD prior to |
|         |        |      |         |             | death.)          |
+---------+--------+------+---------+-------------+------------------+
| 42208/  | p      | 47/  | N/A     | Seizure     | History of       |
|         | lacebo | F    |         |             | seizures and     |
| A       |        |      |         |             | bipolar disorder |
| CD2600g |        |      |         |             |                  |
+---------+--------+------+---------+-------------+------------------+

None of the deaths was attributed to infection. However, the possibility
of pneumonia at the time of death in patient 12062 was reported, but
unconfirmed. This patient died after completion of the follow-up period.

All four of the patient deaths attributed to cardiac causes (3 in the
efalizumab-treated patients and 1 in a placebo-treated patient) took
place in patients ≥ age 50 and in whom were known pre-existing
cardiovascular risk factors.

Reviewer's note:

*For patients28913 and12062 the details of the causes of deaths are
sparse (see narratives below).*

[Narrative patient 28913 (death due to cirrhosis of the
liver):]{.underline}

The subject had psoriasis for 10 years and had not received previous
systemic therapy. The subject had received a total of 15 doses of
efalizumab prior to the onset of the event. Medical history included
migraines, arthritis of the back, hypertension, hyperlipidemia, triple
bypass surgery, and alcohol use of more than 50 years and tobacco use.
The patient was found to have micronodular cirrhosis of the liver after
liver function tests already elevated at baseline were further elevated
approximately 2 months into his treatment course. Study drug was
discontinued one month later. A liver biopsy confirmed the diagnosis of
micronodular cirrhosis of the liver. The subject died one month later of
the "cirrhosis of the liver." The investigator determined the subject's
death to be not related to study drug.

*Reviewer's note: According to this report, the patient went from having
elevated liver function tests to death. Report does not address whether
the patient took concomitant medications. Additionally, the report does
not summarize the course of manifestations or of complications related
to liver disease that may have lead to the patient's death. There is no
mention of whether an autopsy performed.*

*[Narrative patient 12062 (death of unknown cause):]{.underline}*

Six months after receiving her last dose of study drug, the subject
canceled a scheduled doctor's appointment because she reportedly did not
feel well. Later in the afternoon, the subject's husband found her
unresponsive. She was transported to the emergency room and admitted to
the hospital. The subject's husband reported that "some heart tests and
dialysis were performed." He reports hearing the possible diagnosis of
"pneumonia." Two days later, the subject died. The cause of death is
unknown. The investigator determined the subject's death to be not
related to study drug.

### Deaths and Serious Adverse Events in Other Indications

No deaths were reported for subjects in the asthma study, ACD2017g, for
healthy volunteers in Study ACD2389g, and in a study of rheumatoid
arthritis.

Two deaths occurred in the renal transplant program (Study HUKT257),
which were

both judged by the investigators to be related to efalizumab. One death
was related to

posttransplant lymphoproliferative disorder (PTLD), and the other death
was due to

pancreatitis. All subjects in this study received efalizumab in addition
to concomitant triple drug immunosuppressive therapy. In all, three
cases of PTLD occurred in 38 subjects. These cases all occurred in
patients treated with 2.0 mg/kg/wk efalizumab, cyclosporine, MMF, and
prednisone.

### Serious Infections

The incidence of serious infections in the combined efalizumab first
exposure (FE)-controlled experience is shown in Table 67 below.

Table 67 Serious Diagnosed Infections Experienced by Subjects Who
Received Study Drug (Combined Materials) in the First Exposure of
Controlled Studies

  ------------------------ ----------------------- -----------------------
                           Placebo                 All Efalizumab

  Adverse Event            (n=715)                 (n=1620)

  Total ^a^                1 (0.1%)                7 (0.4%)

  Cellulitis               0                       3 (0.2%)

  Sepsis                   0                       1 (\<0.1%)

  Gastroenteritis          1 (0.1%)                2 (0.1%)

  Pneumonia                0                       2 (0.1%)
  ------------------------ ----------------------- -----------------------

The proportion of patients diagnosed with a serious infection in the
first exposure of controlled clinical trials was 0.4% in the efalizumab
group and 0.1% in the placebo group. Although the patient numbers are
small, this represents a possible safety signal with regard to the
incidence of serious infections.

Descriptions of the patients diagnosed with a serious infection during
the first 12-week period of treatment with efalizumab are displayed in
Table 68 below.

Table 68 Serious Infections in the First Exposure Controlled Clinical
Experience (Studies 2058, 2059 and 2390)

+-------------------+------------+-----------------+-----------------+
| Patient/Study     | Treatment  | Age (yr)/       | Event           |
|                   | Group      | Gender          |                 |
+-------------------+------------+-----------------+-----------------+
| 45225/ACD2600     | Efalizumab | 70/ F           | Urosepsis       |
|                   | (GNE) 1.0  |                 | associated with |
|                   |            |                 | possible kidney |
|                   |            |                 | stone           |
+-------------------+------------+-----------------+-----------------+
| 45207/ACD2600     | Efalizumab | 74/ M           | Pneumonia       |
|                   |            |                 |                 |
|                   | (GNE) 1.0  |                 | associated with |
|                   |            |                 | decreased       |
|                   |            |                 | neutrophil      |
|                   |            |                 | count           |
+-------------------+------------+-----------------+-----------------+
| 34229/ACD2390g    | Efalizumab | 53/ F           | cellulitis      |
|                   |            |                 |                 |
|                   | (GNE) 1.0  |                 |                 |
+-------------------+------------+-----------------+-----------------+
| 76802/ACD2059g    | Efalizumab | 54/ M           | cellulitis      |
|                   | (GNE) 2.0  |                 |                 |
+-------------------+------------+-----------------+-----------------+
| 16506/ACD2058g    | Efalizumab | 57/ M           | pneumonia       |
|                   | (XOMA)1.0  |                 |                 |
+-------------------+------------+-----------------+-----------------+
| 17501/ACD2058g    | Efalizumab | 32/ M           | cellulitis      |
|                   | (XOMA) 2.0 |                 | (hand),         |
|                   |            |                 | gastroenteritis |
+-------------------+------------+-----------------+-----------------+
| 17512/ACD2058g    | Efalizumab | 46/ F           | gastroenteritis |
|                   | (XOMA) 1.0 |                 |                 |
+-------------------+------------+-----------------+-----------------+
| 22006/ACD2058g    | Placebo    | 45/ M           | gastroenteritis |
+-------------------+------------+-----------------+-----------------+

Serious infections were noted with both drug products (Genentech- and
XOMA-manufactured efalizumab). Cellulitis accounted for three of six
infectious events requiring hospitalization among patients receiving
efalizumab in the FE controlled clinical experience.

The incidence rate for serious infections in the entire safety database
(controlled and uncontrolled) expressed in terms of patient-years of
exposure is shown by treatment group in Table 69.

Table 69 Incidence Rate for Infection that Required Hospitalization
Total Exposure All Patients by Treatment Group

  --------------- -------- --------------- ----------- --------------- -----------------
                                           95% CI for  Incidence Rate  95% CI for
                                           Observed    Per             Incidence Rate

  Treatment Group Number   Subject-Years   Number of   100             Per 100
                  of                       Events      Subject-Years   Subject-Years
                  Events                                               

  Efalizumab      27       1680            \[17.79,    1.61            \[1.06, 2.34\]
                                           39.28\]                     

                                                                       

  Placebo         2        185             \[0.24,     1.08            \[0.13, 3.89\]
                                           7.22\]                      
  --------------- -------- --------------- ----------- --------------- -----------------

The incidence of serious infections requiring hospitalization per 100
subject years is 1.61 in the efalizumab-treated group and 1.08 in the
placebo-treated patients with overlapping 95% CI for the incidence rate.
The numbers of individual types of serious infections were so few that a
placebo comparison was not possible.

Reviewer's comment: Both the first exposure controlled clinical
experience and the total exposure over the safety database as a whole
show a higher incidence rate of infections requiring hospitalization in
efalizumab-treated patients vs. placebo. However, given the small number
of serious infections (especially in the placebo group) it is not
possible to draw firm conclusions about the relative risk of serious
infections.

The expected incidence rate for serious infections requiring
hospitalization based on an external cohort, the Saskatchewan Health,
was comparable to that seen in both treatment groups in the clinical
trials (data not shown). The external cohort used for comparison,
included adult patients in Saskatchewan who had a diagnosis of psoriasis
between January 1995 and March 2000 and received a prescription for a
systemic oral psoriasis therapy or had PUVA or ultraviolet B light
therapy.

In addition to evaluating overall incidence of serious infectious
adverse events, it is important to note the opportunistic infection and
unusual courses of serious infections occurring in efalizumb-treated
patients. Please see the following narratives.

*[Opportunistic Infections:]{.underline}*

One opportunistic infection was reported, *Legionella* pneumonia.

*Patient 17007: Legionella* pneumonia

A 41-year-old white female with a medical history significant for
tobacco use was enrolled in study ACD2058g where she received 12 weeks
of therapy at the 2-mg/kg-dose level. The patient did not take any
concomitant medications. After her first dose in the extended treatment
period, the patient developed life-threatening *Legionella* pneumonia.
She required intubation for hypoxia and marked respiratory acidosis. CXR
showed bilateral pulmonary infiltrates. Her WBC count was 23 K/mm3.
Bronchial washings revealed *Legionella pneumophila*. The adverse event
resolved in 19 days. Other cases of Legionella were seen and admitted to
the same hospital, and the case was referred to the State Health
Department for investigation. The investigator determined the
*Legionella* pneumonia to be possibly related to study drug.

*[Serious infections with atypical features or unusually severe
course:]{.underline}*

The following are narratives of infections from the various studies in
the BLA submission which have atypical features such as an unusually
severe course. Patients 67615 and 26504 below had severe local
infections with seeding to a distal site requiring surgical
intervention.

*67615 (Study 2059g):*

A 53-year-old male was diagnosed with vertebral staphylococcal
osteomyelitis and *S. aureus* sepsis. Patient had received 17 doses of
study drug at the 2 mg/kg dose. The patient required hospitalization for
IV antibiotics and diskectomy and biopsy of infected bone. Surgical
pathology revealed inflammation consistent with acute osteomyelitis. The
event resolved after 43 days. The investigator determined the
osteomyelitis and sepsis to be related to study drug.

*Reviewer's comment: This case is notable for the severity a of the
osteomyelitis and that it was complicated by sepsis.*

*26504 (Study ACD2243)*: 53-year-old white male completed 2.0 mg/kg dose
and received extended treatment with 1.0 mg/kg. The patient was
hospitalized with bacteremia and MRI revealed bilateral ethmoid
sinusitis. Chest radiographs were negative for pneumonia. Blood cultures
grew Group A beta-hemolytic streptoccoci. The patient simultaneously
experienced cellulitis of the left foot and right orbit. The patient
required surgical fasciotomy for the left foot which was cultured and
grew GABHS streptoccoci. The investigator deemed the sepsis not related
to study drug.

This infection is an example of a common infection, i.e. sinusitis,
which lead to serious complications, namely, orbital cellulitis and
dissemination of infection to a distal site requiring surgical
fasciotomy.

*28008 (Study ACD2243g):* A 66-year-old male was hospitalized with a
severe sinus infection with a protracted course (44 days). The patient
had received weekly efalizumab for approximately one year prior to event
onset. Two days prior to hospitalization, the patient complained of
headache and flu-like symptoms. He presented with cough, dyspnea and
fever of 104°F. A chest-Xray was negative for pneumonia. The patient was
hospitalized for 5 days with the diagnosis of sinus infection and
treated with IV antibiotics. The event resolved after 44 days.
Efalizumab was held during hospitalization but dosing resumed 22 days
after event onset. The investigator deemed the event to be unrelated to
study drug.

*Reviewer's comment: This case is notable for requiring hospitalization
followed by a prolonged course of oral antibiotics.*

*25010 (Study ACD22430):* The patient was a 29-year-old male who had
received 7 doses of efalizumab. He developed cellulitis of the left
thenar eminence and thumb that did not respond to oral antibiotics. The
patient was hospitalized and received multiple antibiotics before the
cellulitis resolved. The investigator deemed the event to be unrelated
to study drug.

*Reviewer's comment: This case is notable for requiring hospitalization
including multiple antibiotics prior to resolution.*

*20510 (Study ACD2062):* A 43 year-old male was hospitalized with an
abscess of the left calf and surrounding cellulits. Duplex
ultrasonography was negative on two occasions but detected a fluid
collection in the left lower extremity. The subject underwent drainage
and irrigation of the abscess. Cultures performed of the fluid were
negative. The abscess responded slowly to antibiotics. He was discharged
from the hospital on day 20. The subject had received a total of 19
doses of efalizumab in studies 2058 and 2062 combined at the 1mg/kg/week
dose level. The investigator deemed the event related to study drug.

*Reviewer's comment: This is not clearly infectious in etiology as the
cultures of the abscess were negative. The case is notable for requiring
prolonged inpatient hospitalization after drainage of the abscess.*

All infectious adverse events (serious and non-serious):

Serious and non-serious infectious adverse events are shown in Table 70
below.

Table 70 Adverse Events Diagnostic of Infection Reported within the
First Exposure Period for Subjects Treated Efalizumab

  ---------------------------- --------------------- ---------------------
                               FE/Controlled         

  Adverse Event                Placebo               All efalizumab

  n                            715                   1620

                                                     

  Infection NOS                110 (15.4%)           225 (13.9%)

  Herpes simplex               24 (3.4%)             74 (4.6%)

  Urinary tract infection      9 (1.3%)              27 (1.7%)

  Bronchitis                   9 (1.3%)              31 (1.9%)

  Viral infection              8 (1.1%)              30 (1.9%)

  Gastroenteritis              24 (3.4%)             34 (2.1%)

  Bacterial infection          4 (0.6%)              19 (1.2%)

  Otitis media                 9 (1.3%)              23 (1.4%)

  Fungal dermatitis            1 (0.1%)              14 (0.9%)

  Cellulitis                   3 (0.4%)              13 (0.8%)

  Fungal infection             0                     7 (0.4%)

  Furunculosis                 3 (0.4%)              7 (0.4%)

  Periodontal abscess          2 (0.3%)              9 (0.6%)

  Pneumonia                    2 (0.3%)              7 (0.4%)

  Abscess                      0                     3 (0.2%)

  Herpes zoster                0                     4 (0.2%)

  Axillary moniliasis          0                     1 (\<0.1%)

  Parasitic infection          0                     2 (0.1%)

  Hepatitis                    0                     1 (\<0.1%)

  Meningitis                   0                     1 (\<0.1%)

  Moniliasis (includes         2 (0.3%)              5 (0.3%)
  axillary, vaginal,oral)                            

  Sepsis                       0                     1 (\<0.1%)
  ---------------------------- --------------------- ---------------------

Overall, the term infection (NOS) among efalizumab-treated patients
(13.9%) did not exceed that of placebo (15.4%). However, certain types
of infections occurred in a higher proportion of efalizumab-treated
patients as compared to placebo. These were HSV, viral infections,
bacterial infections, cellulitis, fungal infection, abscess, oral
thrush, and herpes zoster among others.

During the first exposure period of controlled clinical studies, there
were 13 subjects (4 subjects in the placebo group or 1.5% and 9 in the
XOMA efalizumab group or 1.3%) with 14 severe infections.

### Malignancies

Malignancies in the first course, placebo-controlled experience are
shown in Table 71**.**

Table 71 Serious Malignancies Experienced by Subjects Who Received Study
Drug in the FE/Controlled Studies

  --------------------- ------------ ------------ ------------ ------------
                                     Efalizumab                
                                     (XOMA or                  
                                     Genentech)                

                        Placebo      1.0 mg/kg/wk 2.0 mg/kg/wk All
                                                               Efalizumab

  Adverse Event         (n=715)      (n=1213)     (n=407)      (n=1620)

  Total ^a^             2 (0.3%)     2 (0.2%)     0            2 (0.1%)

  Gastrointestinal      1 (0.1%)     0            0            0

  carcinoma                                                    

  Skin carcinoma        1 (0.1%)     2 (0.2%)     0            2 (0.1%)
  --------------------- ------------ ------------ ------------ ------------

FE=First Exposure

The numbers of malignancies diagnosed during the placebo-controlled FE
experience are very small; however, no increase is noted in the
efalizumab-treated patients vs. placebo-treated patients.

Malignancies (excluding non-melanoma skin cancer) diagnosed during the
clinical trials for psoriasis included the following cases: lung
carcinoma, metastatic rectal carcinoma, two cases prostatic carcinoma,
breast carcinoma, Hodgkin's lymphoma, B cell lymphoma, and malignant
melanoma (Table 72).

Table 72 Subjects with Solid Tumors and Melanoma (updated May 2003)

+------------+-------+--------------+---------+---------+------------+
| Subject    | Age   |              |         |         | Cumulative |
| ID/        | (yr)/ |              |         |         |            |
+------------+-------+--------------+---------+---------+------------+
| Study      | G     | Malignancy   | Manuf   | Dose    | Dose       |
|            | ender |              | acturer | Group   | (mg/kg)    |
|            |       |              |         |         |            |
|            |       |              |         | (m      |            |
|            |       |              |         | g/kg/wk |            |
|            |       |              |         | SC)     |            |
+------------+-------+--------------+---------+---------+------------+
| 81691/     | 70/ F | Colon cancer | XOMA    | Placebo | Placebo    |
| ACD2059g   |       |              |         |         |            |
+------------+-------+--------------+---------+---------+------------+
| 11520/     | 60/ M | Metastatic   | XOMA    | 1.0     | 11.7       |
| ACD2058g   |       |              |         |         |            |
+------------+-------+--------------+---------+---------+------------+
|            |       | rectal       |         |         |            |
|            |       | cancer       |         |         |            |
+------------+-------+--------------+---------+---------+------------+
|            |       | (the subject |         |         |            |
|            |       | died)        |         |         |            |
+------------+-------+--------------+---------+---------+------------+
| 20508/     | 72/ F | Colon cancer | XOMA    | 2.0     | 41.4       |
| ACD2058g   |       |              |         |         |            |
+------------+-------+--------------+---------+---------+------------+
| 73210/     | 64/ F | Breast       | XOMA    | 2.0     | 12.7       |
| ACD2059g   |       | cancer       |         |         |            |
+------------+-------+--------------+---------+---------+------------+
| 23403/     | 51/ M | Prostate     | XOMA    | 1.0     | 22.4       |
| ACD2062g   |       | cancer       |         |         |            |
+------------+-------+--------------+---------+---------+------------+
| 23512/     | 71/ M | Prostate     | XOMA    | 1.0     | 22.4       |
| ACD2058g   |       | cancer       |         |         |            |
+------------+-------+--------------+---------+---------+------------+
| 25902/     | 62/ F | Lung cancer  | Ge      | 2.0     | 22.7       |
| ACD2243g   |       |              | nentech |         |            |
+------------+-------+--------------+---------+---------+------------+
| 28917/     | 61/ F | Colon cancer | Ge      | 1.0     | 64.7       |
| ACD2243g   |       |              | nentech |         |            |
+------------+-------+--------------+---------+---------+------------+
| 25916/     | 62/ M | Malignant    | Ge      | 2.0     |            |
| ACD2243g   |       | melanoma     | nentech |         |            |
|            |       |              |         |         |            |
|            |       | (in situ)    |         |         |            |
+------------+-------+--------------+---------+---------+------------+
| 30408/ ACD | 75/ M | Colon Cancer | Ge      | 1.0     | []{.mark}  |
| 2391g      |       |              | nentech |         |            |
+------------+-------+--------------+---------+---------+------------+

The patient with the melanoma reportedly had a large pigmented lesion
prior to enrollment. The lesion was biopsied by the investigator after
the initiation of efalizumab therapy.

Reviewer's comment: Any unexplained conditions, such as a large
suspicious pigmented lesion, should have prompted exclusion of the
patient into the study.

Table 73 Observed versus Expected Rate of Solid Tumors and Malignant
Melanoma (updated May 2003)

  ----------------------- -------------------- ------------ ---------- ----------- ---------- ----------
                          Efalizumab-Treated                           External               
                          Subjects                                     Reference              
                                                                       Cohorts                

                          Observed                          Observed                          

  Malignancy Category     No. of                            Subject-               Expected   95%
                                                                                   No.        

                          Subjects             95% CI       Years      Cohort ^a^  of         CI
                                                                                   Subjects   
                                                                                   ^b^        

  Solid tumor             8                    3.45,15.76   1,790.06   SH          7.3        4.3,11.6

                                                                       UHC         4.7        2.3,8.1

                                                                       SEER        7.8        NA

                                                                                              

  Malignant melanoma      1                    0.03, 5.57   1,790.82   SH          0.4        0.0, 2.3

                                                                       SEER        0.4        NA

  ^a^ SH=Saskatchewan                                                                         
  Health;                                                                                     
  UHC=UnitedHealthcare;                                                                       
  SEER=Surveillance.                                                                          
  Epidemiology and End                                                                        

  Results.                                                                                    

  ^b^ Calculation of                                                                          
  expected number of                                                                          
  events was based on the                                                                     
  expected rate of events                                                                     
  per                                                                                         

  100 subject-years                                                                           
  multiplied by the                                                                           
  observed number of                                                                          
  subject-years in the                                                                        
  psoriasis efalizumab                                                                        

  trials. 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 sex adjusted.                                                                           
  ----------------------- -------------------- ------------ ---------- ----------- ---------- ----------

The point estimates for malignant melanoma and solid tumors are
comparable in efalizumab-treated subjects compared to the reference
groups and the 95% CI overlap. The one case of malignant melanoma may
have actually been present before the start of treatment.

Table 74 Observed versus Expected Rates of Lymphoproliferative
Malignancies: Efalizumab-Treated Subjects (updated July 25, 2003)

  -------------------- ------------ ---------- -- ----------- ---------- ----------- ----------
  Efalizumab-Treated                              External                           
  Subjects                                        Reference                          
                                                  Cohorts                            

  Observed                          Observed                                         

  No. of                            Subject-                             Expected    95%
                                                                         No.         

  Subjects             95% Cl       Years                     Cohort     of Patients CI
                                                                         ^a^         

                                                                                     

  2                    0.24, 7.22   2203.16       SH                     3.7         1.5, 7.7

                                                  UHC                    2.9         1.1,6.2

                                                  SEER                   0.9         NA
  -------------------- ------------ ---------- -- ----------- ---------- ----------- ----------

SEER=Surveillance, Epidemiology and End Results; SH=Saskatchewan Health;
UHC=UnitedHealthcare; CI=confidence interval.

^a^ Calculation of the expected number of events was based on the
expected rate of events per 100 patient-years multiplied by the observed
number of subject-years in the efalizumab psoriasis 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 sex adjusted.

The number of lymphoproliferative malignancies in the efalizumab-treated
patients (2.0) was higher than the gender- and age-adjusted incidence
derived from the SEER database (0.9) and lower than the incidence
derived from the other reference groups (3.7 and 2.9). The confidence
intervals around these point estimates overlapped.

*Reviewer's comment:* *Overall, the incidence of solid tumors, melanoma
and lymphoma is consistent with what might be expected based on external
reference groups; however, the numbers of cases are too small to draw
definitive conclusions about malignancy risk.*

The two cases of lymphoproliferative malignancy observed among
efalizumab-treated patients in clinical trials for psoriasis, were
Hodgkin's disease and B cell lymphoma. Although, a third patient was
diagnosed with cutaneous T-cell lymphoma after study completion, it is
likely that this patient had pre-existing disease and was incorrectly
enrolled with a misdiagnosis of widespread plaque-type psoriasis (See
narrative below).

The patient who developed Hodgkin's disease received 4.0 mg/kg/wk SC
XOMA efalizumab and had received a total of 29.4 mg/kg efalizumab over
136 days. Biopsy specimen was negative for Epstein-Barr virus. Hodgkin's
disease was judged by the investigator to be related to efalizumab.

The patient who developed B cell lymphoma was a 57-year-old male. He
participated in study ACD2243g, an open-label study in which prolonged
maintenance treatment of efalizumab was evaluated. He had received
regular dosing for approximately 2 years prior to the onset of the event
with the 1-mg/kg/wk dose. He had a history of prior therapy with a
5-month course of methotrexate 4 years prior to his diagnosis of
lymphoma, but had never received cyclosporine. The patient was diagnosed
with B cell lymphoma after presenting with abdominal pain. CT scan
revealed a ureteral stone and also mesenteric changes suggestive of a
neoplastic process. Fine needle aspiration biopsy of an abdominal mass
revealed atypical single cells and mixed small and large malignant cells
which were LCA and CD20 positive suggestive of B cell lymphoma. EBV
status was not obtained. The stage of the lymphoma was assessed as stage
I bulky mixed large and small cell Non-Hodgkin's lymphoma. The
investigator assessed the event of B cell lymphoma as related to
efalizumab.

*Cutaneous T-cell lymphoma*: A 62-year-old male (Subject No. 79608)
enrolled in study ACD 2059g and was randomized to 1.0 mg/kg/wk SC
efalizumab during the first treatment period and re-randomized to
placebo for the extended treatment period. The event occurred following
completion of the study. The subject's medical history was significant
for a seizure disorder, hypothyroidism, and heart disease. Concomitant
medications upon entry into the study were vasotec, synthroid, and
trileptal. During the retreatment period, a cutaneous infection was
suspected, and a skin biopsy revealed lymphocytic atypia. Ciprofloxacin
was initiated, in addition to triamcinolone acetonide for worsening
psoriasis. The patient's skin disease worsened during treatment with
efalizumab during the first treatment period and he was classified as a
"non-responder." After completion of the study, treatment with acitretin
was added for psoriasis. The following month, a repeat biopsy revealed
patterns consistent with cutaneous T-cell lymphoma. Subsequent
evaluations, including a full body CT scan, were negative for
metastases. Treatment included bexarotene and denileukin diftitox. At
the time of this report the subject remains stable and the event is
ongoing. The investigator determined the cutaneous T-cell lymphoma to be
not related to study drug.

Reviewer's comment: Based upon the photographs of the patient's skin
disease at baseline (violaceous annular coalescing plaques), it is the
clinical impression of this reviewer that the patient likely had
widespread cutaneous T-cell lymphoma rather than plaque-type psoriasis
upon entry into the study. Although, the patient was not diagnosed with
cutaneous T-cell lymphoma until after study completion, the diagnosis of
this malignancy is typically delayed for many years, requiring multiple
biopsies to differentiate from non-malignant T-cell mediated skin
disorders such as psoriasis and atopic eczema. Of note, this patient's
skin disease worsened during treatment with efalizumab during the first
treatment period and he was classified as a "non-responder" by PASI, PGA
and OLS.

### Nonmelanomatous Skin Cancers

The most frequently occurring malignancy in clinical trial subjects was
non-melanoma skin cancer (NMSC). Table 75 below shows the observed vs.
expected number of non-melanomatous skin cancer by treatment group based
on two reference cohorts, United Healthcare and Saskatchewan Health. The
SEER database does not contain information with regard to
non-melanomatous skin cancer for comparison.

Table 75 Observed vs. Expected Rate of Non-melanomatous Skin Cancer
Efalizumab vs. Placebo

  ----------------- ---------- --------- ---------- -- ----------- ---------- ----------
  Treatment Group   Study                              External               
                    Subjects                           Reference              
                                                       Cohorts                

                    Observed   95% CI    Observed      Cohort ^a^  Expected   95% CI

                    No. of               Subject-                  No. of     

                    Subjects             Years                     Subjects   
                                                                   ^b^        

  Efalizumab        20         12.22,    1784          SH          7.0        3.9,11.2
                               30.89                                          

                                                       UHC         7.0        4.1,11.1

                                                                              

  Placebo           2          0.24, 7.2 185           SH          0.7        0.4, 1.2

                                                       UHC         0.7        0.4, 1.2

  ^a^                                                                         
  SH=Saskatchewan                                                             
  Health;                                                                     
  UHC=United                                                                  
  Healthcare                                                                  

  ^b^ Calculation                                                             
  of expected                                                                 
  number of events                                                            
  was based on the                                                            
  expected rate of                                                            
  events per                                                                  

  100 subject-years                                                           
  multiplied by the                                                           
  observed number                                                             
  of subject-years                                                            
  in the psoriasis                                                            
  efalizumab                                                                  

  trials. The                                                                 
  unadjusted                                                                  
  expected                                                                    
  incidence rates                                                             
  and number of                                                               
  events were given                                                           
  for the SH and                                                              

  UHC databases                                                               
  ----------------- ---------- --------- ---------- -- ----------- ---------- ----------

The number of efalizumab-treated subjects with non-melanomatous skin
cancer (20) exceeded the expected number based on the reference cohorts
(7) with nonoverlapping confidence intervals.

*Reviewer's comment:* *The higher incidence of non-melanomatous skin
cancer than expected is possibly due to ascertainment bias.
Additionally, it is important to identify an appropriate comparator when
assessing the risk of malignancies in the more severe
psoriasis-population as these patients are at increased risk for both
non-melanoma skin cancer as well as lymphoproliferative malignancies due
to previous treatment (e.g. cyclosporine, PUVA) and, possibly, other
factors relevant in this patient population.*

A comparison of the NMSC incidence rates per 100 subject-years of
treatment between subjects receiving efalizumab and those receiving
placebo is shown below (see Table 76).

Table 76 Observed Rates for Non-Melanomatous Skin Cancer:
Placebo-Treated and Efalizumab-Treated Subjects

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

                 Observed       Observed           Rate/100     

                 No. Of         Subject-           Patient-     95% CI for

                 Subjects       Years              Years        Rate

                                                                

  Placebo        2              185                1.08         0.13, 3.89

                                                                

  Efalizumab     20             1784               1.12         0.68, 1.73
  -------------- -------------- ------------------ ------------ ----------

The NMSC incidence rates per 100 subject-years of treatment between
subjects receiving efalizumab and those receiving placebo are similar
with overlapping confidence intervals. The point estimate was 1.08 for
placebo and 1.12 for efalizumab. Although, the placebo comparison
yielded similar rates between treatment groups, the small number of
cases makes it difficult to exclude an increase in risk of
non-melanomatous skin cancer.

For 20 efalizumab-treated subjects, 13 events of basal cell carcinoma
and 13 events of squamous cell carcinoma were reported. For 2
placebo-treated patients, two events of basal cell and squamous cell
carcinoma each were reported. Thus, for both efalizumab-treated and
placebo-treated subjects, the ratio of basal cell to squamous cell
carcinoma was 1:1. As of December 2002, the ages of patients who were
diagnosed with NMSC ranged from 44 to 68 and the cumulative dose of
efalizumab ranged from 1mg/kg to 68 mg/kg (data not shown).

### CNS Adverse Events

*[Patient 14025: Aseptic meningitis]{.underline}*

A 20-year-old man ( 14025) was randomized to receive 2.0 mg/kg/wk
efalizumab, and a conditioning dose was administered. The day after
receiving his first dose of study drug, the subject experienced the
onset of severe meningitis. He presented to the ER with a severe
throbbing bifrontal headache, nausea without vomiting, chills, and
myalgia and arthralgia of 2--3 days' duration. Results of a cranial CT
scan were negative. Aseptic meningitis was diagnosed with cerebrospinal
fluid showing WBC count of 550/cmm (differential of 14 mononuclear cells
and 86 polymorphonuclear cells), CSF glucose of 54 mg/dL, CSF protein of
55 mg/dL and negative CSF for bacterial antigens. A gram stain of CSF
showed 2+ WBC counts and no organisms. Treatment included
prochlorperazine, promethazine hydrochloride, ibuprofen, lidocaine,
acetaminophen/ hydrocodone bitartrate, butorphanol bitartrate, and
sodium chloride. The event resolved after 7 days with no reported
sequelae. Test results for anti-efalizumab antibodies were negative. The
subject discontinued study drug treatment after the conditioning dose
because of the event. He entered the follow-up period and went on to
complete the study. The investigator classified the adverse event as
related to study drug.

*Reviewer\'s comment: This adverse event is possibly related to study
drug due to the close temporal relationship to study drug administration
and was deemed by the investigator as related. The cause of this adverse
event might be a cytokine release reaction.*

*[Patient 32425: Transverse myelitis]{.underline}*

A 34-year-old white male (32425) received 1 mg/kg of efalizumab in study
ACD2390g.

Two days after the second dose, the patient experienced paresthesia and
pain of right side of his body. MRI showed a central cord enhancing
lesion and Chiari malformation; spinal cord biopsy with foamy
macrophages was interpreted as a demyelinating process. The patient's
condition progressed to involve impairment of bowel, bladder and sexual
function. He discontinued from the study due to the adverse event. The
investigator classified the adverse event as related to study drug.

Reviewer\'s comment: This case represents an example of a potentially
autoimmune-mediated adverse event. The event was ameliorated with the
use of systemic corticosteroids.

### Laboratory Adverse Events/ Changes

#### Hematology

Thrombocytopenia

Table 90 below is a listing of patients who experienced platelet counts
below 50,000 during the clinical trials with efalizumab or who had
serious adverse events of thrombocytopenia. A total of 8 patients are
included. Five of these patients were classified as having serious
adverse events with regard to thrombocytopenia. One of the patients had
a pre-existing diagnosis of idiopathic thrombocytopenia and had a below
normal platelet count at baseline. Two other patients had a history of
autoimmune disease, Grave's disease.

No placebo patients fell into this category. However, one must also take
into consideration differences in the period of observation between
placebo-treated patients and patients during treatment with efalizumab.

Table 77 Subjects with Serious Adverse Event(s) of Thrombocytopenia
[or]{.underline} a Reported Platelet Level below 50,000/cmm

+----+----+---------+---------+--------------+-----+--------+---------+
| S  | A  | Onset   | Medical | Concomitant  | Ba  | Nadir  | Tr      |
| ub | ge |         | history | Medications  | sel |        | eatment |
| je | (y |         |         |              | ine | plat   |         |
| ct | r) |         |         |              | p   | elets/ |         |
|    |    |         |         |              | lat |        |         |
|    | Ge |         |         |              | ele | mm3    |         |
|    | nd |         |         |              | ts/ |        |         |
|    | er |         |         |              |     |        |         |
|    |    |         |         |              | mm3 |        |         |
+----+----+---------+---------+--------------+-----+--------+---------+
| 1  | 6  | 112 d   | n       | Terazosin    | 2   | 52,000 | Study   |
| 05 | 1/ | (3.7    | egative | (12/99),     | 74, |        | drug    |
| 01 | M  | mo)     |         | ibuprofin    | 000 | n      | D/C,    |
|    |    | post    |         | (95),        |     | ormoce | pre     |
| (  |    | first   |         | aspirin      |     | llular | dnisone |
| SA |    | study   |         | (6/00)       |     | bone   |         |
| E) |    | drug (2 |         |              |     | marrow | Event   |
|    |    | mg/kg)  |         |              |     | biopsy | res     |
| 2  |    | and 20  |         |              |     |        | olution |
| 05 |    | days    |         |              |     |        | (10/00) |
| 8g |    | after   |         |              |     |        |         |
|    |    | last    |         |              |     |        |         |
|    |    | study   |         |              |     |        |         |
|    |    | drug    |         |              |     |        |         |
|    |    | (6/00)  |         |              |     |        |         |
+----+----+---------+---------+--------------+-----+--------+---------+
| 2  | 7  | During  | Cardio  | Pravastatin  | 2   | 40,000 | Case    |
| 35 | 1/ | retr    | megaly, | (97-\>),     | 13, |        | ide     |
| 12 | M  | eatment | h       | aspirin      | 000 |        | ntified |
|    |    |         | yperlip | (97-\>),     |     |        | re      |
|    |    |         | idemia, | amoxicillin  |     |        | trospec |
|    |    |         | fistula | /clavilinate |     |        | tively, |
|    |    |         | repair, | (12/00),     |     |        | no      |
|    |    |         | e       |              |     |        | tr      |
|    |    |         | levated |              |     |        | eatment |
|    |    |         | PSA     |              |     |        | r       |
|    |    |         |         |              |     |        | endered |
+----+----+---------+---------+--------------+-----+--------+---------+
| 2  | 2  | 145     | TMJ,    | Nefazodone,  | 1   | 30,000 | Study   |
| 71 | 9/ | days    | se      | amoxicillin/ | 76, |        | drug    |
| 03 | M  | (4.8    | izures, | clavulanate, | 000 |        | D/C,    |
| (  |    | mo)     | m       | PCN,         |     |        | pre     |
| SA |    | post    | igraine | cephalexin,  |     |        | dnisone |
| E) |    | first   | he      | cycl         |     |        |         |
|    |    | dose    | adaches | obenzaprine, |     |        | Event   |
|    |    | study   |         | methadone,   |     |        | r       |
|    |    | drug    |         | divalproex   |     |        | esolved |
|    |    |         |         | sodium       |     |        |         |
+----+----+---------+---------+--------------+-----+--------+---------+
| 3  | 4  | 84 days | Grave's | L            | 1   | 1      | re      |
| 32 | 0/ | (3 mo)  | disease | evothyroxine | 55, | 0,000, | quiring |
| 03 | F  |         |         | (since       | 000 | heavy  | 10 unit |
|    |    |         |         | 1995),       |     | v      | p       |
| (  |    |         |         | simvastatin  |     | aginal | latelet |
| SA |    |         |         | (since 1996) |     | ble    | tran    |
| E) |    |         |         |              |     | eding, | sfusion |
|    |    |         |         |              |     | po     | and     |
|    |    |         |         |              |     | sitive | RhoGAM  |
|    |    |         |         |              |     | antipl | for     |
|    |    |         |         |              |     | atelet | bl      |
|    |    |         |         |              |     | ant    | eeding, |
|    |    |         |         |              |     | iobody | D/C     |
|    |    |         |         |              |     |        | study   |
|    |    |         |         |              |     |        | drug,   |
|    |    |         |         |              |     |        | pre     |
|    |    |         |         |              |     |        | dnisone |
+----+----+---------+---------+--------------+-----+--------+---------+
| 3  | 7  | 24      | Acid    | none         | 1   | 27,000 | Study   |
| 72 | 8/ | weeks   | reflux  |              | 41, |        | drug    |
| 04 | F  | (6 mo)  | ds,     |              | 000 |        | D/C     |
|    |    | after   | r       |              |     |        |         |
|    |    | first   | uptured |              |     |        |         |
|    |    | dose of | aortic  |              |     |        |         |
|    |    | study   | a       |              |     |        |         |
|    |    | drug    | neurysm |              |     |        |         |
+----+----+---------+---------+--------------+-----+--------+---------+
| 4  | 3  | 168     | Hypert  |              | 2   | 1      | Pred    |
| 12 | 9/ | days    | ension, |              | 42, | 6,000, | nisone, |
| 32 | M  | (5.6    | alcohol |              | 000 | normoc |         |
|    |    | mo)     | use,    |              |     | elluar | Event   |
| (  |    |         | asthma  |              |     | bone   | ongoing |
| SA |    |         |         |              |     | marrow |         |
| E) |    |         |         |              |     |        |         |
|    |    |         |         |              |     |        |         |
| 2  |    |         |         |              |     |        |         |
| 60 |    |         |         |              |     |        |         |
| 1g |    |         |         |              |     |        |         |
+----+----+---------+---------+--------------+-----+--------+---------+
| 4  | 7  | 138     | Hypert  | Thyroid,     | 1   | 3,000  | Pre     |
| 42 | 3/ | days    | ension, | quinapril    | 99, |        | dnisone |
| 02 | F  | (4.6    | Grave's | (6/97),      | 000 | ANA    |         |
|    |    | mo)     | disease | atenolol     |     | \>     | Event   |
| (  |    |         |         | (6/97),      |     | 1:1280 | o       |
| SA |    |         |         | hydroxyzine  |     |        | ngoing, |
| E) |    |         |         | (12/02),     |     | Gener  | with    |
|    |    |         |         | cephalexin,  |     | alized | rec     |
|    |    |         |         | propranolol  |     | axonal | urrence |
|    |    |         |         | (1/03),      |     | neur   | of low  |
|    |    |         |         | flurazepam   |     | opathy | pl      |
|    |    |         |         | (1/03)       |     |        | atelets |
|    |    |         |         |              |     |        | upon    |
|    |    |         |         |              |     |        | pre     |
|    |    |         |         |              |     |        | dnisone |
|    |    |         |         |              |     |        | taper   |
+----+----+---------+---------+--------------+-----+--------+---------+
| 2  | 6  | 5.5 mo  | ITP (dx | Diltiazem,   | 94, | 48,000 | Disco   |
| 52 | 3/ |         | 1998    | glyburide,   | 000 |        | ntinued |
| 39 | F  |         | prior   | enalapril,   |     |        | from    |
|    |    |         | to      | isorbide,    |     |        | the     |
| 0  |    |         | enrol   | digoxin,     |     |        | study   |
| 02 |    |         | lment), | furosemide,  |     |        |         |
| 59 |    |         | hypert  | metformin,   |     |        |         |
|    |    |         | ension, | a            |     |        |         |
|    |    |         | c       | torvastatin, |     |        |         |
|    |    |         | oronary | ace          |     |        |         |
|    |    |         | disease | tylsalicylic |     |        |         |
|    |    |         |         | acid         |     |        |         |
+----+----+---------+---------+--------------+-----+--------+---------+

*Reviewer's note: Hematologic evaluation was performed only at baseline
and at study day 84 in some of the clinical trials, e.g. study ACD2600g.
This might partially explain why, in the table above, the onset date was
not shorter than study day 84. Concomitant drugs or medical conditions
could have been responsible for thrombocytopenia in certain patients,
e.g. previous history of idiopathic thrombocytopenia in patient
2523900259.*

Human platelets and megakaryocytes express surface CD11a and LFA-1, and
the murine progenitor of the humanized antibody used in the psoriasis
clinical trials has been reported to bind to human platelets. Therefore,
there is a molecular basis for these adverse events of thrombocytopenia
potentially linking it to the study drug. The delayed time course (at
least 3 months in most cases) of the thrombocytopenia in addition to the
response to systemic steroids suggests an immune-based mechanism of
platelet depletion rather than direct toxicity. Furthermore, one patient
(33203) tested positive for an anti-platelet antibody. It is unknown
whether the other patients were tested.

Narratives for the patients with serious adverse events of
thrombocytopenia are provided below.

*[Patient 44202:]{.underline}*

The patient was a 73-year-old woman enrolled in Study 2601g, an open
label-multicenter study for patients who previously participated in
study 2600g. The patient received efalizumab (1 mg/kg/wk) for psoriasis
in Study 2600g starting in September 25, 2002. On March 6, 2003, her
platelet count was noted to be 3,000/ mm3 without associated symptoms.
She was admitted to the hospital. Her evaluation was positive for
ANA\>1:1280. She was treated with IV steroids and discharged with a
platelet count of 67,000/ mm3 and oral prednisone. Her medical history
and concomitant medications were not reported. The investigator assessed
the event as not related to efalizumab. The sponsor's assessment of
causality is possibly related.

*[Patient 10501]{.underline}*

A 61 year-old man patient treated with efalizumab 2 mg/kg for
approximately 12 weeks prior to the onset of the event. The patient's
platelet count was within the normal range from March 21, 2000 to May
17, 2000. On June 14, 2002 his platelet count was 124, 000 cells/mm3. By
July 19,2000, it had dropped to 63,000 cells/mm3. He had no associated
evidence of bleeding or hepatosplenomegaly. His bone marrow was
normocellular on biopsy. His initial treatment was with systemic
steroids. The event resolved after 112 days. The investigator's
assessment was possibly related.

*[Patient 33203]{.underline}*

41-year-old female treated with efalizumab 1 mg/kg for approximately 22
weeks prior to event onset. She presented with bruising and her platelet
count was found to be 10, 000 cells/mm3. She was permanently
discontinued from the study. On August 24, 2002, she was hospitalized
with heavy vaginal bleeding and required a platelet transfusion of 10
units and RhoGam. The thrombocytopenia resolved after 41 days. The
investigator assessed the event as possibly related.

Reviewer's comment: Although the event was reported to have resolved,
the patient at last report was still receiving prednisone at a dose of
25 mg po per day. Therefore, more follow-up is needed to determine
whether the patient remained prednisone-dependent for the treatment of
her thrombocytopenia.

*[Patient 27103]{.underline}*

A 29-year-old male subject with a past-medical history of
thrombocytopenia and generalized seizures, controlled with medication
(phenitoin and divalproex). The subject received efalizumab 1 mg/kg for
17 months and the dose increased to 2 mg/kg 10 days prior to event
onset. The subject required hospitalization for diminished oral intake
and his platelet count was found to be 6,000 cells/mm3. The event
resolved after 35 days. The subject was permanently discontinued from
the study. The investigator stated that the event was not related to
efalizumab.

####  {#section-4 .unnumbered}

### Psoriasis Flares and Rebound

Of the 2589 subjects treated with SC efalizumab (Genentech or XOMA
materials),

19 (0.7%) had a serious adverse event of psoriasis. These included
psoriasis flares that occurred both during treatment and after treatment
discontinuation.

The following were observed in subjects treated with the to-be-marketed
efalizumab (i.e. Genentech material):

-   In the first exposure of controlled clinical trials of efalizumab,
    adverse events of psoriasis occurred in more subjects receiving
    efalizumab (2.4%, n=22) than placebo (1.1%, n=5).

-   Only subjects receiving efalizumab experienced psoriatic
    erythroderma, pustular psoriasis and palmoplantar psoriasis.

-   In the FE studies, \<1% of subjects experienced severe psoriasis and
    \<0.5% discontinued efalizumab treatment because of psoriasis as an
    adverse event.

-   In the EE studies, the incidence of adverse events of psoriasis was
    lower during Weeks 24--60 of continuous treatment compared with
    Weeks 12--24 of treatment.

-   Adverse events of psoriasis were similar to FE during RE.

-   Adverse events of psoriasis were approximately three times as common
    and more likely to be serious or severe during WO compared with FE.

Table 78 below shows the proportions of patients in the first exposure
controlled period with psoriasis adverse events occurring during
treatment. This table includes all psoriatic adverse events by
morphology, both serious and non-serious.

Table 78 Psoriasis Flares and Variants Reported for First Exposure,
Controlled Period (XOMA and GNE)

  -------------------------------- ------------------ --------------------
  Adverse Event                    Placebo            All Efalizumab

                                   479                1171

  Subjects with psoriasis AEs      8 (1.7%)           42 (3.6%)

  Psoriatic erythroderma           0                  6 (0.51%)

  Pustular psoriasis               0                  4 (0.34%)

  Guttate psoriasis                2 (0.4%)           13 (1.1%)

  Recurrence of plaque psoriasis   4 (0.8%)           9 (0.8%)

  Unusual morphology               2 (0.4%)           6 (0.51%)

  Inverse psoriasis                0                  3 (0.26%)

  Palmo-plantar psoriasis          0                  1 (0.08%)
  -------------------------------- ------------------ --------------------

In this analysis, all the cases of psoriatic erythroderma and pustular
psoriasis occurred in the efalizumab treatment arms. One patient with
erythroderma in the first exposure controlled portion required
hospitalization (25609).

Table 79 below shows the serious adverse events of psoriasis in
efalizumab-treated patients by treatment period.

Table 79 Serious Adverse Events of Psoriasis Flares Experienced by
Subjects Treated with Efalizumab

  ------------------ ------------------- ---------- --------------- ---------- --------
  Subject ID         Event               Exposure   Response to     Admitted   
                                                                    to         

                                         Period     Treatment       Hospital   

  25609              Erythroderma        FE         NR              Yes        

                                                                               

  16513              Erythroderma        EE         NR              Yes        

  82009              Exfoliative         EE         Initial R, then Yes        
                                                    lost                       

                     erythroderma                   efficacy to NR             

  16517              Erythroderma        RE         PR              Yes        

  19515              Erythroderma        WO         NR              Yes        

  21505              Erythrodermic       WO         R               Yes        

                     pustular                                                  

  25906              Pustular von        WO         NR              No         

                     Zumbusch                                                  

  27708              Pustular            WO         PR initially    Yes        
                                                    then lost                  

                                                    efficacy to NR             

  64006              Flare               WO         NR              Yes        

  82024              Erythroderma        WO         R               Yes        

  12516              Pustular            Post-WO    NR              Yes        

  16533              Erythroderma        NC ^a^     NR              Yes        

  25914              Pustular von        Post-WO    PR initially    No         
                                                    then lost                  

                     Zumbusch                       efficacy to NR             

  28615              Pustular            Post-WO    R               No         

  80002              Atypical flare      Post-WO    NR              Yes        

  16511              Erythroderma        NC ^a^     NR              Yes        

  NC=not classified;                                                           
  NR=non-responder                                                             
  or non-response;                                                             
  PR=partial                                                                   
  responder;                                                                   
  R=responder.                                                                 

  WO= washout; FE=                                                             
  first exposure;                                                              
  EE= extended                                                                 
  treatment                                                                    

  ^a^ The event                                                                
  occurred                                                                     
  approximately 4                                                              
  weeks after early                                                            
  discontinuation                                                              
  from FE. The                                                                 
  subject                                                                      

  had received three                     The case                              
  doses of                               was also                              
  efalizumab.                            counted                               
                                         during WO.                            
  ------------------ ------------------- ---------- --------------- ---------- --------

Most of the psoriasis adverse events that required hospitalization
occurred in the extended treatment, washout or post-washout period.
Although most of the patients were classified as non-responders, some
patients who were responders subsequently developed serious
psoriasis-related complications.

*[Narratives of Psoriasis-related Adverse Events:]{.underline}*

**Subject No.:** 12516

**Events:** Psoriasis (pustular psoriasis flare)

This 59-year-old man was randomized to 2.0 mg/kg/wk efalizumab in study
ADC2058g and received his initial dose of 0.7 mg/kg on 15 May 2000. He
also had had psoriasis for 6 years and had previously used systemic
therapies. The patient's only medication at baseline was
chlorpheniramine maleate/phenylpropanolamine hydrochloride, for sinus,
since the 1960's. On FT Day 76, the patient was diagnosed with impetigo
for which he was prescribed doxycycline. On FT Day 77, on the day his
last dose of efalizumab, he began to experience a severe psoriasis flare
accompanied by headaches, nausea and vomiting which lead to
discontinuation from the study. The patient was treated with
methotrexate and corticosteroid therapy. Approximately 10 days later,
while on methotrexate and corticosteroid therapy, a severe diffuse
pustular psoriasis flare was diagnosed for which he was hospitalized.
The pustular psoriasis flare resolved in 8 days, and the headache,
malaise, and vomiting continued beyond the subject's participation in
the study. The investigator determined the psoriasis flare, headache,
malaise, vomiting, and the serious adverse event of pustular psoriasis
flare to be not related to study drug.

*Reviewer\'s comment: Of note, the patient had severe flare of psoriasis
during the first treatment period. This was followed by the episode of
pustular psoriasis while on systemic corticosteroids and methotrexate.
The fact that these events followed so closely and began within 1 day of
dosing would make it seem unlikely that close observation with
institution of alternative treatment could have prevented the sequence
of events. In addition, according to the history, the patient developed
"impetigo" within one day preceding the adverse event of psoriasis
flare. Pustular impetigo is in the clinical differential diagnosis of
pustular psoriasis and therefore, it is conceivable that the patient had
pustular psoriasis rather than the impetigo. If this were the case, the
pustular psoriasis diagnosis would have taken place during the first
treatment period. It is also, worth noting that the patient demonstrated
improvement in his psoriasis during the first treatment period his PASI
improvement was up to 82% on FT day 42, approximately mid-way through
his treatment course. This reviewer disagrees with the investigator's
assessment of causality as the temporal relationship of this event as
well as lack of an alternative explanation would indicate that the
adverse event could possibly be related to use of the study drug.*

**Subject No.:** 16517

This 30-year-old man had had psoriasis for 12 years and had a history of
systemic therapy. He initially participated in the Genentech-sponsored
study ACD2058g. He received placebo for the first 12 weeks followed by
2.0 mg/kg/wk SC efalizumab for the subsequent 12 weeks (ET), for a total
of 12 doses of efalizumab. The patient showed clinical response to his
first exposure to study drug in the ET period and ended the treatment
with a PASI score of 3.9, an 85% improvement in PASI from baseline.
Within one month of discontinuing therapy, during the follow-up period,
however, his PASI increased to 25.7.

Approximately 5 weeks after discontinuation of therapy, the subject
entered Study ACD2062g in the Re-Exposure group with a PASI score of
61.2. The day after receiving his first dose of study drug, the subject
was hospitalized for a severe erythrodermic psoriasis flare. The
investigator determined the event of erythrodermic psoriasis flare to be
not related to study drug.

*Comments: Note, this patient's psoriasis quickly deteriorated within
one month of discontinuation of therapy and the patient suffered an
erythrodermic flare resulting in hospitalization within 5 weeks of
stopping therapy. Of note, this case meets the National Psoriasis
Foundation's definition of rebound:* *a PASI of 125% of baseline or new
generalized pustular, erythrodermic or more inflammatory psoriasis
occurring within 3 months of stopping therapy.*

Four subjects were receiving efalizumab at the time of the serious
adverse event of psoriasis:

**Subject No.:** 25609

This 66-year-old woman had psoriasis for 15 years and a history of
systemic therapy. She entered Study ACD2243g and was randomized to
receive 2.0 mg/kg/wk SC efalizumab without topical corticosteroid
therapy in the FT period. PASI at the time of the conditioning dose was
33. After receiving the fifth dose of study drug, the subject's PASI was
25. A total of seven doses of efalizumab were given.

Six weeks after her first dose, the subject began to develop a severe
psoriasis exacerbation and discontinued efalizumab treatment and study
participation. One week later, she developed a severe erythrodermic
exacerbation of psoriasis and was hospitalized. PASI at this time was
31. Treatment included triamcinolone wraps, cyclosporine, and
methotrexate. The subject was discharged in good condition in 4 days.
The event resolved after 5 days. The investigator determined the
psoriasis exacerbation and erythrodermic exacerbation of psoriasis to be
related to efalizumab.

*Comments: Of note, the patient's PASI score at the time of her
erythrodermic flare, 31, was similar to her baseline PASI score of 33.
The narrative does not address whether the patient had a positive
anti-efalizumab antibody. It is unusual that the patient received both
cyclosporin and methotrexate in the hospital.*

**Subject No.:** 82009

54-year-old man. During the FT period, the subject's PASI scores had
decreased from 13.6 to 2.8, and the percentage of psoriatic BSA had
decreased from 12.9% to 3.0%.

On 4 September (ET Day 4), the subject reported that his psoriasis had
worsened. Within 1 week, his body was covered with psoriatic lesions and
he was erythrodermic. On 14 September 2000, he returned for evaluation
and was noted to be erythrodermic with a PASI of 59.6 and a BSA of 90%
involvement. According to the investigator, the psoriasis flare was not
related to efalizumab.

*Comments: This patient initially improved with efalizumab therapy.
However, in this case, the patient developed clinically significant
worsening requiring hospitalization despite continuing the treatment and
negative anti-efalizumab antibody test results.*

Table 80 below shows the non-serious psoriasis-related adverse events by
treatment period.

Table 80 Non-Serious Adverse Events of Erythrodermic or Pustular
Psoriasis Reported for Efalizumab-Treated Subjects

  ------------------ ---------------- ---------- --------------- -------------
                                      Exposure   Response to     

  Subject ID         Event            Period     Treatment       Intensity

  82026              Erythroderma     FE         NR              Severe

  34229              Erythroderma     FE         NR              Severe

  75610              Erythroderma     FE         NR              Severe

  79202              Pustules in      FE         PR              Severe
                     groin                                       

  69202              Erythroderma     WO         R               Severe

  79208              Pustular lesions WO         PR initially    Severe
                     on                          then lost       

                     groin/buttocks              efficacy to NR  

  80811              Erythroderma     WO         R               Severe

  82003              Erythroderma     WO         PR              Severe

  NR=non-responder                                               
  or non-response;                                               
  PR=partial                                                     
  responder;                                                     
  R=responder.                                                   
  ------------------ ---------------- ---------- --------------- -------------

Each of these non-serious adverse events was listed as severe in
intensity. They occurred both during treatment and after discontinuation
with treatment. In some cases, the patient was classified as a responder
and experienced rebound upon discontinuation of study drug. There were
no cases of psoriasis variants in the control group.

Some of patients (e.g.11504, 17501) who discontinued from the study with
psoriasis-related adverse events including (including some who had
variants of psoriasis) were incorrectly classified as having
discontinued for other causes i.e. "physician's decision."

### Arthritis-Related Adverse Events

The incidence of arthritic adverse events by treatment group in shown in
Table 81 below.

Table 81 Arthritis-Related Adverse Events Studies ACD2058g, ACD2059g,
ACD2390g, and ACD2600g (FT Period): All Subjects

  ----------- ---------------------- ---------------- --------- -------- ------------ -------- ------------ -------- ------------ --------
                                                                         Efalizumab            Efalizumab            Efalizumab   

  COSTART                                             Placebo            1.0 mg/kg/wk          2.0 mg/kg/wk          All Subjects 
  Preferred                                                                                                                       

  Term                               Classification   (N=715)            (N=1213)              (N=407)               (N=1620)     

                                                                                                                                  

                                                                                                                                  

  Subjects                                            715                1213                  407                   1620         
  with                                                                                                                            

  completed                                                                                                                       
  forms                                                                                                                           

                                                                                                                                  

  \- Total -                                          16        (2.2%)   29           (2.4%)   16           (3.9%)   45           (2.8%)

              Arthritis NOS                           7         (1.0%)   8            (0.7%)   9            (2.2%)   17           (1.0%)

              Exacerbation/flare                      2         (0.3%)   13           (1.1%)   4            (1.0%)   17           (1.0%)
              psoriatic arthritis                                                                                                 

              Worsening/increasing                    3         (0.4%)   5            (0.4%)   2            (0.5%)   7            (0.4%)
              psoriatic arthritis                                                                                                 

              Psoriatic arthritis                     3         (0.4%)   2            (0.2%)   1            (0.2%)   3            (0.2%)

              Osteoarthritis                          1         (0.1%)   1 (\<0.1%)            1            (0.2%)   2            (0.1%)
  ----------- ---------------------- ---------------- --------- -------- ------------ -------- ------------ -------- ------------ --------

During the first treatment period, a higher proportion of patients in
the combined efalizumab-treated group experienced exacerbation/ flares
in psoriatic arthritis than placebo (1.1% vs. 0.3%). The incidence of
arthritis not otherwise specified and osteoarthritis was the same in the
combined efalizumab groups as in the placebo group. The incidence of
arthritis-related adverse events was 2.2% in placebo, 2.4% in the
1-mg/kg/wk and 3.9% in the 2-mg/kg/wk groups.

There have been 15 cases of serious adverse events for arthritis, 0.6%
of the studied population. None of the serious adverse events occurred
within the first treatment period of placebo controlled studies.

Some of the serious adverse events for inflammatory arthritis are
notable for occurring in association with other findings of
inflammation, including neuritis, peripheral edema and bilateral
cellulitis, fever and positive ANA. See the narratives below.

> [*New onset inflammatory arthritis, accompanied by fever, peripheral
> edema, and neuritis: patient* (*28336)*]{.underline}

The subject*,* a 49-year-old man, with a three-year history of psoriatic
arthritis, previously treated with systemic corticosteroids, but
negative history for psoriatic arthritis entered Study ACD2243g and was
randomized to receive 2.0 mg/kg/wk SC efalizumab. After receiving, four
doses of efalizumab, the patient experienced severe inflammatory
arthritis, characterized by left ankle pain, followed by moderate
bilateral lower leg peripheral edema and cellulitis of both feet. The
patient was treated with nonsteroidal antiinflammatory medications and
antibiotics without improvement, and continued to receive efalizumab.
Approximately 7 weeks after the first dose, the subject complained of
arthralgias, neuritis to feet, total body joint inflammation, and severe
right knee pain associated with a right knee effusion, and increasing
bilateral lower extremity peripheral edema. The patient was unable to
ambulate subsequently hospitalized for further evaluation. Evaluation
was negative for a deep vein thrombosis. An antinuclear antibody test
done previously was positive and chemistries revealed an elevated
sedimentation rate and creatine kinase. The patient received systemic
corticosteroids and IV antibiotics. By the following day, the edema had
markedly decreased and the subject was discharged on methylprednisolone,
cephalexin, gabapentin. By 8 weeks after the first dose and 1 week after
discontinuation of efalizumab, the subject experienced intermittent
fevers lasting 45 days. He was re-hospitalized for three days for
increased ankle edema and lower extremity pain. He underwent aspiration
of a left knee effusion twice following discharge. He was hospitalized
for left knee debridement, lavage, and antibiotic therapy. Laboratory
results revealed an elevated sedimentation rate. During hospitalization,
the subject experienced intermittent fevers, but an infectious etiology
was ruled out. The subject continued to have an elevated sedimentation
rate, and steroid therapy was initiated. A rheumatologist made the
diagnosis of inflammatory arthritis and initiated methotrexate. The
subject continued to have intermittent pain and edema to his lower
extremities, while his arthritis was improved by 7 months after the
onset of the adverse event. The event remains ongoing. The investigator
determined the inflammatory arthritis and bilateral lower extremity
cellulitis to be related to efalizumab.

*Reviewer\'s comment: This adverse event is unusual because it resulted
in hospitalization on three occasions and (as of the most recent report
to the Agency) failed to resolve after discontinuation of therapy. After
examining the clinical database, it was determined that the patient
tested negative to anti-efalizuamab antibodies during and after
treatment discontinuation.*

[*Psoriatic Arthritis and psoriasis flare* (*25601)*]{.underline}

A 24-year-old Asian female assigned to 1.0 mg/kg/wk efalizumab enrolled
in Study ACD2243g and received the first dose of 2.0 mg/kg/wk efalizumab
on 22 March 2001.

The subject's medical history was significant for adequately controlled
type 1 diabetes

(since 1996) and psoriatic arthritis in the knees (since 1997). The
subject experienced two events of a psoriatic arthritis flares. On 10
September 2002, the subject was evaluated by her physician for left-knee
pain. Treatment included celecoxib. Within a few days she noted swelling
in both knees and an X-ray of the left knee revealed a small joint
effusion. One week later, the subject was unable to ambulate. She was
admitted to the hospital where she was treated for 3 days. An
arthrocentesis was performed, which revealed a white blood cell (WBC)
count of 41,000/μL, with 87% segmented neutrophils, and no crystals and
no organisms identified on Gram stain. The subject's Rhesus factor was
30, erythrocyte sedimentation rate was 40 mm/hr, and an antinuclear
antibody test was positive. The subject noted her psoriasis started to
worsen during hospitalization and continued to worsen despite having
initiated treatment with methotrexate. She was subsequently hospitalized
with an erythrodermic psoriasis flare. The psoriatic arthritis flare was
noted to resolve on December 17, 2002. The investigator determined the
psoriatic arthritis flare to be related to study drug and the psoriasis
flare not to be related to study drug.

*Reviewer's comment:*

This case was notable for a flare in both psoriasis and psoriatic
arthritis.

### Serious Vascular and Thrombotic Events

Table 82 below presents serious cardiovascular events experienced by
subjects within the first treatment period of placebo controlled
studies.

#  {#section-5 .unnumbered}

Table 82 Serious Cardiovascular Adverse Events First Exposure Controlled
Studies

  ------------------------------------ --------------- ------------------
  Adverse Event                        Placebo         Efalizumab
                                                       (combined)

  n                                    715             1620

  Subjects with at least one event     1 (0.1%)        4 (0.2%)

  Coronary artery disorder             0               2 (0.1%)

  Angina pectoris                      0               0

  Arteriosclerosis                     0               0

  Arteriospasm                         0               1(\<0.1%)

  Myocardial infarct                   1 (0.1%)        1(\<0.1%)

  Deep thrombophlebitis                0               0

  Cerebral ischemia                    0               0

  Pulmonary embolus                    0               0

  Peripheral vascular disorder         0               0
  ------------------------------------ --------------- ------------------

The incidence of these serious cardiovascular events was low and was
similar between efalizumab- and placebo-treated subjects. There was no
apparent increase in incidence in serious cardiovascular events
associated with efalizumab treatment. However, the numbers are too small
to draw any definitive conclusions.

### Serious Inflammatory and Autoimmune Reactions

Two cases of pneumonitis occurred in clinical development (See
narratives below). One case was classified as eosinophilic pneumonitis.
In addition, search of the sponsor's safety database was performed which
revealed another case of pneumonitis in a 38 year old-man. One patient
presented with adenopathy, fever, and arthritic symptoms which her
clinician indicated was a diagnosis of a serum-sickness like reaction.

*[Eosinophilic pneumonitis]{.underline}*

The patient (40011) is a 66-year-old male with a history of hypertension
enrolled in trial ACD2601g. His history was negative for previous
autoimmune disease, methotrexate use or lung disease. He received
efalizumab 1 mg/kg/wk SC for 6 months. Concomitant medications included
aspirin, hydrochlorothiazide and propranolol (dates unknown). The
patient was diagnosed after having presented with flu-like symptoms and
shortness of breath beginning on 31-Jan-2003, three months after his
first dose of efalizumab in trial ACD2600g. The drug was temporarily
stopped on 21-Feb-2003 but then resumed on 27-Feb-2003. The patient had
an increased white blood cell count of 19.9x10^3^/mm3 and notable for an
eosinophil count of 13%. Chest radiography and follow-up CT scan both
showed cardiomegaly and bilateral diffuse interstitial lung disease.
Pulmonary function tests showed significant restrictive lung disease
with gas transfer defect. Lung biopsy showed mild, non-specific, chronic
inflammation and interstitial thickening without atypia. The patient was
treated by permanent discontinuation of efalizumab (last dose April 23,
2003) and systemic corticosteroids. The patient's symptoms resolved
after the drug was discontinued. The investigator classified the event
as possibly related to study drug.

Reviewer's comment: The patient continued to receive efalizumab for
several months despite having had continued symptoms of a flu-like
illness and dyspnea, an important protocol violation to note. If
licensed, the label should advise to withhold dosing in the presence of
unexplained pulmonary symptomatology suchas shortness of breath.

*[Pneumonitis]{.underline}*

The second patient is a 38 year-old man who was enrolled in study
ACD2059g. The subject received efalizumab 1.0 mg/kg/wk in the first
treatment course, first dose received on August 8, 2000. On January 15,
2003, the patient was hospitalized for a fever and ongoing dry cough and
was noted to be hypoxic (pO2 level of 52). Chest X ray revealed diffuse
parenchymal changes consistent with drug-induced hypersensitivity.
Bronchoscopy results were unremarkable with all cultures and diagnostic
tests negative. The patient received supplemental oxygen,
trimethoprim/sulfamthoxazole and methylprednisolone. The pneumonitis
resolved on February 26, 2003. The investigator indicated the final
diagnosis was pneumonitis of unknown etiology and assessed the event as
related to study drug.

Serum-sickness-like reaction

The patient (42004) is a 35year-old female who received treatment with
efalizumab 1.0 mg/kg/wk in study ACD2600g. Three and half weeks after
receiving the first dose of efalizumab, the patient presented to the
emergency room with tender cervical lymphadenopathy, fever and slight
chest pressure. She was admitted to the hospital and the following
laboratory evaluations were negative: chest x-ray, blood cultures, EBV
titer, CMV titer, monospot. The patient had psoriatic arthritis at
baseline and while in the hospital she experienced febrile episodes and
an exacerbation of her psoriatic arthritis accompanied with an elevation
of the erythrocyte sedimentation rate. She responded to prednisone at a
dose of 60 mg per day with an improvement in her lymphadenopathy and
psoriatic arthritis symptoms. The investigator's assessment of
relationship to study medication was potentially related while the
physician responsible for the patient's care in the hospital reported
the relationship as causal and advised the patient not to receive
efalizumab in the future. Follow-up information revealed that the
patient's adenopathy had resolved without evidence of recurrence.
Similar adverse events involving adenopathy and fever of unknown origin
are in the efalizumab safety database. This event possibly represents a
serum sickness-like reaction to the study drug.

## Severe Adverse Events

During the first treatment period of controlled clinical trials, the
proportion of patients with at least one severe adverse event was higher
among efalizumab-treated (11.8%) patients than placebo-treated patients
(6.9%).

## Common Adverse Events

The following table depicts the adverse events that occurred in ≥ 3% of
patients treated with the Genentech material in the 1.0 mg/kg/week group
compared to placebo-treated patients in the first exposure in controlled
studies.

Table 83 Adverse Events that Occurred in ≥ 3% of Subjects Treated with
Genentech Material in the 1.0 mg/kg/wk Group or the Placebo Group in the
FE/Controlled Studies

  --------------------------- ----------------- ------------ ------------
                                                Genentech    
                                                Efalizumab   

  COSTART Body                                               

  System/                     Placebo           1.0 mg/kg/wk 2.0 mg/kg/wk

  Preferred Term              (n=219)           (n=420)      (n=61)

  Subjects with at least      156 (71.2%)       338 (80.5%)  56 (91.8%)

  one adverse event                                          

  Body as a whole                                            

  **Headache**                **46 (21.0%)**    **137        **18
                                                (32.6%)**    (29.5%)**

  Infection                   31 (14.2%)        51 (12.1%)   14 (23.0%)

  **Chills**                  **10 (4.6%)**     **52         **8
                                                (12.4%)**    (13.1%)**

  **Pain**                    **11 (5.0%)**     **44         **9
                                                (10.5%)**    (14.8%)**

  **Fever**                   **3 (1.4%)**      **32         **7
                                                (7.6%)**     (11.5%)**

  **Flu syndrome**            **7 (3.2%)**      **28         **2 (3.3%)**
                                                (6.7%)**     

  Asthenia                    12 (5.5%)         25 (6.0%)    4 (6.6%)

  Accidental injury           21 (9.6%)         19 (4.5%)    5 (8.2%)

  Digestive                                                  

  **Nausea**                  **14 (6.4%)**     **43         **8
                                                (10.2%)**    (13.1%)**

  Diarrhea                    14 (5.9%)         21 (5.0%)    5 (8.2%)

  Gastroenteritis             10 (4.6%)         5 (1.2%)     0

  Metabolic/nutritional                                      

  Peripheral edema            9 (4.1%)          16 (3.8%)    3 (4.9%)

  Musculoskeletal                                            

  **Myalgia**                 **8 (3.7%)**      **40         **9
                                                (9.5%)**     (14.8%)**

  Arthralgia                  7 (3.2%)          14 (3.3%)    4 (6.6%)

  Nervous                                                    

  **Dizziness**               **4 (1.8%)**      **16         **4 (6.6%)**
                                                (3.8%)**     

  Hypertonia                  8 (3.7%)          3 (0.7%)     1 (1.6%)

  Respiratory                                                

  **Pharyngitis**             **12 (5.5%)**     **30         **5 (8.2%)**
                                                (7.1%)**     

  Rhinitis                    13 (5.9%)         28 (6.7%)    4 (6.6%)

  Cough increased             9 (4.1%)          17 (4.0%)    5 (8.2%)

  Sinusitis                   8 (3.7%)          16 (3.8%)    5 (8.2%)

  Skin/appendages                                            

  **Herpes simplex**          **8 (3.7%)**      **21         **2 (3.3%)**
                                                (5.0%)**     

  **Acne**                    **0**             **14         **2 (3.3%)**
                                                (3.3%)**     
  --------------------------- ----------------- ------------ ------------

Adverse events with a ≥ 1% higher incidence among the efalizumab-treated
patients compared to placebo-treated patients are highlighted in bold.

Adverse events with a 5% or higher incidence among efalizumab-treated
patients compared to placebo-treated patients were: headache, chills,
pain, fever, and myalgia.

The incidence of adverse events appears to be higher in the 2 mg/kg
group compared to the 1 mg/kg group.

## Hypersensitivity Reactions (serious and non-serious)

The following table provides a placebo-controlled comparison of the
hypersensitivity-related adverse events predefined in the clinical
protocol.

Table 84 Hypersensitivity-Related Adverse Events Studies ACD2058g,
ACD2059g, ACD2390g, and ACD2600g (FT Period): All Subjects Treated with
Combined Materials

  ------------------- ------------------ --------- -------- ------------ -------- ------------ -------- ------------ --------
                                                            Efalizumab            Efalizumab            Efalizumab   

                                         Placebo            1.0 mg/kg/wk          2.0 mg/kg/wk          All Subjects 

  COSTART Body System COSTART Preferred  (N=715)            (N=1213)              (N=407)               (N=1620)     
                      Term                                                                                           

                                                                                                                     

                                                                                                                     

  Subjects with                          715                1213                  407                   1620         
  completed                                                                                                          

  forms                                                                                                              

                                                                                                                     

  Subjects with at                       49        (6.9%)   95           (7.8%)   37           (9.1%)   132          (8.1%)
  least one                                                                                                          
  hypersensitivity-                                                                                                  

  related adverse                                                                                                    
  event                                                                                                              

                                                                                                                     

  Body as a Whole     TOTAL              13        (1.8%)   26           (2.1%)   10           (2.5%)   36           (2.2%)

                      Allergic reaction  6         (0.8%)   14           (1.2%)   5            (1.2%)   19           (1.2%)

                      Face edema         6         (0.8%)   6            (0.5%)   3            (0.7%)   9            (0.6%)

                      Injection site     1         (0.1%)   6            (0.5%)   2            (0.5%)   8            (0.5%)

                      hypersensitivity                                                                               

                                                                                                                     

  Respiratory         TOTAL              14        (2.0%)   15           (1.2%)   7            (1.7%)   22           (1.4%)

                      Dyspnea            3         (0.4%)   9            (0.7%)   3            (0.7%)   12           (0.7%)

                      Asthma             6         (0.8%)   4            (0.3%)   3            (0.7%)   7            (0.4%)

                      Laryngismus        5         (0.7%)   1 (\<0.1%)            1            (0.2%)   2            (0.1%)

                      Bronchiolitis                (0.0%)   1 (\<0.1%)                         (0.0%)   1 (\<0.1%)   

                                                                                                                     

  Skin/Appendages     TOTAL              26        (3.6%)   59           (4.9%)   20           (4.9%)   79           (4.9%)

                      Rash               20        (2.8%)   37           (3.1%)   11           (2.7%)   48           (3.0%)

                      Urticaria          3         (0.4%)   16           (1.3%)   6            (1.5%)   22           (1.4%)

                      Maculopapular rash 3         (0.4%)   8            (0.7%)   2            (0.5%)   10           (0.6%)

                      Angioedema                   (0.0%)   1 (\<0.1%)            3            (0.7%)   4            (0.2%)

                      Erythema                     (0.0%)   1 (\<0.1%)                         (0.0%)   1 (\<0.1%)   
                      multiforme                                                                                     
  ------------------- ------------------ --------- -------- ------------ -------- ------------ -------- ------------ --------

The proportions of patients who experienced at least one
hypersensitivity-related adverse event in the combined efalizumab group
and the placebo group were similar, 8.1% vs. 6.9%.

A single case of erythema multiforme and four cases of angioedema took
place in efalizumab-treated patients. Urticaria was at least three times
more common in efalizumab-treated patients than in control (1.4% vs.
0.4%).

## Immunogenicity

### Anti-efalizumab Antibodies

The screening test for anti-efalizumab antibodies (HAHA) is less
sensitive during treatment with efalizumab, due to interference by the
drug with the assay. Therefore, the preferred analysis is one using the
data from screening done after patients have undergone drug washout. The
incidence of anti-efalizumab antibodies is shown in Table 85.

*Table 85 Incidence of Anti-Efalizumab Antibodies in Genentech Sponsored
Studies by Manufacturer*

+-----------------------+----------+----------+----------+---+----------+
|                       | Ef       |          |          |   |          |
|                       | alizumab |          |          |   |          |
|                       | Manu     |          |          |   |          |
|                       | facturer |          |          |   |          |
+-----------------------+----------+----------+----------+---+----------+
|                       | G        | > XOMA   | Both ^a^ |   | All      |
|                       | enentech |          |          |   | Subjects |
+-----------------------+----------+----------+----------+---+----------+
| No. of HAHA-positive  | 28/904   | > 38/716 | 17/302   |   | 83/1922  |
|                       | (3.1%)   | > (5.3%) | (5.6%)   |   | (4.3%)   |
+-----------------------+----------+----------+----------+---+----------+
| subjects/no. of       |          |          |          |   |          |
| subjects              |          |          |          |   |          |
+-----------------------+----------+----------+----------+---+----------+
| tested (all available |          |          |          |   |          |
| data)                 |          |          |          |   |          |
+-----------------------+----------+----------+----------+---+----------+
|                       |          |          |          |   |          |
+-----------------------+----------+----------+----------+---+----------+
| No. of HAHA-positive  | 12/173   | > 38/623 | 17/267   |   | 67/1063  |
| /no.                  | (6.9%)   | > (6.1%) | (6.4%)   |   | (6.3%)   |
+-----------------------+----------+----------+----------+---+----------+
| of subjects with      |          |          |          |   |          |
| follow-up             |          |          |          |   |          |
+-----------------------+----------+----------+----------+---+----------+
| samples ^b^           |          |          |          |   |          |
+-----------------------+----------+----------+----------+---+----------+
| ^a^ Subjects exposed  |          |          |          |   |          |
| to Genentech          |          |          |          |   |          |
| efalizumab in Study   |          |          |          |   |          |
| ACD2062g after prior  |          |          |          |   |          |
| exposure to XOMA      |          |          |          |   |          |
| efalizumab (subjects  |          |          |          |   |          |
| who are not included  |          |          |          |   |          |
| in                    |          |          |          |   |          |
| manufacturer-specific |          |          |          |   |          |
| columns).             |          |          |          |   |          |
+-----------------------+----------+----------+----------+---+----------+
| ^b^ Only includes     |          |          |          |   |          |
| data from completed   |          |          |          |   |          |
| studies for subjects  |          |          |          |   |          |
| who tested positive   |          |          |          |   |          |
| or who had a negative |          |          |          |   |          |
| sample at least 56    |          |          |          |   |          |
| days after last dose. |          |          |          |   |          |
+-----------------------+----------+----------+----------+---+----------+

The incidence of anti-efalizumab antibodies was 6.3% (67/1063) among
patients treated with either Genentech or XOMA-manufactured, 56 days
after discontinuation of treatment. There was little difference in the
incidence of HAHA antibodies by efalizumab manufacturer.

Six subjects with local injection-site reactions tested positive for
HAHA. The adverse events coded to injection-site mass, hypersensitivity
reaction, or inflammation and were described as irritation,
inflammation, redness, lump, or urticaria. These adverse events resolved
despite continued efalizumab therapy. A potential a relationship between
presence of HAHA and local cutaneous reactions exists.

Of the HAHA-positive patients, 20% achieved a PASI 75 and 53.3% achieved
a PASI 50. These data are consistent with the response rate, overall.
However, the response was on the low side of the range of observed
values in the dose groups tested in the phase 3 and open-label studies.
Titers of the antibodies were generally low.

The long-term immunogenicity of efalizumab is not known.

Reviewer\'s comment: The association of arthritic and other inflammatory
adverse events with HAHA positivity may be underestimated given that
some of the patients may have discontinued the study prematurely due to
their adverse event and thus, have missing data with regard to
anti-efalizumab antibody screening.

### Other Laboratory Changes and Adverse Events Associated with Efalizumab Therapy:

#### Effects on Total White Blood Cell Counts {#effects-on-total-white-blood-cell-counts .unnumbered}

During the FE/Controlled studies, mean WBC counts increased by
approximately 30%--40% relative to baseline among subjects receiving
Genentech efalizumab compared with no increase in placebo-treated
subjects. Table 86 below shows the absolute change in WBC counts by
treatment group. Leukocytosis was sustained throughout efalizumab
treatment, including the EE and RE treatment periods, and subsequently
resolved during WO after efalizumab discontinuation.

Table 86 Change in White Blood Cell Counts (K/cmm) from Baseline to Day
84 of Each Period for Subjects Treated with Genentech Efalizumab

  ------------------ --------- ------------- ---------- ---------- -------------
                               Genentech                           
                               Efalizumab,                         
                               Mean                                

  Type of                      2.0           1.0        2.0        3.0--4.0

  Study/Period       Placebo   mg/kg/qow     mg/kg/wk   mg/kg/wk   mg/kg/wk

  FE/Controlled      -0.15    NA            2.58       3.20       NA

  FE                 NA        2.17          2.59       2.68       3.81

  EE-1               NA        3.03          2.56       2.71       2.72

  EE-2               NA        NA            2.71       3.27       2.84

  EE-3               NA        NA            2.65       2.77       4.92

  EE-4               NA        NA            2.21       3.05       5.23

  RE-1               NA        NA            2.40       2.97       NA

  WO                 NA        0.20         0.06       0.32       0.09

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

NA=not applicable.

The maximal WBC count observed in any efalizumab-treated subject was
26.0 K/cmm

during the first 12 weeks of efalizumab treatment, 24.1 K/cmm during
extended treatment, and 21.5 K/cmm during retreatment. All changes were
between 3 and 4-fold of the upper limit of normal. The increase in WBC
count appeared to be dose dependent.

#### Lymphocyte Counts {#lymphocyte-counts .unnumbered}

Table 87 shows the change in absolute lymphocyte counts from baseline by
treatment group.

Table 87 Change in Absolute Lymphocyte Counts (K/cmm) from Baseline to
Day 84 of First Treatment

  ---------------- ------ ---------- ------ ------ ----- -- -------- ------ ------ ----- --
                          Baseline                          Change                       

  Treatment Group  N      Mean       Mdn    Min    Max      Mean     Mdn    Min    Max   

                                                                                         

  Placebo          664    1.9        1.8    0.4    4.2      0.05     0.0    -2.6   2.5   

  Efalizumab       1538   1.9        1.8    0.5    5.1      2.10     1.9    -1.2   9.4   
  ---------------- ------ ---------- ------ ------ ----- -- -------- ------ ------ ----- --

A mean doubling of absolute lymphocyte counts took place at the end of
the first treatment period in the efalizumab group compared to
negligible changes in the placebo group. The clinical significance of
this finding is unknown. The changes are reversible upon discontinuation
of therapy.

#### Segmented Neutrophils {#segmented-neutrophils .unnumbered}

With the emergence of adverse events of low platelets and given that
segmented neutrophils (among other WBC subsets) express CD11a, it is
important to consider carefully any changes that are occurring in
neutrophils. Mean decreases occur in the percentages of segmented
neutrophils. The percentage change is --13.6% in the efalizumab 1.0
mg/kg/wk group the minimum percentage change is --55%.

#  {#section-6 .unnumbered}

In contrast to percentage changes in neutrophil counts, mean absolute
neutrophil counts increased somewhat with treatment according to mean
values (See Table 88).

Table 88 Change in Absolute Neutrophil Counts (K/cmm) from Baseline to
Day 84 for Subjects Treated with Genentech Efalizumab

  ------------- ----- ---------- ------ ------ ------ ---- -------- ------ ------- ------
                      Baseline                             Change                  

  Treatment     N     Mean       Mdn    Min    Max         Mean     Mdn    Min     Max
  Group                                                                            

                                                                                   

  Placebo       417   4.7        4.4    0.9    15.9        -0.16    -0.1   -11.0   8.0

  Efalizumab    816   4.6        4.5    1.1    18.0        0.26     0.2    -10.0   10.7
  1.0 mg/kg/wk                                                                     

  Efalizumab    60    4.7        4.3    2.1    9.8         0.62     0.7    -4.8    4.0
  2.0 mg/kg/wk                                                                     

  Efalizumab    876   4.6        4.5    1.1    18.0        0.29     0.2    -10.0   10.7
  (combined)                                                                       
  ------------- ----- ---------- ------ ------ ------ ---- -------- ------ ------- ------

Inlcudes Studies ACD2059g, ACD2390g and ACD2600g

Thus, while the mean absolute neutrophil counts increased, the percent
neutrophils decreased because the increase in lymphocytes was relatively
greater.

Shifts to low values of absolute neutrophils were also assessed.
Overall, 0.5%, or 7/1387 patients who received 1.0 mg/kg/wk of
efalizumab in the first exposure of the clinical trials, experienced a
shift in absolute neutrophil counts to low from a normal baseline level.
In addition, a listing of all patients with grade 3 or greater NCI
toxicity criteria was evaluated for decreases in absolute neutrophil
counts and failed to show decreases that were sustained or confirmed by
repeat testing (data not shown).

*Reviewer\'s comment: Most of the grade 3 or 4 abnormalities in absolute
neutrophil counts in efalizumab-treated patients were not sustained and
some of these events were also noted in placebo-treated patients.
However, follow-up is not available on one patient with a grade 4
decrease in absolute neutrophil counts (45223) and one patient with a
grade 3 decrease in neutrophil counts (45207). The clinical significance
of the transient decreases in absolute neutrophils is not known.*

#### Eosinophils {#eosinophils .unnumbered}

Mean values of eosinophils were increased in efalizumab-treated patients
by 50% and there was an increase in high-value abnormalities.
Approximately 10% of efalizumab-treated patients had treatment emergent
elevations in eosinophil count compared to 3% of placebo-treated
patients. While the mean absolute eosinophils increased, the percent
eosinophils decreased because the increase in lymphocytes was relatively
greater.

Chemistry

Consistently observed in the chemistry panel, was an increase in mean
alkaline phosphatase in efalizumab-treated patients compared with
placebo-treated patients (See Table 89).

**Table 89 Change in Alkaline Phosphatase (U/L) from** Baseline to Day
84 of Each Period for Subjects Treated with Genentech Efalizumab

  --------------- ---------- ----------- ------------- ----------- -------------
                                         Genentech                 
                                         Efalizumab,               
                                         Mean                      

  Type of                    2.0         1.0           2.0         3.0--4.0

  Study/Period    Placebo    mg/kg/qow   mg/kg/wk      mg/kg/wk    mg/kg/wk

  FE/Controlled   −0.08      NA          6.87          9.57        NA
                  (11.69)                                          

  FE              NA         −1.27       6.71          11.09       23.17

  EE-1            NA         9.27        7.78          33.40       0.87

  EE-2            NA         NA          7.97          13.54       9.25

  EE-3            NA         NA          7.03          11.90       12.00

  EE-4            NA         NA          10.49         9.98        15.50

  RE-1            NA         NA          14.43         8.63        NA

  WO              NA         0.95        0.46          5.21        −1.42
  --------------- ---------- ----------- ------------- ----------- -------------

The degree of elevation was higher in the 2.0 mg/kg/wk group than in the
1.0 mg/kg/wk group suggesting a dose effect. Both the liver and
intestinal isoenzymes have demonstrated shifts to the upper limit of
normal.

Liver function tests have been examined for concordant elevations in
multiple tests for the first treatment period in the four phase 3
placebo-controlled studies: ACD2058g, ACD2059g, ACD2390g, and ACD2600g.
See Table 90 below.

Table 90 Summary of High Shift in One or More Liver Function Tests
during the First 12 Weeks in Studies ACD2058g, ACD2059g, ACD2390g, and
ACD2600g

  --------------------------- ------------------ ------------------------
                              Placebo            Efalizumab

  No shift                    562/604 (93.0%)    1203/1374 (87.6%)

  Shift on one liver function 31/604 ( 5.1%)     120/1374 ( 8.7%)
  test                                           

  Shift on two liver function 9/604 ( 1.5%)      43/1374 ( 3.1%)
  tests                                          

  Shift on three liver        2/604 ( 0.3%)      8/1374 ( 0.6%)
  function tests                                 

  Shift on four liver         0/604 ( 0.0%)      0/1374 ( 0.0%)
  function tests                                 

  Shift on five liver         0/604 ( 0.0%)      0/1374 ( 0.0%)
  function tests                                 
  --------------------------- ------------------ ------------------------

The summary represents the proportion of subjects with a shift from low
or normal baseline values to values above the upper limit of normal at
Day 84 on one or more liver

function tests. The number of subjects with shifts on one or more liver
function tests was higher in the efalizumab group than in the placebo
group. No subjects had a shift above upper limit of normal on four or
five liver function tests.

Transaminase elevations accounted for other shifts in liver function
tests. Adverse events consisting of increases in SGPT occurred in 1.1%
(n=29) of patients and SGOT occurred in 0.7% (n=19) patients.
Bilirubinemia occurred as an adverse event in 0.1% of patients (n=3).

#### Inflammation-associated laboratory changes

Adverse events of thrombocythemia were observed in a small number of
patients and appear to be reactive in etiology. In one patient (17512)
thrombocythemia was associated with increases in peripheral white blood
cell count, increases in serum CRP and peripheral edema. The clinical
significance is unknown. Overall the frequency of high platelet counts
was 4.0% (n=35) in efalizumab-treated patients vs. 2.7% (n=11) in
placebo-treated patients.

Examination of changes in representative acute phase reactants and in
complement activation products demonstrated some increases in
efalizumab-treated subjects. In Study ACD2600g, mean levels of
C-reactive protein and fibrinogen increased more in the efalizumab group
(0.4 mg/dL and 46.8 mg/dL, respectively) than in the placebo group (0.1
mg/dL and 13.6 mg/dL, respectively) (See Table 91). Mean levels of both
C3a and C5a decreased during the study. The decrease was greater in the
placebo group for both analytes (data not shown). Shifts to elevated
levels of CRP, fibrinogen, C3a, and C5a were all observed at rates
approximately 10% higher in subjects receiving efalizumab compared with
those receiving placebo. All of these markers show mean changes
consistent with higher inflammation in the efalizumab-treatment group.
The clinical significance of these changes in markers of inflammation is
not known.

Table 91 C- Reactive Protein (mg/dL) Mean Changes from Baseline

  ---------------------- ---------------- ---------------- ----------------
  Treatment Group        Baseline         Day 84 (min-max) Change (max)
                         (min-max)                         

  Placebo (N=216)        0.6 (0.4-8.9)    0.7 ( 0.4-7.0)   0.09 (6.6)

  Efalizumab             0.6 (0.4-5.4)    1.0 (0.4-22)     0.40 (22)
  (1.0mg/kg/wk) (N=425)                                    
  ---------------------- ---------------- ---------------- ----------------

# SUMMARY OF SAFETY 

-   Serious adverse events occurred at a comparable incidence in the two
    treatment groups, 2.2% in efalizumab-treated patients vs. 1.7% in
    placebo-treated patients.

-   Serious infections

    -   There has been a safety signal for serious infections in the
        controlled portion of clinical trials with efalizumab. The
        incidence of serious infection in the first exposure of the
        controlled studies was 0.4% for efalizumab (sepsis, pneumonia,
        cellulitis, gastroenteritis) and 0.1% for placebo
        (gastroenteritis).

    -   Some of these infections have had atypical and life-threatening
        courses (vertebral Staphyloccal osteomyelitis with sepsis) and
        have required prolonged courses of antimicrobial therapy.

    -   One opportunistic infection, *Legionella* pneumonia, has been
        reported in an efalizumab-treated patient.

-   Malignancies

    -   There is no clear evidence of increased risk of malignancy, but
        the numbers are small. Based upon the immunosuppressive action
        of efalizumab, further study is needed.

    -   There have been two cases of lymphoproliferative malignancies in
        clinical trials of efalizumab.

    -   The incidence of non-melanoma skin cancer was similar in
        efalizumab-treated patients vs. placebo (1.12% and 1.08% per 100
        subject years, respectively). The incidence of non-melanoma skin
        cancer was higher in efalizumab-treated subjects than in the
        external reference cohort. The difference may represent
        ascertainment bias.

    -   The point estimates for malignant melanomas and solid tumors in
        efalizumab-treated subjects are within the range expected based
        on external cohorts.

-   Psoriasis-related adverse events

    -   An increased incidence of psoriasis-related adverse events in
        placebo-controlled portions of clinical trials was seen in
        efalizumab-treated patients.

    -   Serious and life-threatening psoriasis-related adverse events
        including psoriasis variants have occurred with a frequency that
        is greater than placebo.

    -   Such adverse events have occurred during treatment as well as
        following discontinuation of efalizumab.

    -   Further study is needed to assess how to identify patients at
        risk of psoriatic flare and manage these patients appropriately.

-   Thrombocytopenia

    -   There have been eight cases of clinically significant
        thrombocytopenia, (serious and/or with platelet counts of less
        than 50,000 cells per ul) among efalizumab-treated patients.

    -   Thrombocytopenia associated with efalizumab appears to be
        immune-mediated. Treatment with systemic corticosteroids results
        in improvement in platelet counts. In some cases, where systemic
        corticosteroids were withdrawn, the thrombocytopenia recurred.
        Where performed, bone marrow biopsies have shown normal
        maturation indicating a peripheral consumption or sequestration
        of platelets.

-   Arthritis-related adverse events

    -   Arthritis-related adverse events have occurred during treatment
        with efalizumab and have occasionally been serious.

-   Inflammatory/ Autoimmune-related adverse events

    -   Other rare, unexpected cases of potentially autoimmune adverse
        events- e.g. transverse myelitis, pneumonitis, and
        arthritis-have occurred in association with
        efalizumab-treatment.

    -   One case of a serum sickness-like illness has occurred in an
        efalizumab-treated patient.

-   Severe adverse events occurred at a rate of 10% in
    efalizumab-treated patients, nearly twice that seen in the
    placebo-treated group.

-   Dose-related acute adverse events (e.g. fever, headache, nausea,
    vomiting, meningismus) occur after the first administration of
    therapeutic doses of efalizumab. The incidence of these events is
    lessened by the use of a subtherapeutic "conditioning dose" (0.7
    mg/kg) as first dose. In some cases patients have had serious
    adverse events, e.g. aseptic meningitis, that have shown a temporal
    relationship to initiation of dosing despite the use of a
    conditioning dose.

-   Laboratory abnormalities

    -   Inflammation-associated laboratory analytes were higher in
        efalizumab-treated patients as compared to placebo. These
        included C reactive protein, fibrinogen and C3a and C5a.

    -   Hematologic changes included increases in mean total white blood
        cell counts, approximate doubling of mean lymphocyte counts and
        smaller degrees of elevations in absolute eosinophil and
        neutrophil counts.

    -   Elevations in alkaline phosphatase levels which are mostly
        unassociated with elevations in other hepatic tests. Both the
        intestinal and hepatic fractions are shown to be elevated. Other
        liver function tests (e.g.transaminases) have been also elevated
        in efalizumab-treated patients compared to placebo.

    -   Efalizumab has been associated with anti-efalizumab antibody
        (HAHA) in 6.3% of patients. Injection site reactions may be
        associated with HAHA in some patients. The clinical association
        of HAHA with other adverse events is under investigation.

# USE OF EFALIZUMAB IN SPECIAL POPULATIONS

See Appendix 2 for the use of efalizumab in special populations.

# CONCLUSIONS: EFFICACY AND SAFETY OF EFALIZUMAB FOR THE TREATMENT OF PATIENTS WITH MODERATE TO SEVERE PSORIASIS 

Patient population and efficacy outcomes:

Efalizumab has been studied in four efficacy trials in patients with
moderate-to-severe stable, plaque psoriasis. Patients studied have had
long-standing psoriasis (median 19 years), and 66% of patients have had
a history of systemic therapy for psoriasis. The median PASI score was
19 and median body surface area involvement was 30%.

The treatment effect (proportion of PASI 75% responders) for efalizumab
(1mg/kg/wk for 12 weeks SC) ranges from 18% to 37% depending on the
study. Responses according to physician's static global assessment
(19%-26%) and PASI 50 criteria (36%-46%) support the primary efficacy
endpoint.

Efalizumab remains active during an extended treatment period. In
patients who responded to 12 weeks of therapy with efalizumab, 77%
maintain full clinical response during an additional 12-week treatment
period.

When used to retreat responders who relapse off-treatment (loss of 50%
of efalizumab treatment effect) efalizumab has shown limited ability to
recapture response. Only about one third of patients respond upon
retreatment.

With continuous treatment for an additional contiguous 12-week treatment
period, an additional proportion of responders were captured (11-14%)
who were non-responders to the first treatment period.

Safety Assessments:

-   No deaths in psoriasis trials have been linked causally to the use
    of efalizumab.

-   Malignancies in the first exposure, placebo controlled portion of
    trials were few (n=4) and were not higher in in efalizumab-treated
    patients relative to control or to external cohorts. However, the
    numbers of cases are too small to make any definitive conclusions
    with regard to cancer risk.

-   There is no apparent increase in the incidence of NMSC in
    efalizumab-treated patients compared to placebo. However, the
    numbers are too small to assess the potential for increased risk due
    to efalizumab.

-   Serious infections have been reported in the first exposure of
    controlled clinical trials in a higher proportion of
    efalizumab-treated patients than placebo (0.4% vs. 0.1%). One
    opportunistic infection was observed, *Legionella* pneumonia. Other
    serious infections have consisted of severe local infections
    complicated by sepsis and seeding of distal sites.

-   Of the 2589 subjects treated with SC efalizumab,19 (0.7%) had a
    serious adverse event of psoriasis (including psoriatic erythroderma
    and pustular psoriasis). In the first exposure of controlled
    clinical trials of efalizumab, adverse events of psoriasis occurred
    in more subjects receiving efalizumab (2.4%, n=22) than placebo
    (1.1%, n=5).

```{=html}
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-   Thrombocytopenia consisting of platelets \< 50,000 cells/cmm
    occurred in a total of 8 efalizumab-treated patients. Clinical
    response to treatment with systemic corticosteroids suggests an
    immune-mediated thrombocytopenia. One patient had clinically
    significant bleeding requiring hospitalization.

-   Rare cases of serious inflammatory and/or potentially autoimmune
    events (e.g. transverse myelitis, pneumonitis, idiopathic hepatitis,
    serum sickness) have occurred in efalizumab-treated patients.

-   Laboratory abnormalities

    -   Inflammation-associated laboratory analytes were higher in
        efalizumab-treated patients as compared to placebo. These
        included C reactive protein, fibrinogen and C3a and C5a.

    -   Hematologic changes included increases in mean total white blood
        cell counts, approximate doubling of mean lymphocyte counts and
        smaller degrees of elevations in absolute eosinophil and
        neutrophil counts.

    -   Elevations in alkaline phosphatase levels which are mostly
        unassociated with elevations in other hepatic tests. Both the
        intestinal and hepatic fractions are shown to be elevated.

-   Efalizumab has been associated with anti-human antibody (HAHA) in
    6.3% of patients. There is no apparent decrease in clinical efficacy
    associated with HAHA positivity. The clinical significance with
    regard to safety is under investigation.

[]{.mark}

[]{.mark}

[]{.mark}

[]{.mark}

# APPENDIX 1: AUDIOLOGIC ASSESSMENTS

## Audiology

Audiologic testing was performed in three studies (HUPS254, HUPS256,
ACD2058g) after 1 subject in the Phase 2 study (HUPS252) experienced a
serious adverse event of transient unilateral hearing loss. All
audiologic testing was performed in studies using XOMA efalizumab.

The criteria for meaningful threshold change in one ear relative to a
pretreatment, baseline assessment were the same in all studies as
follows:

• ≥ 20-dB Change at any one frequency

• ≥15-dB Change at any two frequencies

• ≥ 10-dB Change at any three frequencies

These criteria were used in the 1997 Anti-Infectives Drugs Advisory
Committee Meeting

review of tobramycin. An increase in decibels (dB) indicated worsening,
and a decrease

in decibels indicated improvement in hearing threshold.

Audiologic testing by air and bone conduction was performed by a
certified audiologist prior to study drug administration and at the end
of the FT, RT, and ET periods. Frequencies from 500 Hz to 8000 Hz were
routinely assessed. If the audiologist had equipment and training for
performance of high-frequency testing up to 16,000 Hz, this assessment
was also conducted. The baseline audiogram was obtained up to 14 days
prior to FT Day 0 and prior to study drug administration. A second
audiogram was obtained within ±7 days of FT Day 84. Subjects who were
responders at FT Day 84 entered the OB period, and when relapse
occurred, began the RT period. These subjects were scheduled to have a
third audiogram obtained ±7 days of RT Day 84. Subjects who were partial
responders or non-responders at FT Day 84 were followed during the ET
period when a third audiogram was obtained within ±7 days of ET Day 84.
Retests were to be conducted after 2 weeks for any subject with a
significant threshold shift, as defined in the Audiology Manual for
Study ACD2058g. Determination of a significant threshold shift was made
at the FT Day 84, the ET Day 84, and the RT Day 84 visits.

At screening, subjects were asked about their hearing history. Questions
included whether they had experienced a hearing loss in the previous
year, had experienced tinnitus, had been diagnosed with hearing
problems, had previous surgery or trauma to the ear, had frequent
exposure to loud noises, and whether their employer required periodic
hearing tests. If hearing problems were diagnosed, six conditions were
ascertained, including noise exposure.

A decrease in threshold (dB) at a frequency in either ear represented a
potential improvement in hearing at that frequency; an increase in
threshold (dB) at a frequency in either ear represented a potential
worsening in hearing. For any of the criteria listed above, a worsening
in one ear took precedence over an improvement in the same or in the
other ear. Changes in values by bone conduction were not considered part
of the "significant threshold shift" determination.

Based on the criteria above, a subject was classified as:

• "Worsened" if the subject's hearing was worse by any one individual

criterion

• "Improved" if the subject's hearing was improved by any one individual

criterion and had not been classified as "worsened"

• "Unchanged" otherwise

####  {#section-7 .unnumbered}

The tables below summarize the changes measured by audiologic tests.

Table 92 Study HUPS254:Treatment-Emergent Changes in Audiogram Testing

  ---------------------------- ------------------- -----------------------
                               Hearing Test Result 

  Dose Group                   Improved            Worsened

  Group C (n=15) 1.0 mg/kg/wk  1 (6.7%)            1 (6.7%)
  SC                                               

                                                   

  Group E ^a^ (n=15) 2.0       5 (33.3%)           4 (26.7%)
  mg/kg/wk SC                                      

                                                   

  Total (n=30)                 6 (20.0%)           5 (16.7%)

  ^a^ One of the 16 subjects                       
  enrolled did not have                            
  audiograms performed.                            
  ---------------------------- ------------------- -----------------------

Table 93 Treatment-Emergent Changes in Audiogram Testing: Study HUPS256

  --------------------------- --------------------- ----------------------
                              Hearing Test Result   

  XOMA Efalizumab                                   

  Dose Group                  Improved              Worsened

  0.3 mg/kg/wk IV (n=5)       1 (20.0%)             0 (0)

  1.0 mg/kg/wk IV (n=10)      4 (40.0%)             1 (10.0%)

  All IV subjects (n=15)      5 (33.3%)             1 (6.7%)

  1.0 mg/kg/wk SC (n=20)      3 (15.5)              7 (35.0%)

  2.0 mg/kg/wk SC (n=19)      6 (31.6%)             6 (31.6%)

  4.0 mg/kg/wk SC (n=21)      6 (28.6%)             6 (28.6%)

  All SC efalizumab (n=60)    15 (25.0%)            19 (31.7%)

  Total (n=75)                20 (26.7%)            20 (26.7%)

  Note: The numbers of                              
  subjects who improved or                          
  worsened differs slightly                         
  between the                                       

  SCS and final report                              
  because of differences in                         
  analysis.                                         
  --------------------------- --------------------- ----------------------

Table 94 Treatment-Emergent Changes in Audiogram Testing: Study ACD2058g

  ---------------------------------------- -------------- ---------------
                                           Hearing Test   
                                           Result         

  Dose Group                               Improved       Worsened

  Placebo (n=156)                          8 (5.1%)       6 (3.8%)

  XOMA efalizumab 1.0 mg/kg/wk (n=148)     14 (9.5%)      11 (7.4%)

  XOMA efalizumab 2.0 mg/kg/wk (n=152)     13 (8.6%)      16 (10.5%)

  Total All XOMA efalizumab (n=300)        27 (9.0%)      27 (9.0%)
  ---------------------------------------- -------------- ---------------

The audiology testing in studies HUPS254, HUPS256 and ACD2058g showed no
evidence of efalizumab-induced hearing loss. Audiology testing was not
performed in the clinical studies that followed.

# APPENDIX 2 Use of Efalizumab in Special Populations

## Pediatric Studies

Genentech, Inc. asked for and received a deferral of its obligation to
carry out pediatric studies in the phase 3 program.

## Pregnancy

Pregnant/ lactating women were excluded from the clinical trials. Female
patients were monitored monthly with pregnancy testing and were
instucted to use contraception during and 3 months after the study. Nine
subjects became pregnant during clinical trial program. Study dosing was
immediately discontinued in these patients. Patients were followed
during pregnancy and for 6 months following birth.

*Table 95 Pregnancies that Occurred during the Efalizumab Psoriasis
Program*

  ------------- ----------------- -----------------------------------------
  Subject ID/                     

  Study         Treatment Group   Outcome and Comments

  15065/        1.0 mg/kg/wk XOMA Vaginal delivery of healthy infant.
                                  Eleven doses of

  ACD2058g      efalizumab        efalizumab were administered before
                                  discovery of

                                  pregnancy, 5 weeks from last dose.

  16004/        2.0 mg/kg/wk XOMA Delivery of healthy infant. Twelve doses
                                  of

  ACD2058g      efalizumab        efalizumab were administered before
                                  discovery of

                                  pregnancy, 10 weeks from last dose.

  81216/        2.0 mg/kg/wk XOMA Vaginal delivery of healthy infant.
                                  Twelve doses of

  ACD2059g      efalizumab        efalizumab were administered before
                                  discovery of

                                  pregnancy, 5 days from last dose.

  19505/        1.0 mg/kg/wk      Partner of male subject became pregnant.

  ACD2062g      Genentech         Pregnancy ended in spontaneous
                efalizumab        miscarriage.

                                  Thirty-one doses of efalizumab were
                                  administered

                                  before discovery of pregnancy, 9 weeks
                                  from last

                                  dose

  21406/        1.0 mg/kg/wk XOMA Vaginal delivery of healthy infant.
                                  Twelve doses

  ACD2062g      efalizumab        were administered in Study ACD2062g
                                  before

                                  discovery of pregnancy, 3 months from
                                  last dose

  27106/        2.0 mg/kg/wk      Estimated date of delivery was 28 January
                                  2002.

  ACD2243g      Genentech         Fourteen doses of efalizumab were
                efalizumab        administered

                followed by 1.0   before discovery of pregnancy, 7 days
                                  from last

                mg/kg/wk          dose. Subject was lost to follow-up.
                efalizumab        

  27130/        2.0 mg/kg/wk      Estimated date of delivery was 8 August
                                  2002.

  ACD2243g      Genentech         Thirty-eight doses of efalizumab were
                efalizumab        administered

                followed by 1.0   before discovery of pregnancy, 1 day from
                                  last

                mg/kg/wk          dose.
                efalizumab        

  27706/        2.0 mg/kg/wk      Subject voluntarily terminated pregnancy.

  ACD2243g      Genentech         
                efalizumab        

                followed by 1.0   

                mg/kg/wk          
                efalizumab        

  29208/        2.0 mg/kg/wk      Partner of male subject became pregnant
                                  and

  ACD2243g      Genentech         voluntarily terminated pregnancy.
                efalizumab        

                followed by 1.0   

                mg/kg/wk          
                efalizumab        

  547/          1.0 mg/kg/wk XOMA Estimated date of delivery as 28
                                  September 2002.

  ACD2389g      efalizumab        One dose of efalizumab was administered
                                  before

                                  the discovery of pregnancy, 4 weeks from
                                  last dose.

                                  Subject was lost to follow-up.

  2564130607/   4.0 mg/kg/wk XOMA Subject delivered healthy infant.

  HUPS256                         
  ------------- ----------------- -----------------------------------------

The data of use during pregnancy are limited. Thus far, there is no
evidence for fetal harm. Prospective studies are needed to further
evaluate the risks of use during pregnancy if the product is licensed.

## Safety and Efficacy in the Geriatric Population

The numbers of patients over the age of 65 are limited. However,
efficacy was not decreased among patients over the age of 65.

With regard to adverse events, of the two cases of hypothyroidism, both
were in patients older than 65. Skin related adverse events that were
more commonly seen in patients older than age 65 were psoriaisis,
pruritus and rash. For example, 4.8% of patients over 65 had
psoriasis-related adverse events vs. 2.9% of patients 41-64 and 1.9% of
patients 18-40. Otherwise, no clear safety signals were identified in
patients over the age of 65.

The table below shows the incidence rate for infections that required
hospitalization for patients by age group.

Table 96 Incidence Rate for Infections that Required Hospitalization by
Age Group Total Exposure All Subjects Treated with Efalizumab in
Psoriasis Studies

  --------------- ------- -------- --------------- ---------- --------------- ---------------
                          Number                   95% CI for Incidence Rate  95% CI for
                          of                       Observed   Per             Incidence Rate

  COSTART         Age     Events   Subject-Years   Number of  100             Per 100
  Preferred Term  Group                            Events     Subject-Years   Subject-Years

                                                                              

                                                                              

  \- TOTAL -      18 - 40 7        634.60          \[2.81,    1.10%           \[0.44, 2.27\]
                  yr                               14.42\]                    

                  41 - 64 18       942.06          \[10.67,   1.91%           \[1.13, 3.02\]
                  yr                               28.45\]                    

                  \>= 65  2        104.02          \[0.24,    1.92%           \[0.23, 6.95\]
                  yr                               7.22\]                     

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

Although the numbers are small, there is not an indication of an
increased incidence of hospitalization for infections among patients
over the age of 65.

Overall, no clear safety concerns arose with the use of efalizumab in
the geriatric population.

# APPENDIX 3: Phase 1 study protocols

## Selected Phase 1 Studies of Efalizumab in Patients with Psoriasis

The Phase 1 clinical studies were conducted in patients with psoriasis.
These studies are reviewed primarily from the perspective of clinical
safety and activity of efalizumab.

### Protocol HU9602

Xoma completed the first Phase 1 study of efalizumab, HU9602, in 1998.
This study investigated single intravenous (IV) doses ( 0.03, 0.1, 0.3,
0.6, 1.0, 2.0, 3.0 or 10.0 mg/kg) of efalizumab administered in a
dose-escalation manner to 31 subjects moderate to severe plaque
psoriasis. The subjects were enrolled at seven study centers. Of the 31
subjects, 4 subjects each were enrolled in the 0.03 and 0.1 mg/kg
groups, 8 were enrolled in the 0.3 mg/kg group, 1 was enrolled in the
0.6 mg/kg group, 8 were enrolled in the1.0 mg/kg group, 1 was enrolled
in the 2.0 mg/kg group, 4 were enrolled in the 3.0 mg/kg group and 1 was
enrolled in the 10.0 mg/kg group.

The subjects were to be followed for a minimum of 72 days after dosing.

Table 97 Summary of Most Frequently^a^ Reported Adverse Events Subjects
Evaluable for Safety

  -------------------------- -------------- ---------------- -------------
  Body System and            ≤ 0.3 mg/kg    ≥ 0.6 mg/kg      Combined

  Preferred term             N              N                N (%)

  Total Number of Subjects   16             15               31

  Body as a Whole            12             14               26 (84)

  Headache                   4              8                12 (39)

  Chills                     2              8                10 (32)

  Infection^b^               4              4                8 (26)

  Fever                      1              6                7 (23)

  Pain                       4              1                5 (16)

  Skin and Appendages        6              9                15 (48)

  Psoriasis^c^               5              6                11 (36)

  Pruritus                   4              1                5 (16)

  Digestive System           6              6                12 (39)

  Nausea                     0              5                5 (16)

  ^a^ Defined as any adverse                                 
  event reported by ≥ 5                                      
  subjects.                                                  

  ^b^ Infections included                                    
  cold symptoms (four                                        
  subjects), infection at                                    
  biopsy site (three                                         

  subjects), and infection                                   
  at left buttock suture                                     
  site (one subject).                                        

  ^c^ Indicated worsening of                                 
  psoriasis post treatment.                                  
  -------------------------- -------------- ---------------- -------------

Table 98 Summary of Serious Adverse Events

  -------------- --------- -------- ----- -------------- ------- ---------- -------------
  Dose           Subject   Gender   Age   Adverse Event  Onset   Severity   Relation:
  group(mg/kg)                                           (Day)              Study Drug

  0.6            031       F        35    Meningismus    0       Severe     Probable

  1.0            028       F        59    Carcinoma skin 36      Mild       Possible

  1.0            029^a^    M        55    Ataxia         11      Moderate   Possible

                                          Vertigo        11      Severe     Possible

                                          Nausea         11      Moderate   Possible

                                          Vomiting       11      Severe     Possible

                                          Nystagmus      12      Mild       Possible

  1.0            007       M        51    Aseptic        0       Moderate   Probable
                                          meningitis                        

  3.0            010       M        56    Chills         0       Moderate   Probable

                                          Hypertension   0       Moderate   Probable

                                          Fever          0       Moderate   Probable

  10.0           013       M        28    Vomiting       0       Severe     Probable
  -------------- --------- -------- ----- -------------- ------- ---------- -------------

There were no deaths in the study. Fever was commonly reported within 24
hours after completion of infusion. A dose-related incidence and
severity of headache, chills, fever and nausea was observed.

Infusion reactions had not been observed in a safety study conducted in
chimpanzees, a species that shares a similar binding affinity for
efalizumab as humans, after administration of up to 40 mg/kg efalizumab.
However, adverse side effects, including fever, headache and nausea,
were seen in the several hours after the first intravenous infusion of
efalizumab in psoriasis patients. Body temperature began to increase
within 2 hours after the infusion, and returned to the normal range
within 24 hrs. In addition, white blood cell counts were elevated within
8 hours of infusion and increased expression of the activation marker
CD69 was observed on a subpopulation of circulating T cells. The
circulating CD69-positive T cells do not seem to express CD25,
suggesting that they are not fully activated. Plasma samples collected
after efalizumab administration indicated elevated levels of TNF-α, IL-6
and the acute phase proteins CRP and LBP within the first 48 hours of
dosing. Plasma TNF-α was detected in some patients 2 hours after
infusion, but showed no correlation with dose level or severity of
adverse events. Adverse symptoms and the associated neutrophil counts
and CD69 expression usually subsided after the first 48 hours, even when
plasma levels of efalizumab remained relatively high. In subsequent
studies where efalizumab was administered multiple times on a weekly
basis, adverse events were most common after the first dose hence the
phenomenon was called a "first-dose" effect. The first dose response may
be initiated by activation of cells of the monocytic/macrophage lineage.
Activation of macrophages in vitro could be induced by immobilized
efalizumab..

*Reviewer's comments*

It was concluded that efalizumab was poorly tolerated at doses needed to
achieve target serum levels of drug. The repeat-dosing studies would be
designed to achieve these safety objectives: to find an initial
tolerable dose of efalizumab and determine if upon repeated dosing the
infusion reactions continued or worsened. The starting dose level for
the study would be conservative to take into account the potential for
additive toxicity of repeated dosing. The hypothesis would also be
tested that the initial infusion reaction would induce tolerization and
would permit ratcheting up to the optimal paharmacologic dose. This lead
to the dev of an initial low "tolerization dose." Treatment with
acetaminophen or nonsteroidal anti-inflammatory medications was allowed
in the clinical trials for management of these acute adverse events.

### Protocol HUPS249

Another Phase 1 study (HUPS249) investigated multiple IV doses (0.1-1.0
mg/kg/wk), which were also administered in a dose-escalation manner.

This study was to examine the safety, immunogenicity, and tolerability
of multiple doses of efalizumab in subjects with moderate to severe
plaque psoriasis; to determine the pharmacokinetics and pharmacodynamics
of efalizumab; and to determine the in vitro and in
vivoimmunosuppression correlates to drug dose levels.

Reviewer\'s comment:

Following the Phase 2 study (HUPS252), a transition was made to
subcutaneous (SC) dosing.

### Protocol HUPS254 

#### Study Title

"A Single-dose and Multiple-dose, Escalating-dose Study to Evaluate the
Safety,

Pharmacokinetics, and Biological Activity of Subcutaneously Administered
hu1124

(Efalizumab) in Subjects with Moderate to Severe Plaque Psoriasis"

#### Study Objectives 

The objectives of this study were as follows:

To evaluate the safety, immunogenicity, and tolerability of a single
dose and

multiple doses of efalizumab administered by subcutaneous injection to
subjects

with moderate to severe plaque psoriasis

To determine the pharmacokinetics and pharmacodynamics of efalizumab.

#### Study Design

A Phase I study (HUPS254) evaluated the safety, PK, and PD of multiple
SC doses (0.5--2.0 mg/kg/wk) administered for 8 weeks in a
dose-escalation manner. For groups C-E, the study employed both an
inter-patient dose escalation (escalation between dose groups and an
intra-patient dose escalation (higher maintenance doses after an intial
"tolerization" dose.

At least 56 subjects were to receive subcutaneous injections of
efalizumab

administered as a single dose of 0.3 mg/kg or as escalating multiple
doses of 0.5-2.0 mg/kg.

The dose groups evaluated in this study were:

0.3 mg/kg administered as a single dose (Group A),

0.5 mg/kg administered weekly for 8 weeks (Group B),

0.5 mg/kg escalated to 1.0 mg/kg (Group C and C.1),

0.7 mg/kg escalated to 1.5 mg/kg (Group D),

1.0 mg/kg escalated to 2.0 mg/kg (Group E and E.1) administered weekly
for 8 weeks.

Subjects in the single-dose group were followed for a minimum of 28 days
and subjects in the multiple-dose groups were followed for a minimum of
91 days.

Subjects in Groups C.1 and E.1 had extra target lesion and hearing
assessments.

*Reviewer\'s comment:*

*In the phase 1 studies, the adverse events included facial, vestibular
and auditory nerve impairment and meningeal irritation. In addition to
careful neurologic assessments, auditory testing was added to assess the
potential for development of subclinical ototoxicity.*

#### Results and Discussion

Safety:

The total proportion of patients experiencing a drug-related adverse
event was 58%. The most frequently reported adverse events were headache
(19/57 \[33%\]), pain (14/57 \[25%\]), rhinitis (11/57 \[19%\]),
leukocytosis (10/57 \[18%\]), pharyngitis (10/57 \[18%\]), increased
cough (9/57 \[16%\]), nausea (7/57 \[12%\]), chills (6/57 \[11%\]), and
myalgia (6/57 \[11%\]). There was only one adverse event (peripheral
edema) in the single-dose group. Acute adverse events of fever,
headache, nausea, chills, and myalgia within 48 hours after study drug
administration were reported by 21/57 (37%) of the subjects.

One (2%) subject in the study (Subject 22 in the 1.0-2.0 mg/kg group)
experienced a serious adverse event. The serious adverse event of kidney
calculus was severe in nature and considered to be unrelated to the
study drug.

Audiology tests were performed for the 31 subjects in Groups C.1
(0.5-1.0 mg/kg) and E.1 (1.0-2.0 mg/kg). The hearing abnormalities
observed during this study were not consistent with a pattern of
ototoxicity because improvements in hearing were observed in some
subjects at the same time as deteriorations in hearing, and because
deteriorations in hearing were not consistently evident in the higher
sound frequencies. One (2%) subject experienced a hearing-related
adverse event (decreased hearing secondary to impacted cerumen), which
was considered to be unrelated to the study drug.

The proportion of subjects who experienced an infection-related adverse
event was 75% in the 0.5 mg/kg group, 24% in the 0.5-1.0 mg/kg group,
17% in the 0.7-1.5 mg/kg group, and 58% in the 1.0-2.0 mg/kg group. The
most frequently reported infection-related adverse events were rhinitis,
pharyngitis, and increased cough. Additionally, two subjects (4%) in the
0.5-1.0 mg/kg group experienced *Herpes simplex* infections.

The incidence of CMV disease and evidence of CMV reactivation was
evaluated in this study because CMV disease is known to increase in
subjects who receive immunosuppressive medications. One subject
developed a new positive CMV IgM response at Day 91, having had a
negative CMV IgM response at screening. This subject had a positive IgG
titer at baseline and did not experience any clinical signs or symptoms
of CMV disease.

*Reviewer\'s comment:*

*The report does not state whether the patient had a symptomatic
illness.*

Lymphocyte counts approximately doubled within 2--7 days after the first
dose of study drug in the multiple-dose groups. No increase was observed
in the single-dose group. The mean proportion of B and T lymphocytes
remained consistent throughout the study; however, a significant
decrease in the proportion of NK cells was noted from a pretreatment
level of 10% to approximately 6% after Day 14. The average CD11a
expression on circulating T lymphocytes decreased by 70-80% within 2-3
days after treatment in all dose groups, and a small increase in CD69
expression was observed. Efalizumab binding sites were not saturated in
the single-dose group, but were generally more than 95% saturated in the
multiple-dose groups during treatment. Lymphocyte counts, CD11a and CD69
expression, and available binding sites returned to pretreatment levels
by Day 91 in all treatment groups; however, the mean percentage of NK
cells had not returned to pretreatment levels.

Antibody response to the study drug was assessed in 53/57 patients in
the study. A positive response (4.7 ng/mL equivalents/mL) was detected
in 1/53 of the subjects (1.0--2.0 mg/kg dose group). Competition studies
indicated the response was anti-idiotypic in nature. The positive
response was not associated with any adverse events

that would be expected during immune complex formation and deposition.

PK results:

In the multiple-dose groups, the average peak levels after the last dose
were 4.7 µg/mL for the 0.5 mg/kg group, 7.4 µg/mL for the 0.5-1.0 mg/kg
group, 20 µg/mL for

the 0.7-1.5 mg/kg group, and 22 µg/mL for the 1.0-2.0 mg/kg group.
Average

bioavailability (compared to IV administration) varied between 39.0% and
76.0% among the multiple-dose groups, with an overall average
bioavailability of 51% ± 32% (mean ± sd, n = 41). In the single-dose
group, the peak level was below the level of detection and
bioavailability was not applicable for a single dose.

### Protocol HUPS256

[Study Title]{.underline}

An Open-Label, Extended-Duration, Multiple-Dose Study to Evaluate the
Safety, Pharmacokinetics, and Biological Activity of Intravenously and
Subcutaneously Administered hu1124 in Subjects with Moderate to Severe
Plaque Psoriasis

#### Study Objectives

This Phase 1 study evaluated the safety, efficacy, PK, and PD of
multiple IV or SC doses (0.3--1.0 mg/kg/wk IV and 1.0--4.0 mg/kg/wk SC)
administered for 12 weeks.

In addition, it evaluated the safety, pharmacokinetics, immunogenicity,
and tolerability of 12 multiple doses of efalizumab administered weekly
by subcutaneous injection.

#### Protocol 

Eligible patients were required to have a minimum PASI score of 12 and a
minimum BSA of 15%.

For the intravenous phase, 16 patients were assigned to a dose group.
The dose groups

evaluated in this phase of the study were 0.3 mg/kg or 0.3--1.0 mg/kg
administered weekly for 12 weeks.

For the subcutaneous phase, a total of 61 subjects were assigned to a
dose group. The doses evaluated were: 0.7-1.0 mg/kg, 0.7-2.0 mg/kg, and
0.7-4.0 mg/kg weekly for 12 weeks.

All subjects were to be followed for up to Day 180.

#### Outcome Measures

-   PGA and PASI scores at Day 84 were compared with baseline.

-   Additionally, arthritis symptoms and psoriatic itching evaluations
    were performed.

#### Clinical and Laboratory Assessments

-   Safety assessments included: adverse events, hearing assessments,
    clinical laboratory assessments, physical and neurological
    examinations, and pre- and post-treatment vital signs.

-   Immunologic activity was assessed by analyzing lymphocyte
    subpopulations by flow cytometry and testing for human
    anti-humanized antibody (HAHA) response. Immunologic recovery
    assessments for the reconstitution of CD11a on T lymphocytes
    compared with baseline measurement were performed; patients were to
    be monitored every 20 to 30 days up to 90 days after the final visit
    until recovery of ≥ 75% expression of CD11a.

-   The pharmacodynamic assessments were also performed.

#### Results and Discussion

#### Intravenous Phase

A total of 16 subjects with moderate to severe plaque psoriasis were
enrolled at six study

centers. Of these 16 subjects, 6/16 received 12 weekly doses of 0.3
mg/kg and 10/16 received 12 weekly doses of 0.3-1.0 mg/kg. The majority
of subjects were male 9/16 and Caucasian 14/16. Subjects ranged in age
from 21 to 70 years of age and from 63 to 119 kg in weight. Median
baseline BSA affected by psoriasis ranged were 27.1 and 37.5, and the
median baseline PASI scores were 16.8 and 20.6. Five of 16 patients had
previous exposure to efalizumab. All subjects were evaluated for safety
and efficacy.

#### Subcutaneous Phase

A total of 61 subjects with moderate to severe plaque psoriasis were
enrolled at 11 study

centers. Of these subjects, 20/61 received a single conditioning dose of
0.7 mg/kg followed by 11 weekly doses of 1.0 mg/kg, received 12 weekly
doses of 0.7--2.0 mg/kg, 20/61 (33%) received a single conditioning dose
of 0.7 mg/kg followed by 11 weekly doses of 2.0 mg/kg, and 21/61 (34%)
received a single conditioning dose of 0.7 mg/kg followed by 11 weekly
doses of 4.0 mg/kg. The majority of subjects were male 41/61 and
Caucasian 51/61. Subjects ranged in age from 21 to 71 years of age and
from 65 to 123 kg in weight. Median BSA affected by psoriasis ranged
from 25.3 to 28.5, and the median baseline PASI scores ranged from 17.6
to 20.6.

The most frequently reported adverse events (reported by at least 10% of
subjects) are tabulated below.

Table 99 Summary of Most Frequently Reported Drug-related Adverse Events
in IV Groups (HUPS256)

  -------------------- ---------------- ---------------- ----------------
  Body System          0.3 mg/kg        0.3-1.0 mg/kg    Total Combined

                       (N = 6)          (N = 10)         (N = 16)

                       n (%)            n (%)            n (%)

  Subjects Reporting   6 (100)          10 (100)         16 (100)
  at Least One Drug                                      
  --Related AE                                           

                                                         

  Body as a Whole      5 (83)           5 (50)           10 (63)

  Headache             2 (33)           3 (30)           5 (31)

  Pain                 2 (33)           1 (10)           3 (19)

  Asthenia             2 (33)           0                2 (13)

  Chills               0                2 (20)           2 (13)

  Skin and Appendages  2 (33)           6 (60)           8 (50)

  Psoriasis            1 (17)           2 (20)           3 (19)

  Pruritus             1 (17)           1 (10)           2 (13)

  Urticaria            0                2 (20)           2 (13)

  Hemic and Lymphatic  0                3 (30)           3 (19)

  Lymphadenopathy      0                2 (20)           2 (13)

  Respiratory          2 (33)           1 (10)           3 (19)

  Rhinitis             1 (17)           1 (10)           2 (13)

  Digestive            1 (17)           1 (10)           2 (13)

  Nausea               1 (17)           1 (10)           2 (13)
  -------------------- ---------------- ---------------- ----------------

Acute events of headache, nausea, and chills within one day after study
drug

administration were reported for 7/16 (44%) of the subjects. Two of the
sixteen subjects (13%) experienced at least one hearing-related adverse
event. One of these subjects, with decreased hearing as a result of
impacted cerumen, was considered to have hearing loss unrelated to the
study drug. The other subject experienced two incidences of vertigo
which were possibly related to the study drug, but resolved within 5
hours.

### Protocol HUPS252

#### Study Title

A Double-blind, Placebo-controlled, Multi-center Phase 2 Study to Assess
the Safety,

Biological Activity, and Efficacy of hu1124 (Efalizumab) in Patients
with Moderate to

Severe Plaque Psoriasis

#### Study Objectives

The study objective were to evaluate

-   the safety of multiple dosing with efalizumab when administered to
    subjects with moderate to severe plaque psoriasis

-   the pharmacodynamic effects of 8 weekly intravenous treatments with
    efalizumab on the expression of CD11a and skin histology, as
    compared with placebo; and

-   the efficacy of 8 weekly treatments with efalizumab on the severity
    of psoriasis as compared with placebo.

###  {#section-8 .unnumbered}

#### Study Design

This was a Phase 2, double-blind, multiple-dose, placebo-controlled,
multi-center study to evaluate the effects of two different doses of
efalizumab compared with placebo in subjects with moderate to severe
plaque psoriasis. A total of 145 subjects with a minimum Psoriasis Area
and Severity Index (PASI) of 12 and at least 10% of BSA coverage by
psoriasis were randomized to receive 8 weekly intravenous infusions of
efalizumab or placebo at a 2:1 ratio within each of the two dose groups.
The first 31 subjects were randomized to receive either efalizumab
0.1mg/kg (n = 22) or placebo (n = 9). The remaining subjects were
randomized to receive either efalizumab 0.3 mg/kg (n = 75) or placebo (n
= 39). Subjects were to be followed for at least 91 days after the last
treatment.

#### Results and Discussion

A total of 145 subjects were randomized to receive treatment at 10 study
centers. One subject randomized to placebo in the 0.3 mg/kg treatment
group did not receive treatment. Of the 144 subjects randomized and
dosed, 22/144 (15%) of the subjects received efalizumab 0.1 mg/kg,
75/144 (52%) received efalizumab 0.3 mg/kg, and 47/144 (33%) received
placebo.

The majority of treated subjects were Caucasian (93%) and men (66%). The
subjects ranged from 21 to 72 years of age. Baseline BSA affected by
psoriasis ranged from 10.5 to 73%, with the median BSA affected by
psoriasis ranging from 18.2% to 26.5% across treatment groups. Baseline
PASI ranged from 11.4 to 57.2, with the median PASI ranging from 14.5 to
17.7 across treatment groups.

A dose-dependent improvement in the severity of psoriasis was noted by
primary outcome measures (PGA) and by secondary outcomes (PASI score).

Table 100 Reduction in PASI score at Endpoint (day 56)

+--------------------------+-------------+------------+---------------+
|                          | PASI score  |            | \% Reduction  |
|                          | Mean        |            | [+SD          |
|                          | [+SD]{      |            | ]{.underline} |
|                          | .underline} |            |               |
|                          |             |            |               |
|                          | [Baseline   |            |               |
|                          | Endpoint]{  |            |               |
|                          | .underline} |            |               |
+--------------------------+-------------+------------+---------------+
| Placebo (n=48)           | 16.2        | 1          | 16.5[+]{      |
|                          | [+]{.un     | 3.9[+]{.un | .underline}27 |
|                          | derline}4.4 | derline}27 |               |
+--------------------------+-------------+------------+---------------+
| Efalizumab 0.1 mg/kg     | 18.2[+]{.un | 14         | 24.2[+]{.u    |
| (n=22)                   | derline}6.7 | .2[+]{.und | nderline}28.9 |
|                          |             | erline}8.9 |               |
+--------------------------+-------------+------------+---------------+
| 0.3 mg/kg (n=75)         | 19.1[+]{.un | 10         | 43.8[+]{.u    |
|                          | derline}7.3 | .9[+8.4]{. | nderline}29.4 |
|                          |             | underline} |               |
+--------------------------+-------------+------------+---------------+

There were no deaths in the study. A total of 16 subjects discontinued
study drug prematurely. Of these, six discontinued treatment because of
adverse events. In the efalizumab 0.1 mg/kg group, 2/22 (9%) (headache,
worsening psoriasis). In the efalizumab 0.3 mg/kg group, 2/75 (3%)
(worsening psoriasis,hearing loss and tinnitus). In the placebo group,
2/47 (4%) (worsening psoriasis,dizziness).

Acute adverse events of headache, fever, chills, nausea, and vomiting
within 24 hours after study drug administration were higher in the
efalizumab 0.3 mg/kg group (42/75 \[56%\]) than the efalizumab 0.1 mg/kg
(8/22 \[36%\]) or the placebo (11/47 \[23%\]) groups.

Antibody response to efalizumab was detected in 1/19 (5%) of the
subjects in the efalizumab 0.1 mg/kg group, 10/70 (14%) of the subjects
in the efalizumab 0.3 mg/kg group, and none of the subjects in the
placebo group. Competition experiments indicated that the response was
anti-idiotypic in nature. These were low titer antibodies and were not
associated with any adverse events suggestive of immune complex
formation and deposition.

#### Safety

Table 101 Patients with Serious Adverse Events

+-----------+-----+---+---+------------+----+------+------+---------+
| Treatment | P   | S | A | Adverse    | O  | Seve | Rela | Number  |
|           | ati | e | g | Event      | ns | rity | tion |         |
|           | ent | x | e |            | et |      | to   |         |
+-----------+-----+---+---+------------+----+------+------+---------+
| Group     |     |   |   | \          | D  |      | S    | of      |
|           |     |   |   | [Preferred | ay |      | tudy | Doses   |
|           |     |   |   | Term\]     |    |      |      |         |
+-----------+-----+---+---+------------+----+------+------+---------+
|           |     |   |   |            |    |      | Dru  | R       |
|           |     |   |   |            |    |      | g^a^ | eceived |
+-----------+-----+---+---+------------+----+------+------+---------+
| 0.1 mg/kg | 462 | F | 5 | Fractured  | 36 | Se   | U    | 8       |
|           |     |   | 0 | r hand     |    | vere | nrel |         |
|           |     |   |   |            |    |      | ated |         |
+-----------+-----+---+---+------------+----+------+------+---------+
|           |     |   |   | \[bone     |    |      |      |         |
|           |     |   |   | frac       |    |      |      |         |
|           |     |   |   | tspontan\] |    |      |      |         |
+-----------+-----+---+---+------------+----+------+------+---------+
| 0.3 mg/kg | 422 | M | 5 | Psoriatic  | 61 | Se   | Poss | 8       |
|           |     |   | 5 | Arthritis  |    | vere | ible |         |
+-----------+-----+---+---+------------+----+------+------+---------+
|           |     |   |   | \[a        |    |      |      |         |
|           |     |   |   | rthritis\] |    |      |      |         |
+-----------+-----+---+---+------------+----+------+------+---------+
|           |     |   |   | Ca         | 1  | Se   | Poss |         |
|           |     |   |   | rpaltunnel | 22 | vere | ible |         |
+-----------+-----+---+---+------------+----+------+------+---------+
|           |     |   |   | syndrome   |    |      |      |         |
+-----------+-----+---+---+------------+----+------+------+---------+
|           |     |   |   | \[tenos    |    |      |      |         |
|           |     |   |   | ynovitis\] |    |      |      |         |
+-----------+-----+---+---+------------+----+------+------+---------+
| 0.3 mg/kg | 582 | M | 4 | Synovitis  | 20 | Se   | U    | 8       |
|           |     |   | 9 |            |    | vere | nrel |         |
|           |     |   |   |            |    |      | ated |         |
+-----------+-----+---+---+------------+----+------+------+---------+
|           |     |   |   | \[s        |    |      |      |         |
|           |     |   |   | ynovitis\] |    |      |      |         |
+-----------+-----+---+---+------------+----+------+------+---------+
| 0.3 mg/kg | 642 | M | 5 | Hearing    | 36 | Se   | Poss | 6^b^    |
|           |     |   | 4 | loss --    |    | vere | ible |         |
|           |     |   |   | lear       |    |      |      |         |
+-----------+-----+---+---+------------+----+------+------+---------+
|           |     |   |   | (sen       |    |      |      |         |
|           |     |   |   | sorineural |    |      |      |         |
+-----------+-----+---+---+------------+----+------+------+---------+
|           |     |   |   | hearing    |    |      |      |         |
|           |     |   |   | loss)      |    |      |      |         |
+-----------+-----+---+---+------------+----+------+------+---------+
|           |     |   |   | \[deaf\]   |    |      |      |         |
+-----------+-----+---+---+------------+----+------+------+---------+
| 0.3 mg/kg | 703 | M | 6 | Retros     | 1  | Mode | U    | 8       |
|           |     |   | 8 | ternalpain | 34 | rate | nrel |         |
|           |     |   |   |            |    |      | ated |         |
+-----------+-----+---+---+------------+----+------+------+---------+
|           |     |   |   | \[pain     |    |      |      |         |
|           |     |   |   | chest      |    |      |      |         |
|           |     |   |   | substern\] |    |      |      |         |
+-----------+-----+---+---+------------+----+------+------+---------+
| Placebo   | 239 | F | 3 | Gastr      | 1  | Se   | U    | 8       |
|           |     |   | 4 | oenteritis | 12 | vere | nrel |         |
|           |     |   |   |            |    |      | ated |         |
+-----------+-----+---+---+------------+----+------+------+---------+
|           |     |   |   | \[gastroe  |    |      |      |         |
|           |     |   |   | nteritis\] |    |      |      |         |
+-----------+-----+---+---+------------+----+------+------+---------+
| Placebo   | 419 | M | 2 | Psoriatic  | 1  | Se   | U    | 8       |
|           |     |   | 9 | arthritis  | 00 | vere | nrel |         |
|           |     |   |   |            |    |      | ated |         |
+-----------+-----+---+---+------------+----+------+------+---------+
|           |     |   |   | (Hands and |    |      |      |         |
|           |     |   |   | Feet)      |    |      |      |         |
+-----------+-----+---+---+------------+----+------+------+---------+
|           |     |   |   | \[a        |    |      |      |         |
|           |     |   |   | rthritis\] |    |      |      |         |
+-----------+-----+---+---+------------+----+------+------+---------+
| Placebo   | 464 | M | 6 | Fractured  | 38 | Mode | U    | 8       |
|           |     |   | 6 | r ribs     |    | rate | nrel |         |
|           |     |   |   |            |    |      | ated |         |
+-----------+-----+---+---+------------+----+------+------+---------+
|           |     |   |   | \[bone     |    |      |      |         |
|           |     |   |   | fract      |    |      |      |         |
|           |     |   |   | spontan\]  |    |      |      |         |
+-----------+-----+---+---+------------+----+------+------+---------+
| Placebo   | 641 | M | 4 | Chestpain  | 58 | Se   | Poss | 8       |
|           |     |   | 2 | (notyet    |    | vere | ible |         |
+-----------+-----+---+---+------------+----+------+------+---------+
|           |     |   |   | diagnosed) |    |      |      |         |
+-----------+-----+---+---+------------+----+------+------+---------+
|           |     |   |   | \[pain     |    |      |      |         |
|           |     |   |   | chest\]    |    |      |      |         |
+-----------+-----+---+---+------------+----+------+------+---------+
| ^a^ As    |     |   |   |            |    |      |      |         |
| judged by |     |   |   |            |    |      |      |         |
| the       |     |   |   |            |    |      |      |         |
| inve      |     |   |   |            |    |      |      |         |
| stigator. |     |   |   |            |    |      |      |         |
+-----------+-----+---+---+------------+----+------+------+---------+
| ^b^       |     |   |   |            |    |      |      |         |
| Patient   |     |   |   |            |    |      |      |         |
| 642 did   |     |   |   |            |    |      |      |         |
| not       |     |   |   |            |    |      |      |         |
| receive   |     |   |   |            |    |      |      |         |
| thefinal  |     |   |   |            |    |      |      |         |
| two doses |     |   |   |            |    |      |      |         |
| of study  |     |   |   |            |    |      |      |         |
| drug      |     |   |   |            |    |      |      |         |
|           |     |   |   |            |    |      |      |         |
| due to    |     |   |   |            |    |      |      |         |
| this      |     |   |   |            |    |      |      |         |
| adverse   |     |   |   |            |    |      |      |         |
| event.    |     |   |   |            |    |      |      |         |
+-----------+-----+---+---+------------+----+------+------+---------+

### Protocol ACD2389g

#### Study Title 

A Randomized, Open-Label, Single-Center, Two-Period Crossover Study in
Healthy, Adult Volunteers to Evaluate the Pharmacokinetic Comparability
and Safety of Single 1.0 mg/kg Subcutaneous Doses of XOMA-Manufactured
and Genentech-Manufactured Efalizumab (ACD2389g)

#### Study Objectives

The study's primary objective was to determine the pharmacokinetic (PK)
comparability of single, subcutaneous (SC) doses of XOMA and Genentech
efalizumab as measured by the area under the concentration--time curve
from time 0 until infinity (AUCinf). The goal of the study was to obtain
a 90% confidence interval on the relative bioavailability of Genentech
to XOMA efalizumab and to determine whether the interval was completely
within 80%--125%.

Study Design

Subjects were randomized in an equal ratio to one of two treatment
sequences: Genentech efalizumab on Day 0 of Period 1 with crossover to
XOMA efalizumab on Day 0 of Period 2 (GX Group) or XOMA efalizumab on
Day 0 of Period 1 with crossover to Genentech efalizumab on Day 0 of
Period 2 (XG Group). A single 1.0 mg/kg dose was administered
subcutaneously at Day 0 of each period. Each dose was followed by a
5-week sample collection period, during which serial blood draws were
taken for both PK and pharmacodynamic (PD) measurements. The total time
from screening to study completion was approximately 13 weeks.

A population of healthy volunteers was chosen to avoid concomitant
medications and co-existing disease state interactions. A 6-week washout
period was selected based on the expected half-life of approximately 7
days and previous clinical data demonstrating that CD11a expression
returns to baseline approximately 4 weeks after a single intravenous
(IV) dose of efalizumab.

#### Results and Discussion

Ninety-nine subjects were randomized in this study. A total of 81
subjects completed the study.

Of the 20 subjects who were not PK evaluable, 10 were randomized to the
XG group and 10 were randomized to the GX group, leaving 39 PK evaluable
subjects from the XG group and 40 subjects from the GX group for a total
of 79 PK evaluable subjects.

Overall, the treatment groups were comparable with regard to demographic
and baseline characteristics.

Pharmacokinetics:

**Table 102** Mean ±SD Efalizumab Pharmacokinetic Parameters

+-----------------------+-----------------------+-----------------------+
| Parameter             | XOMA Efalizumab       | Genentech Efalizumab  |
|                       |                       |                       |
|                       | (n=79)                | (n=79)                |
+-----------------------+-----------------------+-----------------------+
| Cmax (μg/mL)          | 4.1±2.0               | 4.9±2.0               |
+-----------------------+-----------------------+-----------------------+
| Tmax (day) a          | 3.5 (1.0--7.0)        | 3.5 (1.4--8.0)        |
+-----------------------+-----------------------+-----------------------+
| AUCt (μg day/mL)      | 32.6±18.9             | 43.6±24.5             |
+-----------------------+-----------------------+-----------------------+
| AUCinf (μg day/mL)    | 33.4±19.1             | 44.9±24.8             |
+-----------------------+-----------------------+-----------------------+
| Linear t1/2 (day)     | 5.0±2.1               | 5.6±2.4               |
+-----------------------+-----------------------+-----------------------+
| Nonlinear t1/2 (day)  | 1.7±1.6               | 1.7±1.7               |
+-----------------------+-----------------------+-----------------------+

The results of the study demonstrated that single 1.0 mg/kg SC doses of
Genentech efalizumab produced an approximately 30% higher exposure
(AUCinf) and an approximately 20% higher Cmax in healthy volunteers
compared with an identical dose of XOMA efalizumab. The
protocol-specified secondary outcome variables,AUCt and Cmax, were also
significantly higher after administration of the Genentech efalizumab
dose.

+---------+--------+---------+---------+----------+--------+--------+
|         | n      | Ge      |         | Ratio    | 90% CI |        |
|         |        | ometric |         |          |        |        |
|         |        | LS mean |         | GNE/Xoma |        |        |
|         |        |         |         |          |        |        |
|         |        | Xoma    |         |          |        |        |
|         |        | GNE     |         |          |        |        |
+---------+--------+---------+---------+----------+--------+--------+
| A       | 79     | 27.8    | 36.9    | 1.32     | 1.19   | 1.47   |
| UC~inf~ |        |         |         |          |        |        |
| (g     |        |         |         |          |        |        |
| ∙day/ml |        |         |         |          |        |        |
+---------+--------+---------+---------+----------+--------+--------+

The point estimate and confidence intervals were outside the
prespecified 80%--125% interval and therefore did not meet the criterion
for comparability.

This difference in exposure did not translate into differences in extent
or duration of PD activity (CD11a saturation and CD11a down-modulation
on T lymphocytes). XOMA and Genentech efalizumab induced a rapid
decrease in CD11a expression and available binding sites with maximal
decrease by day 2. This effect was maintained until day 14, when
efalizumab serum levels

decreased to \<1 g/mL . These PD effects appeared to be similar for all
cell types measured for both XOMA and Genentech (T lymphocytes, NK
cells, monocytes, and neutrophils).

Figure 8

![](media/image11.png){width="4.395833333333333in"
height="4.395833333333333in"}

No differences in safety including immunogenicity of the two products
were detectable in this small study.

Reviewer's comments.

This study was conducted at the request of the Agency. The sponsor
hypothesized that the cause of these observed differences in exposure
was related to differences in systemic bioavailability of the two
products. Differences in the formulation of the two products might
account for these differences; in particular the higher concentration of
surfactant (polysorbate 20) in the GNE formulation.

The 30% higher serum concentrations of GNE efalizumab did not raise
safety concerns strictly on the grounds of exposure given the available
clinical safety data that exceeded that exposure. The lack of
appreciable difference in the magnitude and duration of CD11a receptor
saturation and down-modulation induced by the Xoma and GNE products was
also interpreted as suggesting that the GNE product would not manifest
higher immunosuppressant clinical activity (including treatment
response). The sponsor and the agency agreed that an adequate safety
database would be required to demonstrate the safety of GNE efalizumab.
Whether or not the clinical safety data using Xoma efalizumab could be
supportive of the safety of GNE efalizumab would become a review issue.