![](media/image1.wmf)**Department of Health & Human Services [Public
Health Service]{.smallcaps}**

> **Food and Drug Administration**
>
> **Center for Biologics Evaluation and Research**
>
> **1401 Rockville Pike**
>
> **Rockville, MD 20852**

Division of Clinical Trial Design and Analysis

Date: April 18, 2003

**BRIEFING DOCUMENT ON SAFETY**

**BLA STN 103976/0**

**Genentech, Inc.**

**Omalizumab (Xolair)**

**(recombinant humanized monoclonal antibody to IgE)**

**for treatment of allergic asthma**

**Table of Contents**

  ------------------------------------------------------------- -- --------
  *Heading*                                                        *Page*

  **1. Introduction**                                              **4**

  A. Regulatory history                                            4

  B. Materials reviewed                                            4

  **2. Proposed Indication, dose and dose regimen**                **4**

  **3. Product background (chemistry, manufacturing,               **6**
  controls)**                                                      

  **4. Clinical background**                                       **6**

  **5. Summary of major safety observations**                      **8**

  A. Overview                                                      8

  B. Serious adverse events                                        10

  1\. Malignancy                                                   10

  2\. Anaphylaxis                                                  11

  C. Adverse events                                                12

  1\. Adverse events among all subjects in controlled studies      12

  2\. Adverse events among the geriatric population in             14
  controlled studies                                               

  D. Other observations                                            14

  1\. Clinical laboratory                                          14

  2\. Antibody formation                                           15

  **6. Preclinical studies**                                       **15**

  **7. Clinical studies overview**                                 **16**

  A. Exploratory Studies                                           16

  B. Major Studies                                                 17

  **8. Safety database composition**                               **19**

  A. Sample size                                                   19

  B. Baseline characteristics and drug exposure                    20

  C. In-study characteristics                                      22

  D. Subject disposition                                           23

  1\. Controlled studies                                           23

  2\. Uncontrolled studies                                         25

  **9. Serious adverse events**                                    **26**

  A. Deaths                                                        26

  B. Nonfatal serious adverse events                               26

  C. Neoplasia (malignant and benign)                              29

  1\. Malignancies                                                 29

  2\. Benign neoplasms                                             33

  **10. Adverse events**                                           **33**

  A. Adverse events by body system and preferred term              33

  B. Adverse events by severity                                    35

  C. Digestive, respiratory and female genitourinary AE            37

  1\. Digestive system adverse events, including appendicitis      37

  2\. Respiratory system adverse events                            39

  3\. Female genitourinary adverse events                          39

  D. Hypersensitivity adverse events                               40

  1\. Anaphylaxis                                                  40

  2\. Skin rash, including urticaria                               41

  3\. Urticaris with bronchospasm                                  42

  4\. Serum sickness                                               42

  E. Other immune-type adverse events                              43

  F. Bleeding-related AE and hemoglobin data                       43

  G. Injection site reactions/adverse events                       46

  **11. Laboratory results**                                       **48**

  A. Hematology                                                    48

  1\. Hemoglobin and leukocytes                                    48

  2\. Platelets                                                    48

  B. Blood chemistry                                               53

  1\. Liver tests                                                  53

  2\. Renal tests                                                  53

  **12. Antibody formation**                                       **54**

  **13. Retreatment data**                                         **54**

  **14. Pregnancy**                                                **55**

  **15. Drug-level effects and adverse events**                    **55**

  **16. Adverse events by drug exposure duration**                 **56**

  **17. Adverse events by demographic subsets / in-study           **57**
  characteristics**                                                

  **18. Summary**                                                  **58**

  19\. Appendix A: AE tables cited in text                         62

  20\. Appendix B: Narratives for subjects with                    69
  anaphylaxis/anaphylactoid AE                                     

  21\. Appendix C: Summaries of clinical study designs             70

  22\. Appendix D: Narratives for subjects with appendicitis       83

  23\. Appendix E: Narratives for subjects with malignancy         85

  24\. Appendix F: Laboratory data tables cited in text            93

  25\. Appendix G: Narratives for subjects with other AE           96
  ------------------------------------------------------------- -- --------

Abbreviations

  ------------- ---------------------------------------------------------
  *Acronym*     *Definition*

  AA            Allergic asthma

  AD            Allergic dermatitis

  AE            Adverse event

  BLA           Biological license application

  CV            Cardiovascular

  DB            Double blind

  ER            Emergency room

  GU            Genito-urinary

  ICS           Inhaled corticosteroids

  IV            Intravenous

  LLN           Lower limit of normal

  LTR           Leukotriene

  MDI           Metered dose inhaler

  MV            Mechanical ventilation

  OCS           Oral corticosteroids

  PAR           Perennial allergic rhinitis

  PC            Placebo controlled

  PI            Package insert

  PK            Pharmacokinetic

  SAR           Seasonal allergic rhinitis

  SAE           Serious adverse experience

  SC            Subcutaneous

  SEER          Surveillance, Epidemiology and End Results database

  SIR           Standardized incidence ratio

  STC           Standard therapy controlled

  ULN           Upper limit of normal
  ------------- ---------------------------------------------------------

**1. Introduction:**

This document is a summary of the safety information contained within
the Biological License Application (BLA) submitted to FDA by Genentech,
Inc for Omalizumab, a recombinant humanized monoclonal antibody proposed
for treatment of allergic asthma.

Omalizumab binds to human IgE at the same epitope as that of the high
affinity IgE receptor (FcεRI) on mast cells and basophils. This IgE
binding blocks IgE from binding to mast cells and basophils. Once bound
to Omalizumab, IgE is proposed to be cleared from the body by macrophage
endocytotic clearance. Although the proposed indication is for the
treatment of allergic asthma, the sponsor has performed a series of
clinical studies that examine the effect of Omalizumab upon patients
with allergic asthma (AA), seasonal allergic rhinitis (SAR), perennial
allergic rhinitis (PAR) and allergic dermatitis (AD). This review
encompasses the entire safety database, however the AA safety findings
form a special focus of this review.

**A. Regulatory history:**

The major milestones in the regulatory history of this BLA are
summarized in Table 1.

Table 1. Regulatory history

  ------------------------- ---------------------------------------------
  *Date*                    *Action*

  June 2, 2000              Original BLA submission

  July 5, 2001              FDA issued Complete Review Letter

  December 18, 2002         Sponsor submitted response to Complete Review
                            Letter
  ------------------------- ---------------------------------------------

Within the original BLA submission, the sponsor had sought licensure for
use of Omalizumab in the prophylaxis and treatment of asthma and SAR.
The July 5, 2001 Complete Review Letter from the FDA highlighted a
number of limitations within the original submission including the
limited size of the clinical safety database and the inability to
meaningfully assess certain safety signals. The letter noted that
substantially greater safety information was necessary in order to form
a judgement of the risks and benefits related to the proposed asthma
indication and that even greater amounts of clinical safety information
were necessary for the proposed SAR indication. In response to this
letter, the sponsor filed a December 18, 2002 BLA amendment (Complete
Response to Complete Review Letter) that included clinical data from
approximately three-fold more subjects exposed to Omalizumab than were
originally submitted in June, 2000. The December 18, 2002 Complete
Response also limited the proposed indication to AA.

**B. Materials reviewed:**

This review is focused upon the safety data contained in the June 2,
2002 and December 18, 2002 license application submissions as well as
the safety data submitted to the pertinent investigational new drug
applications.

**2. Proposed indication, dose and dose regimen:**

The information listed below are quotes from the proposed package insert
(PI).

Proposed Indication:

\"XOLAIR is indicated as maintenance therapy for the prophylaxis of
asthma exacerbations and control of symptoms in adults and adolescents
(12 years and above) with moderate to severe allergic asthma that is
inadequately controlled despite the use of inhaled corticosteroids.\"

Proposed regimen:

\"Xolair 150 to 375 mg is administered SC every 2 or 4 weeks. Doses (mg)
and dosing frequency are determined by baseline serum total IgE level
(IU/mL), measured before the start of treatment, and body weight (kg).\"
Table 2 duplicates the package insert\'s dose determination charts.

**Table 2. Dose determination charts from package insert**

+-------------+-------+------------+-----------+----------+---------+
|             | *     |            |           |          |         |
|             | *ADMI |            |           |          |         |
|             | NISTR |            |           |          |         |
|             | ATION |            |           |          |         |
|             | EVERY |            |           |          |         |
|             | 4     |            |           |          |         |
|             | WE    |            |           |          |         |
|             | EKS** |            |           |          |         |
+-------------+-------+------------+-----------+----------+---------+
| XOLAIR      |       |            |           |          |         |
| Doses       |       |            |           |          |         |
| (           |       |            |           |          |         |
| milligrams) |       |            |           |          |         |
| A           |       |            |           |          |         |
| dministered |       |            |           |          |         |
| by          |       |            |           |          |         |
| S           |       |            |           |          |         |
| ubcutaneous |       |            |           |          |         |
| Injection   |       |            |           |          |         |
+-------------+-------+------------+-----------+----------+---------+
| Every 4     |       |            |           |          |         |
| Weeks for   |       |            |           |          |         |
| Adults and  |       |            |           |          |         |
| Adolescents |       |            |           |          |         |
| (12 Years   |       |            |           |          |         |
| of Age and  |       |            |           |          |         |
| Older)      |       |            |           |          |         |
+-------------+-------+------------+-----------+----------+---------+
|             |       | with       |           |          |         |
|             |       | Allergic   |           |          |         |
|             |       | Asthma     |           |          |         |
+-------------+-------+------------+-----------+----------+---------+
|             |       |            |           |          |         |
+-------------+-------+------------+-----------+----------+---------+
| Baseline    | Body  |            |           |          |         |
| IgE         | W     |            |           |          |         |
|             | eight |            |           |          |         |
| (IU/mL)     | (kg)  |            |           |          |         |
+-------------+-------+------------+-----------+----------+---------+
|             | 30    | \> 60 − 70 | \> 70     | \> 80    | \> 90   |
|             | − 60  |            | − 80      | − 90     | − 150   |
+-------------+-------+------------+-----------+----------+---------+
| ≥ 30− 100   | 150   | 150        | 150       | 150      | 300     |
+-------------+-------+------------+-----------+----------+---------+
| \> 100− 200 | 300   | 300        | 300       | 300      |         |
+-------------+-------+------------+-----------+----------+---------+
| \> 200− 300 | 300   |            |           |          |         |
+-------------+-------+------------+-----------+----------+---------+
| \> 300− 400 |       | **ADMI     |           |          |         |
|             |       | NISTRATION |           |          |         |
|             |       | EVERY 2    |           |          |         |
|             |       | WEEKS**    |           |          |         |
+-------------+-------+------------+-----------+----------+---------+
| \> 400− 500 |       |            | **(SEE    |          |         |
|             |       |            | TABLE     |          |         |
|             |       |            | BELOW)**  |          |         |
+-------------+-------+------------+-----------+----------+---------+
| \> 500− 600 |       |            |           |          |         |
+-------------+-------+------------+-----------+----------+---------+

+---------------+-------+------------+----------+---+----------+---------+
|               | *     |            |          |   |          |         |
|               | *ADMI |            |          |   |          |         |
|               | NISTR |            |          |   |          |         |
|               | ATION |            |          |   |          |         |
|               | EVERY |            |          |   |          |         |
|               | 2     |            |          |   |          |         |
|               | WE    |            |          |   |          |         |
|               | EKS** |            |          |   |          |         |
+---------------+-------+------------+----------+---+----------+---------+
| XOLAIR Doses  |       |            |          |   |          |         |
| (milligrams)  |       |            |          |   |          |         |
| Administered  |       |            |          |   |          |         |
| by            |       |            |          |   |          |         |
| Subcutaneous  |       |            |          |   |          |         |
| Injection     |       |            |          |   |          |         |
+---------------+-------+------------+----------+---+----------+---------+
| Every 2 Weeks |       |            |          |   |          |         |
| for Adults    |       |            |          |   |          |         |
| and           |       |            |          |   |          |         |
| Adolescents   |       |            |          |   |          |         |
| (12 Years of  |       |            |          |   |          |         |
| Age and       |       |            |          |   |          |         |
| Older)        |       |            |          |   |          |         |
+---------------+-------+------------+----------+---+----------+---------+
|               |       | with       |          |   |          |         |
|               |       | Allergic   |          |   |          |         |
|               |       | Asthma     |          |   |          |         |
+---------------+-------+------------+----------+---+----------+---------+
|               |       |            |          |   |          |         |
+---------------+-------+------------+----------+---+----------+---------+
| Baseline IgE  | Body  |            |          |   |          |         |
|               | W     |            |          |   |          |         |
| (IU/mL)       | eight |            |          |   |          |         |
|               | (kg)  |            |          |   |          |         |
+---------------+-------+------------+----------+---+----------+---------+
|               | 30    | \> 60 − 70 | \> 70    |   | \> 80    | \> 90   |
|               | − 60  |            | − 80     |   | − 90     | − 150   |
+---------------+-------+------------+----------+---+----------+---------+
| ≥ 30− 100     | *     |            |          |   |          |         |
|               | *ADMI |            |          |   |          |         |
|               | NISTR |            |          |   |          |         |
|               | ATION |            |          |   |          |         |
|               | EVERY |            |          |   |          |         |
|               | 4     |            |          |   |          |         |
|               | WE    |            |          |   |          |         |
|               | EKS** |            |          |   |          |         |
+---------------+-------+------------+----------+---+----------+---------+
| \> 100− 200   |       | **(SEE     |          |   |          | 225     |
|               |       | TABLE      |          |   |          |         |
|               |       | ABOVE)**   |          |   |          |         |
+---------------+-------+------------+----------+---+----------+---------+
| \> 200− 300   |       | 225        | 225      |   | 225      | 300     |
+---------------+-------+------------+----------+---+----------+---------+
| \> 300− 400   | 225   | 225        | 300      |   | 300      |         |
+---------------+-------+------------+----------+---+----------+---------+
| \> 400− 500   | 300   | 300        | 375      |   | 375      |         |
+---------------+-------+------------+----------+---+----------+---------+
| \> 500− 600   | 300   | 375        |          |   | **DO NOT |         |
|               |       |            |          |   | DOSE**   |         |
+---------------+-------+------------+----------+---+----------+---------+
| \> 600− 700   | 375   |            |          |   |          |         |
+---------------+-------+------------+----------+---+----------+---------+

Once reconstituted, a vial of Omalizumab contains a 150 mg dose within
1.2 mL (125 mg/mL). For the maximum monthly dose of 750 mg, three
injections (a total of 3.0 mL) must be given every two weeks.

*Comment: Serum IgE normally accounts for a very small proportion of
total serum immunoglobulin concentration. Within one large
population*[^1]*, the average serum IgE concentration was estimated to
be 32 IU/mL. The upper limit of a \"normal\" serum IgE concentration may
reach 90 IU/mL*[^2]*. Most of the sponsor\'s multi-dose studies enrolled
only subjects with baseline serum IgE concentrations ≥ 30 IU/mL but ≤
700 IU/mL (Studies 006, 007, 008, 009, 010, IA04, 012, 014 and 011).
However, some studies allowed enrolled subjects with baseline IgE ≥ 30
IU/mL but ≤ 1300 IU/mL (Studies Q2143g, D01 and 013). In all the major
multi-dose studies, the Omalizumab doses did not exceed 750 mg/month. As
will be noted, one of the sponsor\'s exploratory multi-dose studies
(Study Q0694g), examined a higher Omalizumab dose than that proposed for
marketing.*

**3. Product background (chemistry, manufacturing, controls):**

Omalizumab is produced by a stably transfected Chinese hamster ovary
(CHO) cell line. The final drug product is a lyophilized formulation
that, upon reconstitution with Sterile Water for Injection (SWFI),
delivers a 150 mg dose in 1.2 mL for subcutaneous administration.

Formulation changes during the clinical development program included a
shift from a liquid solution to a lyophilized formulation, changes in
the reconstitution directions for the lyophilized formulation and
changes in the manufacturing following the completion of certain major
clinical studies. Early versions of Omalizumab were examined in pilot
studies that examined intravenous (IV), subcutaneous (SC) and
aerosolization administrations and culminated in the development of a
lyophilized product for SC administration. Certain changes in
manufacturing occurred during terminal product development. Biochemical
comparability data and clinical pharmcokinetic/pharmacodynamic were used
to support the findings that the definitive premarketing clinical
studies used an Omalizumab product comparable to that proposed for
marketing.

**4. Clinical background:**

The sponsor has performed clinical studies that primarily examine the
use of Omalizumab in two major clinical settings: AA and SAR. More
limited clinical studies examined the use of Omalizumab in PAR and AD.
These various manifestations of allergic disease are generally thought
to share certain common pathophysiological correlates. The most notable
of these correlates is the role of IgE. Indeed, the adjective,
\"allergic,\" is a qualifier that has been used synonymously with
\"IgE-mediated\" disease by many clinicians.[^3] The term \"atopy\" is
also commonly used to describe IgE-mediated diseases, diseases such as
AA, SAR, and AD. The presence of \"atopy\" is (generally) clinically
characterized by the presence of an immediate skin reaction response, an
IgE-mediated response, to a SC injection of a suspected allergen.
Consequently, certain \"allergic\" diseases may be loosely designated as
\"IgE-mediated\" diseases.

IgE-mediated diseases are thought to have a strong hereditary component
and studies have shown that certain genetic mutations are detected more
commonly among patients with IgE-mediated diseases than among the
general population. However, efforts to identify the genes responsible
for abnormal or excessive IgE production is an intense area of clinical
investigation.

Allergic reactions result, in part, from the release of preformed
granule-associated mediators from mast cells or basophils. This release
is prompted by the binding of an allergen to the IgE already coating
these cells. Omalizumab is thought to act by binding to certain epitopes
on circulating IgE and preventing this IgE from binding to the mast cell
and basophil. In effect, Omalizumab is proposed to act as a \"sump\" for
the systemic burden of circulating IgE.

The symptoms and manifestations of IgE-mediated diseases overlap with
many non-IgE-mediated disease. Consequently, it is difficult or
impossible to distinguish some \"allergic\" diseases from
\"non-allergic\" diseases based on clinical examination findings alone.
This difficulty is especially notable for rhinitis and asthma\--very
common diseases/syndromes. In addition, the difficulty of distinguishing
\"allergic\" from \"non-allergic\" disease has resulted in imprecise
estimates of the prevalence of these two categories of diseases. The
complexity of making \"allergic\" diagnoses is compounded by the finding
that up to 22% of \"normal\" humans may have positive skin test
responses to allergens\--skin test reactions that suggest the
individuals have preformed (and conceivably, pathologic) IgE formation.

*Comment: Given the imprecision of diagnosis of \"allergic\" diseases,
identification of the pertinent patient population for use of Omalizumab
may hinge, in part, upon the criteria and definitions used for
\"allergic\" asthma. Notably, all the sponsor\'s major safety and
efficacy studies examined subjects with skin test reactivity to certain
aeroallergens. The proposed PI does not describe the criteria for
diagnosis of \"allergic\" asthma and does not directly refer to skin
testing for hypersensitivity to aeroallergens.*

The National Heart, Lung, and Blood Institute (NHLBI) defines asthma as
\"a chronic inflammatory disorder of the airways in which many cells and
cellular elements play a role, in particular, mast cells, eosinophils, T
lymphocytes, macrophages, neutrophils and epithelial cells. In
susceptible individuals, this inflammation causes recurrent episodes of
wheezing, breathlessness, chest tightness and coughing, particularly at
night or in the early morning. These episodes are usually associated
with widespread but variable airflow obstruction that is often
reversible either spontaneously or with treatment. The inflammation also
causes an associated increase in the existing bronchial
hyperresponsiveness to a variety of stimuli.\"[^4]

The NHLBI definition notes that there are multiple potential cellular
and soluble mediator components to the inflammatory process associated
with asthma. This report also notes that the specific role and impact of
each of these various components upon the clinical manifestations of
asthma remain hypothetical. Within clinical publications and textbooks,
asthma has been subdivided into several loosely defined categories.
These various categories or \"types\" of asthma include the following:
allergic asthma, non-allergic asthma, exercise-induced asthma, status
asthmaticus, refractory asthma, glucocorticoid-dependent asthma,
nocturnal asthma and a host of other less common forms of asthma that
are identified by various adjectives and eponyms. There are no well
accepted epidemiologic data assessing the prevalence of each of the
various \"types\" of asthma.

No precise definition of AA appears to exist even though the general
clinical field has long recognized that asthma patients may be broadly
grouped into categories of \"allergic-type\" versus
\"non-allergic-type.\" For practical and investigational purposes, one
of the most common AA definitions employs the requirement of skin test
positivity to a suspected aeroallergen along with a diagnosis of asthma.
The subjectivity involved in making the diagnosis of AA is illustrated
by the finding that skin test positivity to a suspected allergen is
common (approximately 20% of the general population) while the incidence
of asthma is considerably smaller (approximately 5% of the general
population)\--an observation that suggests factors other than atopy are
involved in causing asthma.[^5] Estimates for the prevalence of
\"asthma\" (without qualifying adjectives) note that approximately 14 to
18 million Americans have the condition.

Asthma generally has two peaks of onset during human life, in childhood
and after age 40. It is generally recognized that asthma in children
commonly resolves with time and that asthma developing in older adults
is frequently associated with complications.

Overall, death from asthma is very uncommon (estimated at less than 1%
of all asthmatic patients dying annually). Most deaths from asthma occur
among adults even though deaths among children with asthma may receive a
larger amount of public attention. Epidemiological studies performed
among residents of Rochester, Minnesota and Philadelphia, Pennsylvania
have shown that the overwhelming majority of deaths due to asthma occur
over the age of 50 years.[^6] This observation is especially pertinent
because studies have suggested that the patient population most
vulnerable to death from asthma (patients with \"refractory\" asthma)
may have airway inflammatory processes that are uniquely different from
those inflammatory processes active in milder forms of asthma (i.e., the
role of IgE-mediated processes may be different between patients with
milder forms of asthma and those with refractory asthma).[^7]

Important aspects of Omalizumab action are the potential consequences of
inducing a form of IgE-deficiency. Following the administration of
Omalizumab, the blood content of free IgE is markedly reduced. Chronic
dosing with Omalizumab has the potential for maintaining, on a long term
basis, an almost complete lack of any free IgE within the blood. While
IgE has generally been implicated as a pro-inflammatory mediator with
little, if any positive impact upon health, certain clinical
observations have raised questions about a protective role of the
immunoglobulin in mucosal defenses and in the defense against neoplasia.

One especially notable clinical report is that of a family with an
inherited (isolated) deficiency of IgE. This deficiency was associated
with severe sinopulmonary disease (focal emphysema and bronchitis).[^8]
The report\'s authors hypothesized that IgE may function in a protective
role by inducing a mucosal \"anaphylaxis\" response to invading
microorganisms and other antigens. This mucosal anaphylaxis might
produce increased vascular permeability and result in the localized
release of protective cell scavengers and soluble mediators.

Another concern with IgE physiology is its role in neoplasia survey. A
number of epidemiological studies have described inverse correlations
between the incidence of atopy and the development of
neoplasms.[^9]^,^[^10]^,^[^11] At least one study has suggested that
patients with atopy may have more favorable prognoses in association
with certain neoplasms.[^12] Overall, these publications are far from
definitive in establishing a protective role for IgE in the defense
against neoplasia. However, the publications suggest that modification
of the body\'s content of IgE may, in some manner, impact the immunity
to cancer.

*Comment: The clinical literature associated with the protective role of
IgE is extremely limited. To a certain extent this may be because
deficiencies of IgE are generally found in association with other
immunoglobulin deficiencies. Nevertheless, the isolated reports raise*
*questions about the potential for long term administration of
Omalizumab to alter the susceptibility to diseases related to altered
mucosal immunity and neoplasia.*

**5. Summary of major safety issues:**

**A. Overview:**

The safety database consists of detailed information from 3,507 subjects
exposed to Omalizumab within the major multi-dose AA, SAR, PAR and AD
studies (see Appendix C for a summary of the design of these studies).
Approximately 70% of the subjects (2,359) were enrolled in AA studies
and approximately 60% (2,076) were enrolled in controlled AA studies.
The AA studies used the Omalizumab dosages proposed for marketing and
were, with the exception of one small study, of at least six months
duration. SAR and PAR studies contribute safety data for 1,132 subjects
and the one AD study provides safety data for 16 subjects. In general,
the SAR, PAR and AD studies were controlled studies of short durations
that, in some cases, examined Omalizumab dosages lower than those
proposed for use in AA.

Consequently, the group of \"all controlled clinical studies\" is a
combination of the AA data with the SAR, PAR and AD data, a combination
that may not be fully informative with respect to the proposed AA
indication because of the SAR, PAR and AD study design limitations. The
group of AA studies, especially the controlled AA studies, provide the
most directly applicable safety data for the AA indication. Throughout
this review, the safety data from controlled studies are divided into
two major groups: \"AA controlled studies\" and \"all controlled
studies.\"

All uncontrolled studies examined Omalizumab use in AA and these studies
contribute 283 subjects to the safety database.

Overall, safety information from controlled and uncontrolled studies is
generally limited to no more than one year of total Omalizumab exposure
for any single subject, although some subjects in on-going studies
supply preliminary data following three years of Omalizumab exposure.

The clinical development program for Omalizumab use in AA collected
substantial safety data from unblinded studies that used control
subjects receiving standard therapy. Only 20% of the Omalizumab-exposed
adult/adolescent AA subjects had their safety data collected within one
of the three placebo controlled studies designed to assess safety and
efficacy (Studies 008, 009 and 011). The two unblinded, standard therapy
controlled studies (Studies Q2143g and IA04) enrolled a total of 2,211
subjects. Hence, a large portion of the safety data were obtained from
studies in which the investigators were aware of subjects\' treatment
assignment, a design feature that might have influenced certain aspects
of safety reporting, especially investigators\' assessments of AE causal
associations with Omalizumab.

The safety database consists of a predominance of Caucasian subjects
(85%) and subjects aged between 18 and 64 years (75%). Adolescents and
geriatric subjects account for only nine and four percent of the safety
database, respectively.

The most noteworthy safety findings are presented in summary immediately
below and a comprehensive safety review follows. The noteworthy findings
are:

-   Serious adverse events

    -   Malignancy

    -   Anaphylaxis

-   Other adverse events

    -   Rash

    -   Disgestive system events

    -   Bleeding-related events

    -   Female genitourinary events

    -   Events among the geriatric population

The noteworthy findings are derived from the comparisons of adverse
event rates between the study groups in the controlled clinical studies.
Due to the potentially large numbers of patients exposed to a product
marketed for AA, even small differences in adverse event rates within
the controlled studies suggest that many patients may ultimately
experience drug-related adverse events.

**B. Serious adverse events:**

During the completed clinical studies, two Omalizumab-exposed subjects
died, both of events that appeared unrelated to Omalizumab exposure (a
motor vehicle accident in one case and ischemic heart disease in
another). One additional death has been reported for an
Omalizumab-exposed subject in an on-going clinical study. This subject
died of rapidly progressive meningococcal sepsis following the onset of
fever and chills. The subject had received approximately one year of
Omalizumab administration within Study 011Ext. The impact of Omalizumab
exposure upon this death event is unclear.

Nonfatal SAE occurred at a slightly higher rate among Omalizumab-exposed
subjects in both the group of all controlled studies (4.2% versus 3.8%)
and the group of AA adolescent/adult controlled studies (5.6% versus
4.6%). No single type of event or cluster of events appeared to account
for the small excess of SAE among Omalizumab-exposed subjects. However,
two types of SAE are of special concern: malignancy and anaphylaxis.

**1. Malignancy:**

Among all completed studies, malignant neoplasms occurred in 20/4127
(0.5%) Omalizumab-exposed subjects compared to 5/2236 (0.2%) control
subjects. Excluding non-melanoma skin cancer, malignancies were detected
among 16 (0.4%) Omalizumab-exposed subjects and two (0.1%) control
subjects, a difference in rate of 0.3%. The duration of Omalizumab
exposure varied among the clinical studies and was generally less than
one year for most subjects. Consequently, the rates are better expressed
in terms related to exposure times. Table 3 summarizes the malignancy
rates in terms of events per 1000 patient years of exposure.

Table 3. Malignancy rates (events/1000 patient years) in all complete
studies

+----------------------------+----------+--------+---------+---------+
| **Malignancy type**        | **Omal   | **Con  | **Rate  | **Rate  |
|                            | izumab** | trol** | diffe   | ratio** |
|                            |          |        | rence** |         |
|                            | **(n =   | **(n = |         | **(95%  |
|                            | 4127)**  | 2      | **(95%  | CI)**   |
|                            |          | 236)** | CI)**   |         |
+----------------------------+----------+--------+---------+---------+
| First malignancy           | 6.3      | 3.3    | 3.0     | 1.9     |
|                            |          |        |         |         |
| (events/patient-years)     | 20/3160  | (5     | (-1.0,  | (0.7,   |
|                            |          | /1513) | 7.0)    | 6.5)    |
+----------------------------+----------+--------+---------+---------+
| First malignancy           | 5.1      | 1.3    | 3.7     | 3.8     |
|                            |          |        |         |         |
| excluding non-melanoma     | (        | (2     | (0.7,   | (0.9,   |
| skin cancer                | 16/3160) | /1513) | 6.8)    | 34.3)   |
|                            |          |        |         |         |
| (events/patient-years)     |          |        |         |         |
+----------------------------+----------+--------+---------+---------+

all rates and their differences are calculated as per 1000 patient years

In addition to these malignancies, two Omalizumab-exposed subjects
(2/1420 patient years of exposure) in on-going clinical studies have
been diagnosed with malignancies (colon cancer, prostate cancer).
Because most of the on-going studies are uncontrolled, the corresponding
exposure time for controls was only 374 patient years.

The overall pattern of malignancies within the Omalizumab group is
remarkable for a predominance of solid organ/epithelial cancers and only
one case of a hematological/lymphatic cancer.

Comparisons of malignancy rates suggest (but do not definitively
establish) an increased rate for the Omalizumab-exposed subjects. Table
3 suggests that, on average, the cancer rate might double (see rate
ratio) with Omalizumab exposure\--the confidence interval suggesting
that the potential change might result in a rate ranging from one-third
lower than baseline to one that is six fold higher than baseline. Of
more concern is the comparison of rates for malignancies, exclusive of
non-melanoma skin cancer. Table 3 suggests that Omalizumab
administration might be associated with a four fold increase in the rate
of these malignancies\--the confidence interval suggesting that rate
might be considerably higher. Comparisons of the numbers of subjects
diagnosed with cancer within the sponsor\'s clinical studies to the
numbers expected based upon a large epidemiological database (SEER)
suggested that, on average, the Omalizumab group had a higher number of
malignancies than might be expected while the control group had a lower
number than might be expected.

No submitted or published data establish a direct pathophysiological
link between anti-IgE therapy and cancer development or progression.
However, the potential for alterations in IgE-mediated effector cell
function must be considered. For example, innate immunity to neoplasia
may be altered by effects on eosinophil or mast cell function.
Eosinophils are known to bear IgE receptors. Increased malignant tissue
eosinophil infiltration has been correlated with increased survival, an
effect that may be related to eosinophil function in tumor cell
lysis.[^13]^,^[^14] Potentially, anti-IgE therapy may alter IgE-mediated
eosinophil priming and effector cell function. Similarly, alteration of
mast cell IgE-mediated signaling may impact the immunity to cancer. Mast
cells and their mediators are known to alter tissue structure, blood
flow, and immunologic milieu.[^15] Alteration of these functions by
anti-IgE therapy may, conceptually, impact the resistance to cancer.
Overall, no direct biological evidence links IgE antagonism and
oncogenesis, although several pathophysiological pathways may be cited
in order to provide a biological plausibility for an association of
anti-IgE therapy and cancer risks.

Overall, there was a numeric excess of malignancies among
Omalizumab-exposed subjects\--an observation that raises the concern the
excess may be study drug-related.

**2.** **Anaphylaxis:**

Within all the sponsor\'s clinical studies, anaphylaxis or anaphylactoid
reactions were experienced by four subjects exposed to Omalizumab and
one subject in a control group. Table 4 briefly summarizes the
Omalizumab-exposed subjects with anaphylaxis/anaphylactoid reactions.
One Omalizumab-exposed subject experienced an anaphylaxis/anaphylactoid
reaction following receipt of IV Omalizumab in an exploratory study,
while the three other Omalizumab subjects had reactions following SC
dosing within a major clinical study. One (peanut-allergic) control
subject experienced an anaphylactoid reaction/anaphylaxis after the
accidental ingestion of peanuts.

All subjects experiencing anaphylaxis/anaphylactoid reactions survived.
The anaphylaxis reactions were managed with various combinations of
epinephrine, steroids and antihistamine therapies (see Appendix B). No
subject developed respiratory failure. Notably, one Omalizumab-exposed
subject experienced anaphylaxis following exposure to Levaquin. This
subject continued in the clinical study and received subsequent
Omalizumab dosages with no recurrence of anaphylaxis. Overall, the data
suggest that Omalizumab may, on a rare basis, be associated with
life-threatening anaphylactic reactions.

Table 4. Anaphylaxis or anaphylactoid reactions following Omalizumab
exposure

  ------------- ----------- ----------------------------------- ------------------
  **Subject**   **Study**   **Features**                        **Outcome**

  2712          Q0694       30 y o male experienced             discontinued
                            anaphylactoid reactions 1.5 hours   Omalizumab
                            after first Omalizumab dose (IV)    

  4621          008         39 y o female with a history of     continued
                            penicillin and trimethoprim-sulfa   Omalizumab
                            allergy developed facial edema,     
                            hives, dyspnea 30 minutes after a   
                            Levaquin tablet ingestion and 21    
                            days after last Omalizumab dose     

  12411         Q2143g      19 y o female developed hives,      discontinued
                            itching and dyspnea 90 minutes      Omalizumab
                            after her first Omalizumab dose     

  11756         Q2143g      28 y o female developed injection   discontinued
                            site edema, throat and tongue edema Omalizumab
                            2 hours after her fourth Omalizumab 
                            dose                                
  ------------- ----------- ----------------------------------- ------------------

y o = year old

**C. Adverse events:**

**1. AE among all subjects in controlled studies:**

The tables within Appendix A summarize the common AE that occurred in
the controlled studies. Most of the common AE rates were similar between
the study groups, although the Omalizumab group had a higher rate for
the following events: rash, bleeding-related AE, various digestive
system AE, and certain female genitourinary AE. Underscoring the
disproportion in the rates of certain AE is the observation that the
proportions of subjects discontinuing a study due to AE was higher among
the Omalizumab groups than control groups (3% versus 1%).

**a. Rash:**

All grades of rash AE occurred in excess among Omalizumab-exposed
subjects in the group of all controlled studies (Table 5). The excess
appeared related to the occurrence of a broad range of non-urticarial
reactions among subjects in the open label studies. The extent to which
knowledge of treatment assignment may have impacted the reporting of
rash AE is unclear. Nevertheless, the incidence of rash AE paralleled
increases in blood Omalizumab concentrations, a pattern suggestive of
correlation with Omalizumab exposure. Table 6 summarizes the rates of
rash according to quartiles of end-of-study, trough Omalizumab blood
concentrations.

**Table 5.** Rash in controlled studies, by severity

+-----------------------+-----------------------+-----------------------+
| **Severity**          | **Any rash, n (%)**   |                       |
+-----------------------+-----------------------+-----------------------+
|                       | Omalizumab,           | Control,              |
|                       |                       |                       |
|                       | n = 3224              | n = 2019              |
+-----------------------+-----------------------+-----------------------+
| Any event             | 211 (6.5)             | 98 (4.9)              |
+-----------------------+-----------------------+-----------------------+
| Mild                  | 127 (3.9)             | 62 (3.1)              |
+-----------------------+-----------------------+-----------------------+
| Moderate              | 74 (2.3)              | 34 (1.7)              |
+-----------------------+-----------------------+-----------------------+
| Severe                | 10 (0.3)              | 2 (0.1)               |
+-----------------------+-----------------------+-----------------------+

**Table 6. Rash AE in controlled studies, by quartile of terminal
serum**

Omalizumab trough concentration

+-----------------+---------+---------+----------+---------+---------+
| **AE term**     | **Oma   |         |          |         | **Co    |
|                 | lizumab |         |          |         | ntrol** |
|                 | Qua     |         |          |         |         |
|                 | rtile** |         |          |         | n =     |
|                 |         |         |          |         | 1216    |
+-----------------+---------+---------+----------+---------+---------+
|                 | 1 (low) | 2       | 3        | 4       |         |
|                 |         |         |          | (high)  |         |
|                 | n = 426 | n = 419 | n = 423  |         |         |
|                 |         |         |          | n = 422 |         |
+-----------------+---------+---------+----------+---------+---------+
| Rash            | 10      | 13      | 13 (3.1) | 22      | 25      |
|                 | (2.3)   | (3.1)   |          | (5.2)   | (2.1)   |
+-----------------+---------+---------+----------+---------+---------+

Overall, the data suggest that, compared to controls, Omalizumab
administration may be associated with a higher incidence of
non-urticarial rashes, some of which are severe.

**b. Digestive system events:**

A small excess of digestive system AE was noted among Omalizumab-exposed
subjects in the controlled studies. As summarized in Table 7 and shown
in Appendix A, Omalizumab-exposed subjects experienced a modestly higher
rate for a broad range of specific digestive system AE (nausea,
vomiting, diarrhea, abdominal pain). The excess appeared largely related
to AE of mild to moderate severity. However, digestive system SAE also
occurred at a slightly higher rate among Omalizumab-exposed subjects.
Although uncommon, appendicitis occurred among more Omalizumab-exposed
subjects than control subjects (six versus three subjects). Increases in
end-of-study, trough blood Omalizumab concentrations generally
paralleled the increased incidence of digestive system AE.

Table 7. Digestive system AE by severity grade

+-------------+-------------+-------------+-------------+-------------+
| **Severity  | **All       |             | **AA        |             |
| grade**     | controlled  |             | controlled  |             |
|             | studies, n  |             | studies\*,  |             |
|             | (%)**       |             | n (%)**     |             |
+-------------+-------------+-------------+-------------+-------------+
|             | Omalizumab  | Control     | Omalizumab  | Control     |
|             |             |             |             |             |
|             | n = 3224    | n = 2019    | n = 2076    | n = 1383    |
+-------------+-------------+-------------+-------------+-------------+
| Any event   | 612 (19.0)  | 360 (17.8)  | 444 (21.4)  | 260 (18.8)  |
+-------------+-------------+-------------+-------------+-------------+
| Mild        | 273 (8.5)   | 163 (8.1)   | 201 (9.7)   | 117 (8.5)   |
+-------------+-------------+-------------+-------------+-------------+
| Moderate    | 271 (8.4)   | 153 (7.6)   | 190 (9.2)   | 109 (7.9)   |
+-------------+-------------+-------------+-------------+-------------+
| Severe      | 68 (2.1)    | 44 (2.2)    | 53 (2.6)    | 34 (2.5)    |
+-------------+-------------+-------------+-------------+-------------+

\*adolescent/adult subjects (ages ≥ 12 yrs in Studies 008, 009, 011C,
012, IA04 and Q2143g)

**c. Bleeding-related AE:**

A small excess of bleeding-related AE among Omalizumab-exposed subjects
was observed in the controlled studies (Table 8). The excess was largely
attributable to mild to moderate severity grades of the following AE:
epistaxis, menorrhagia and hematoma. Analyses of platelet changes showed
that, compared to controls, a higher rate of Omalizumab-exposed subjects
had mild decreases in platelet counts. The magnitude of the platelet
count decreases appeared clinically unremarkable, both for the
Omalizumab-exposed subjects with and without bleeding-related AE. These
observations suggest that the Omalizumab group\'s platelet count
changes, alone, did not account for the group\'s excess in bleeding
related AE.

Table 8. Bleeding-related AE, by severity

+-----------------+-------------+-------------+-------------+----------+
| **              | **All       |             | **AA        |          |
| Outcome/grade** | controlled  |             | controlled  |          |
|                 | studies**   |             | studies\*** |          |
+-----------------+-------------+-------------+-------------+----------+
|                 | Omalizumab  | Control     | Omalizumab  | Control  |
|                 |             |             |             |          |
|                 | n = 3224    | n = 2019    | n = 2076    | n = 1383 |
+-----------------+-------------+-------------+-------------+----------+
| Any event       | 81 (2.5)    | 33 (1.6)    | 60 (2.8)    | 24 (1.7) |
+-----------------+-------------+-------------+-------------+----------+
| Mild            | 55 (1.7)    | 20 (1.0)    | 38 (1.8)    | 14 (1.0) |
+-----------------+-------------+-------------+-------------+----------+
| Moderate        | 23 (0.7)    | 9 (0.4)     | 19 (0.9)    | 7 (0.5)  |
+-----------------+-------------+-------------+-------------+----------+
| Severe          | 3 (0.1)     | 4 (0.2)     | 3 (0.1)     | 3 (0.2)  |
+-----------------+-------------+-------------+-------------+----------+

\*adolescent/adult subjects (ages ≥ 12 yrs in Studies 008, 009, 011C,
012, IA04 and Q2143g)

**d. Female genitourinary (GU) AE:**

Although uncommon, female GU AE appeared at a higher rate among
Omalizumab-exposed subjects than control subjects (Table 9). This excess
appeared related, in part, to more Omalizumab-exposed subjects
experiencing severe dysmenorrhea AE (0.2% versus 0) and severe grade
urinary tract infection AE (0.2% versus 0), as well as a broad variety
of milder GU AE. A correlate of these comparisons is the observation
that menorrhagia bleeding AE were more common among Omalizumab-exposed
subjects than controls.

**Table 9. Female GU and reproductive system AE (females ≥ 12 years)**

by severity grade

+-------------+-------------+-------------+-------------+-------------+
| **Severity  | **All       |             | **AA        |             |
| grade**     | controlled  |             | controlled  |             |
|             | studies, n  |             | studies\*,  |             |
|             | (%)**       |             | n (%)**     |             |
+-------------+-------------+-------------+-------------+-------------+
|             | Omalizumab  | Control     | Omalizumab  | Control     |
|             |             |             |             |             |
|             | n = 1662    | n = 1042    | n = 1239    | n = 794     |
+-------------+-------------+-------------+-------------+-------------+
| Any event   | 187 (11.3)  | 108 (10.4)  | 162 (13.1)  | 98 (12.3)   |
+-------------+-------------+-------------+-------------+-------------+
| Mild        | 78 (4.7)    | 33 (3.2)    | 66 (5.3)    | 27 (3.4)    |
+-------------+-------------+-------------+-------------+-------------+
| Moderate    | 93 (5.6)    | 68 (6.5)    | 80 (6.5)    | 64 (8.1)    |
+-------------+-------------+-------------+-------------+-------------+
| Severe      | 16 (1.0)    | 7 (0.7)     | 16 (1.3)    | 7 (0.9)     |
+-------------+-------------+-------------+-------------+-------------+

\*adolescent/adult female subjects (ages ≥ 12 yrs in Studies 008, 009,
011C, 012, IA04 and Q2143g)

**2. AE among the geriatric population in controlled studies:**

The safety database consists of information from Omalizumab exposure
among 151 geriatric subjects (subjects ≥ 65 years of age), 142 of whom
received Omalizumab in a controlled study. The controlled studies show
an excess of multiple types of AE among these subjects. Table 10
summarizes the AE rates by clusters according to body system. The bolded
rows denote body systems where the rates for Omalizumab-exposed subjects
exceed those of control subjects.

**Table 10.** AE by body system, rates for ages \> 65 years in
controlled studies

+---------------+-----------+------------+------------+-------------+
| **System**    | **All     |            | **AA       |             |
|               | c         |            | controlled |             |
|               | ontrolled |            | studies\*, |             |
|               | studies,  |            | n (%)**    |             |
|               | n (%)**   |            |            |             |
+---------------+-----------+------------+------------+-------------+
|               | Om        | Control, n | O          | Control, n  |
|               | alizumab, | = 71       | malizumab, | = 65        |
|               |           |            |            |             |
|               | n = 142   |            | n = 134    |             |
+---------------+-----------+------------+------------+-------------+
| Any event     | 102       | 54 (76.1)  | 99 (73.9)  | 51 (78.5)   |
|               | (71.8)    |            |            |             |
+---------------+-----------+------------+------------+-------------+
| **Body as     | **28      | **6        | **28       | **5 (7.7)** |
| whole**       | (19.7)**  | (8.5)**    | (20.9)**   |             |
+---------------+-----------+------------+------------+-------------+
| **Car         | **14      | **3        | **14       | **3 (4.6)** |
| diovascular** | (9.9)**   | (4.2)**    | (10.4)**   |             |
+---------------+-----------+------------+------------+-------------+
| **Digestive** | **20      | **7        | **20       | **7         |
|               | (14.1)**  | (9.9)**    | (14.9)**   | (10.9)**    |
+---------------+-----------+------------+------------+-------------+
| He            | 2 (1.4)   | 1 (1.4)    | 2 (1.5)    | 1 (1.5)     |
| mic/lymphatic |           |            |            |             |
+---------------+-----------+------------+------------+-------------+
| Infections    | 26 (18.3) | 16 (22.5)  | 26 (19.4)  | 15 (23.1)   |
| /infestations |           |            |            |             |
+---------------+-----------+------------+------------+-------------+
| Lab           | 4 (2.8)   | 2 (2.8)    | 4 (3.0)    | 2 (3.1)     |
| abnormality   |           |            |            |             |
+---------------+-----------+------------+------------+-------------+
| **Musc        | **11      | **3        | **29       | **13        |
| uloskeletal** | (7.7)**   | (4.2)**    | (21.6)**   | (20.0)**    |
+---------------+-----------+------------+------------+-------------+
| **Nervous**   | **23      | **6        | **23       | **6 (9.2)** |
|               | (16.2)**  | (8.5)**    | (17.2)**   |             |
+---------------+-----------+------------+------------+-------------+
| Respiratory   | 67 (47.2) | 35 (49.3)  | 66 (49.3)  | 34 (52.3)   |
+---------------+-----------+------------+------------+-------------+
| Sk            | 17 (12.0) | 10 (14.1)  | 17 (12.7)  | 9 (13.8)    |
| in/appendages |           |            |            |             |
+---------------+-----------+------------+------------+-------------+
| Special       | 10 (7.0)  | 6 (8.5)    | 9 (6.7)    | 6 (9.2)     |
| senses        |           |            |            |             |
+---------------+-----------+------------+------------+-------------+
| **GU/r        | **9       | **2        | **9        | **2 (3.1)** |
| eproductive** | (6.3)**   | (2.8)**    | (6.7)**    |             |
+---------------+-----------+------------+------------+-------------+

\*Studies 008, 009, 011, 012, IA04 and Q2143g

When the body system AE clusters were further analyzed according to
preferred terms (ie. the specific types of AE), the numbers of subjects
experiencing each specific event was very small such that it is not
feasible to attribute the excesses cited in Table 10 to a
disproportionate occurrence of specific events. Overall, the available
data do not rule out the possibility of an excess of some types of AE
among geriatric subjects exposed to Omalizumab.

**D. Other observations:**

**1. Clinical laboratory:**

The most remarkable clinical laboratory finding was the observation of a
disproportionate number of Omalizumab-exposed subjects with decreases in
hemoglobin. Overall, approximately 14% Omalizumab-exposed subjects and
10% control subjects had a hemoglobin value lower than baseline detected
at some point during follow-up. Shift analyses of hemoglobin changes are
summarized in Table 11. Within this table, \"notably low\" refers to a
hemoglobin value of \< 0.8 X LLN. The decreases in hemoglobin were
generally mild for both study groups and could not be related to
alterations in blood platelet counts or to bleeding-related AE. The
basis for the modest excess in Omalizumab-exposed subjects with
decreases in hemoglobin is unclear.

Table 11. Shift analyses of hemoglobin

+--------------------+----------+----------+-----------+-------------+
| **Category**       | **All    |          | **AA      |             |
|                    | co       |          | c         |             |
|                    | ntrolled |          | ontrolled |             |
|                    | studies, |          | s         |             |
|                    | n (%)**  |          | tudies,\* |             |
|                    |          |          | n (%)**   |             |
+--------------------+----------+----------+-----------+-------------+
|                    | Oma      | Control, | Om        | Control,    |
|                    | lizumab, |          | alizumab, |             |
|                    |          | n = 1946 |           | n = 1328    |
|                    | n = 3125 |          | n = 2004  |             |
+--------------------+----------+----------+-----------+-------------+
| **Normal or high   | 2883     | 1820     | 1857      | 1236        |
| at baseline**      |          |          |           |             |
+--------------------+----------+----------+-----------+-------------+
| Shift to low       | 290      | 151      | 221       | 109 (8.8)   |
|                    | (10.1)   | (8.3)    | (11.9)    |             |
+--------------------+----------+----------+-----------+-------------+
| Shift to notably   | 2 (0.1)  | 1 (0.1)  | 1 (0.1)   | 1 (0.1)     |
| low                |          |          |           |             |
+--------------------+----------+----------+-----------+-------------+
| **Low at           | 242      | 126      | 147       | 92          |
| baseline**         |          |          |           |             |
+--------------------+----------+----------+-----------+-------------+
| Shift to even      | 131      | 51       | 95 (64.6) | 42 (45.7)   |
| lower              | (54.1)   | (40.5)   |           |             |
+--------------------+----------+----------+-----------+-------------+
| **Low at baseline, | 227      | 123      | 135       | 89          |
| but not notably    |          |          |           |             |
| low**              |          |          |           |             |
+--------------------+----------+----------+-----------+-------------+
| Shift to notably   | 7 (3.1)  | 4 (3.3)  | 5 (3.7)   | 4 (4.5)     |
| low                |          |          |           |             |
+--------------------+----------+----------+-----------+-------------+

\*adolescent/adult female subjects (ages ≥ 12 yrs in Studies 008, 009,
011C, 012, IA04 and Q2143g

The clinical laboratory data review examined in detail platelet count
changes because of a preclinical finding of thrombocytopenia in monkeys
receiving high doses of Omalizumab. The Omalizumab doses associated with
thrombocytopenia in monkeys were considerably in excess of those
proposed for use in humans. All clinical subjects exposed to the
Omalizumab dose proposed for marketing had blood Omalizumab
concentrations well below those concentrations associated with
thrombocytopenia in monkeys. No Omalizumab-exposed subject in the
clinical studies with normal or high baseline platelet counts developed
thrombocytopenia, although a mild decrease in blood platelet count was
observed in more Omalizumab-exposed subjects than control subjects.
Overall, the clinical studies suggest Omalizumab administration may have
been associated with mild decreases in platelet counts in approximately
7% of exposed subjects. The decrease in platelet counts was largely by a
magnitude of \< 100 X 10^9^/L and resulted in counts that were still
within normal limits.

**2. Antibody formation:**

No antibody formation to Omalizumab was reported in any clinical study.
However, FDA review of antibody formation data is pending the submission
of additional information regarding the antibody assay performance
characteristics. No conclusions can be formed regarding the antibody
formation data at this time.

**6. Preclinical studies:**

The sponsor\'s preclinical studies are especially notable for the
demonstration of dose/serum concentration-related thrombocytopenia in
monkeys. This finding was documented most extensively within cynomologus
monkeys but was also observed in rhesus, African green monkeys and
chimpanzees. The notable findings include the following:

-   Thrombocytopenia in monkeys was dose/Omalizumab serum
    concentration-dependent with no thrombocyopenia detected at
    \"clinically relevant serum concentrations\" of Omalizumab but
    thrombocytopenia at higher serum Omalizumab concentrations.

-   Juvenile monkeys were more susceptible to thrombocytopenia than
    adult monkeys. The serum \"threshold\" to cause a 50% reduction in
    blood platelets was approximately 400 mcg/mL for juvenile monkeys
    and 836 mcg/mL for adult monkeys.

-   The sponsor reports that the Omalizumab serum \"threshold\" to cause
    a 50% reduction in blood platelets in adult monkeys is approximately
    four to 19-fold (estimated 90% CI) higher than anticipated
    Omalizumab serum concentrations in patients receiving the highest
    proposed clinical dose of Omalizumab.

-   Thrombocytopenia in monkeys was reversible following cessation of
    Omalizumab dosing.

-   *In vitro* studies using radiolabeled Omalizumab failed to show
    binding of Omalizumab to monkey platelets. However, studies using
    radiolabeled monkey (as well as human) platelet proteins showed an
    exceptionally low binding of Omalizumab to some of the proteins. *In
    vitro* studies also showed no activation of primate platelets
    (including human) nor inhibition of usual platelet aggregation
    responses.

-   The mechanism of Omalizumab-associated thrombocytopenia in monkeys
    is unclear.

**7. Clinical studies overview:**

Overall, the sponsor submits clinical data from 26 completed clinical
studies and preliminary clinical data from nine on-going clinical
studies. These 35 studies may be broadly grouped into exploratory
studies (generally phase 1 or 2), major studies assessing safety and/or
efficacy or on-going studies. The completed studies consist of 11
exploratory studies and 15 major studies, as described below. The major
studies supply the most meaningful clinical safety data and form the
safety database. Notable findings from the exploratory studies and
on-going studies are also summarized in this review.

**A. Exploratory Studies:**

Most of the Exploratory Studies used early manufacturing iterations of
the product and examined either single dose or a small number of repeat
doses (Table 12). Many of these studies examined IV administration. For
simplicity, Study 2203 (a PK study assessing the comparability of two
late-development product iterations) is listed among the Exploratory
Studies in Table 12.

Table 12. Exploratory studies

+------+--------------------+----+---------+-------------+-----------+
| *    | **Design**         | *  |         | *           | **S       |
| *Stu |                    | *S |         | *Omalizumab | ubjects** |
| dy** |                    | ub |         | Dose**      |           |
|      |                    | je |         |             |           |
|      |                    | ct |         |             |           |
|      |                    | s, |         |             |           |
|      |                    | n  |         |             |           |
|      |                    | ** |         |             |           |
+------+--------------------+----+---------+-------------+-----------+
|      |                    | T  | Oma     |             |           |
|      |                    | ot | lizumab |             |           |
|      |                    | al |         |             |           |
+------+--------------------+----+---------+-------------+-----------+
| Q0   | OL, SD with a      | 77 | 59      | 0.005 mg/kg | atopic    |
| 572g | non-dosed control  |    |         | to 1.0      | and       |
|      | group              |    |         | mg/kg, IV   | n         |
|      |                    |    |         | or SC       | on-atopic |
|      |                    |    |         |             | adults    |
+------+--------------------+----+---------+-------------+-----------+
| Q0   | OL, MD,            | 25 | 25      | 0.015 mg/kg | AA or SAR |
| 619g | uncontrolled       |    |         | to 0.5      | adults    |
|      |                    |    |         | mg/kg, IV   |           |
|      |                    |    |         | or SC, X 5  |           |
|      |                    |    |         | to 6 doses  |           |
+------+--------------------+----+---------+-------------+-----------+
| Q0   | Single blind, SD   | 34 | 21      | 0.15 to 0.5 | pediatric |
| 626g | or MD,             |    |         | mg/kg, IV   | AA        |
|      | placebo-controlled |    |         | or SC, X    |           |
|      |                    |    |         | 1 - 3 doses |           |
+------+--------------------+----+---------+-------------+-----------+
| Q0   | Single blind, MD,  | 12 | 8       | 0.15 to 0.5 | AA adults |
| 637g | placebo-controlled |    |         | mg/kg       | with      |
|      |                    |    |         |             | elevated  |
|      |                    |    |         | IV or SC, X | IgE       |
|      |                    |    |         | 3 doses     |           |
+------+--------------------+----+---------+-------------+-----------+
| Q0   | OL, MD,            | 47 | 47      | 2.4 to 10.0 | adult SAR |
| 673g | uncontrolled       |    |         | mg/kg IV q  | patients  |
|      |                    |    |         | 2 weeks for | w or w/o  |
|      |                    |    |         | \~ 1 year   | AA        |
+------+--------------------+----+---------+-------------+-----------+
| Q0   | OL, MD,            | 46 | 46      | 0.014       | adult and |
| 723g | uncontrolled       |    |         | mg/kg/IU/mL | pediatric |
|      |                    |    |         | weekly, IV  | AA        |
|      |                    |    |         | or SC, X 4  | patients  |
|      |                    |    |         | doses       |           |
+------+--------------------+----+---------+-------------+-----------+
| Q0   | Randomized, DB,    | 2  | 181     | 0.15 or 0.5 | adult SAR |
| 624g | placebo-controlled | 40 |         | mg/kg Q 2   |           |
|      |                    |    |         | weeks X 12, |           |
|      |                    |    |         | IV or SQ    |           |
+------+--------------------+----+---------+-------------+-----------+
| Q0   | Randomized, DB,    | 20 | 11      | 2 mg/kg IV  | adult AA  |
| 630g | placebo-controlled |    |         | on day 0,   |           |
|      |                    |    |         | then 1      |           |
|      |                    |    |         | mg/kg IV on |           |
|      |                    |    |         | day 7, 14   |           |
|      |                    |    |         | and Q 2     |           |
|      |                    |    |         | weeks X     |           |
|      |                    |    |         | total of 10 |           |
|      |                    |    |         | doses       |           |
+------+--------------------+----+---------+-------------+-----------+
| Q0   | Randomized, DB,    | 19 | 10      | 0.5 mg/kg   | adult AA  |
| 634g | placebo-controlled |    |         | IV weekly X |           |
|      |                    |    |         | 9 doses     |           |
+------+--------------------+----+---------+-------------+-----------+
| Q0   | Randomized, DB,    | 3  | 212     | 0.006 or    | adult and |
| 694g | placebo-controlled | 17 |         | 0.014       | pediatric |
|      |                    |    |         | mg/kg/IU/mL | (≥12 yrs) |
|      |                    |    |         | IV, q 2     | AA        |
|      |                    |    |         | weeks for   |           |
|      |                    |    |         | 20 weeks    |           |
+------+--------------------+----+---------+-------------+-----------+
| 2203 | Randomized, OL, PK | 87 | 87      | 150 or 300  | Adult     |
|      |                    |    |         | mg, SC      | healthy   |
|      |                    |    |         |             | v         |
|      |                    |    |         |             | olunteers |
+------+--------------------+----+---------+-------------+-----------+
| T    |                    |    | 707     | \-          |           |
| otal |                    |    |         |             |           |
| assi |                    |    |         |             |           |
| gned |                    |    |         |             |           |
| to   |                    |    |         |             |           |
| Om   |                    |    |         |             |           |
| aliz |                    |    |         |             |           |
| umab |                    |    |         |             |           |
+------+--------------------+----+---------+-------------+-----------+

Design information: OL = open label, SD = single dose, MD = multiple
dose, DB = double blind; PK = pharmacokinetic

Subject information: AA = allergic asthma, SAR = seasonal allergic
rhinitis;

Dose information: Q = every, yrs = years

**B. Major Studies:**

Table 13 summarizes the 15 major studies composing the safety database.
Brief summaries of each study design are provided in Appendix C.

Table 13. Major studies

+--------+--------+-------+----+-------------------------------------+
| **S    | **De   | **    |    | **Features**                        |
| tudy** | sign** | Subje |    |                                     |
|        |        | cts** |    |                                     |
+--------+--------+-------+----+-------------------------------------+
|        |        | **Oma | ** |                                     |
|        |        | -lizu | Co |                                     |
|        |        | mab** | nt |                                     |
|        |        |       | ** |                                     |
+--------+--------+-------+----+-------------------------------------+
| 008C/E | R, DB, | 268   | 2  | AA definitive study, ages 12 - 74,  |
|        | PC     |       | 57 | one year                            |
+--------+--------+-------+----+-------------------------------------+
| 009C/E | R, DB, | 274   | 2  | AA, definitive study, ages 12 - 76, |
|        | PC     |       | 72 | one year                            |
+--------+--------+-------+----+-------------------------------------+
| 010C   | R, DB, | 225   | 1  | AA, ages 5 - 12, 7 month controlled |
|        | PC     |       | 09 | study                               |
+--------+--------+-------+----+-------------------------------------+
| 010E   | OL, UC | 309   | \- | AA, ages 5 - 12, 4 month extension  |
|        |        |       |    |                                     |
|        |        | (     |    |                                     |
|        |        | 99)\* |    |                                     |
+--------+--------+-------+----+-------------------------------------+
| 011C   | R, DB, | 176   | 1  | AA, ages 12 - 75, 8 month study     |
|        | PC     |       | 65 | focused on ability to decrease high |
|        |        |       |    | doses of ICS                        |
+--------+--------+-------+----+-------------------------------------+
| 012    | R, DB, | 22    | 23 | AA, ages 18 - 50, 4 month           |
|        | PC     |       |    | bronchoscopic study focused on      |
|        |        |       |    | sputum & biopsy findings            |
+--------+--------+-------+----+-------------------------------------+
| IA04   | OL,    | 206   | 1  | AA, ages 12 - 75, 1 year European   |
|        | STC    |       | 06 | study focused on comparison of      |
|        |        |       |    | asthma events among subjects who    |
|        |        |       |    | had to have an ER visit or          |
|        |        |       |    | hospitalization + oral steroids in  |
|        |        |       |    | past year                           |
+--------+--------+-------+----+-------------------------------------+
| Q2143g | OL,    | 1261  | 6  | \"asthma\"\--did not require skin   |
|        | STC    |       | 38 | test +, ages 6 - 75, 6 month study  |
| (ALTO) |        |       |    | focused on comparison of SAE among  |
|        |        |       |    | subjects who had to be receiving    |
|        |        |       |    | ICS or OCS + another med            |
+--------+--------+-------+----+-------------------------------------+
| Q      | OL, UC | 613   | \- | \"asthma\", ages 6 - 75, 6 month    |
| 2195g  |        |       |    | extension study                     |
|        |        | (1    |    |                                     |
| (ALTO  |        | 88)\* |    |                                     |
| E)     |        |       |    |                                     |
+--------+--------+-------+----+-------------------------------------+
| 006    | R, DB, | 400   | 1  | SAR, ages 12 - 75, 3 month study    |
|        | PC     |       | 36 |                                     |
+--------+--------+-------+----+-------------------------------------+
| 007    | R, DB, | 165   | 86 | SAR, ages 17 - 66, 3 month study    |
|        | PC     |       |    |                                     |
+--------+--------+-------+----+-------------------------------------+
| D01    | R, DB, | 114   | 1  | SAR, ages 6 - 17, 6 month study     |
|        | PC     |       | 11 |                                     |
+--------+--------+-------+----+-------------------------------------+
| 006 E  | OL, UC | 287   | \- | SAR, ages 12 - 75, 3 month          |
|        |        |       |    | retreatment                         |
|        |        | (0)\* |    |                                     |
+--------+--------+-------+----+-------------------------------------+
| 014    | R, DB, | 144   | 1  | PAR, ages 12 - 75, 4 month study    |
|        | PC     |       | 45 |                                     |
+--------+--------+-------+----+-------------------------------------+
| 013    | R, DB, | 16    | 9  | AD, ages 6 - 16, 6 month study      |
|        | PC     |       |    |                                     |
+--------+--------+-------+----+-------------------------------------+
| Total  |        | 3558  | 20 | \-                                  |
| su     |        |       | 57 |                                     |
| bjects |        |       |    |                                     |
+--------+--------+-------+----+-------------------------------------+

Cont = control; R = randomized; DB = double-blind; PC = placebo
controlled; STC = standard therapy controlled; OL = open label; UC =
uncontrolled; ICS = inhaled corticosteroids; OCS = oral corticosteroids

\*newly exposed

The subject numbers cited within Table 13 refer to the numbers of
subjects assigned to Omalizumab or control within each specific study,
not the numbers of subjects who received the study drug or provided
safety data. All subjects within the safety database (the \"safety
analyzable\" population) either received some study drug or (for a
standard therapy controlled, STC subject) had been randomized and
provided some post-randomization data. Consequently, the sample sizes
within the safety database are slightly smaller than the total subject
numbers cited within Table 13. Overall, the major studies consist of 12
controlled studies and 3 uncontrolled studies.

**8. Safety database composition:**

**A. Sample size:**

The safety database consists of 3507 \"safety analyzable\" subjects from
the major studies, as shown in Table 14.

Table 14. Safety database composition

+-------------------------------------------+-----------+-------------+
| **\# subjects from Major Studies**        | **Oma     | **Control** |
|                                           | lizumab** |             |
+-------------------------------------------+-----------+-------------+
| Randomized within a controlled study      | 3558      | 2057        |
|                                           |           |             |
| (Studies 008C/E, 009C/E, 010C, 011C, 012, |           |             |
| 006, 007, D01, 014, 013, IA04 and Q2143g) |           |             |
+-------------------------------------------+-----------+-------------+
| Randomized within a controlled study but  | 334       | 38          |
| received no study drug or (if in STC      |           |             |
| control group) had no f/u data            |           |             |
+-------------------------------------------+-----------+-------------+
| \"Safety analyzable\" subjects from       | 3224      | 2019        |
| controlled studies                        |           |             |
+-------------------------------------------+-----------+-------------+
| Enrolled in uncontrolled study having     | 287       | not         |
| received no Omalizumab in past (Studies   |           | applicable  |
| Q2195g and 010E)                          |           |             |
+-------------------------------------------+-----------+-------------+
| Enrolled in uncontrolled study but        | 4         | not         |
| received no Omalizumab or had no f/u data |           | applicable  |
+-------------------------------------------+-----------+-------------+
| \"Safety analyzable\" subjects from       | 283       | not         |
| uncontrolled studies                      |           | applicable  |
+-------------------------------------------+-----------+-------------+
| Total Safety Database                     | 3507      | 2019        |
+-------------------------------------------+-----------+-------------+

f/u = follow-up

For summary purposes, this review will focus upon the safety database\'s
subjects from the controlled studies. However, important findings from
the safety database\'s uncontrolled studies will be noted. The
controlled study findings will be summarized according to those from:

-all controlled studies (all 12 major controlled studies, all
indications)

-all adolescent/adult controlled AA studies (Subjects ≥ 12 yrs of age in

> studies 008C/E, 009C/E, 011C, 012, IA04 and Q2143g)

Additionally, at times, the placebo controlled studies will specifically
be cited, as follows:

-all [placebo controlled]{.underline} studies (all 10 placebo controlled
studies, all indications)

-all [placebo controlled]{.underline} adolescent/adult controlled AA
studies (Subjects ≥ 12 yrs

> of age in studies 008C/E, 009C/E, 011C and 012)

*Comment: Among the 12 major controlled studies, three were designed
specifically for the assessment of safety and efficacy in
adult/adolescent AA\--studies 008, 009 and 011. These three studies used
extensive exclusion criteria (especially studies 008 and 009) to limit
enrollment to a fairly select subset from moderate-to-severe persistent
AA patients. Indeed, approximately 50% of all screened subjects were
excluded from enrollment in these three studies. These exclusions were
based upon many criteria including:*

*-use of certain common maintenance AA medications*

*-screening blood IgE concentrations outside the applicable dosage
limits*

*-presence of certain common co-morbid conditions.*

*The subject selectivity involved in these three studies may limit the
ability to generalize their findings to a broad range of patients as
regards certain issues. To address this problem, the sponsor submits
clinical data from several other controlled clinical studies (\"safety
studies\")\--especially from Study Q2143g, an open label study that used
relatively broad asthma eligibility criteria and had no requirement for
documentation of skin test reactivity to aeroallergens. Notably,
approximately 40% of all controlled safety data comes from the Study
Q2143g, a study with two major limitations with respect to the ability
to directly compare findings from the active treatment group to the
standard therapy control group:*

*-the study design entailed a difference in the process for collection
of adverse event (AE)*

> *data (subjects in the active treatment group had more AE
> ascertainment visits than subjects in the control group). Hence, the
> finding of more AE in the active treatment group may relate to greater
> efforts at ascertainment.*

*-the open label nature of the study. Investigators may have been more
or less likely to*

> *record AE given knowledge of a subject\'s treatment assignment.*

*The most readily interpretable, comparative AA safety data are derived
from the placebo controlled studies, Studies 008, 009, 011C, and, to a
lesser extent, Study 012 (a small bronchoscopic study). This
Omalizumab-exposure safety sample accounts for approximately 22%
(738/3224) of all the controlled clinical safety data. These placebo
controlled, AA studies are important because of the rigor of their*
*methodology, the use of market-applicable clinical Omalizumab dosages
and the administration of Omalizumab over relatively prolonged periods
of time. These are also important considerations because inclusion of
clinical safety data from several of the supportive, controlled clinical
studies examining Omalizumab in other indications (e.g., SAR, PAR and
AD) may not provide a clinically meaningful representation of
comparative Omalizumab safety. Some of these non-AA controlled studies
involved short Omalizumab exposure times (3 months or less), relatively
low Omalizumab dosages and uneven randomization ratios.*

**B. Baseline characteristics and drug exposure:**

Baseline characteristics and drug exposure data for the safety database
of all subjects who received Omalizumab are summarized in Tables 15 and
16, respectively.

Table 15. Baseline characteristics in safety database, n (%)

+------------------------------------+---------------------------------+
| **Parameter**                      | **Safety Database,**            |
|                                    |                                 |
|                                    | **n = 3507**                    |
+------------------------------------+---------------------------------+
| Sex                                |                                 |
+------------------------------------+---------------------------------+
| Female                             | 1930 (55)                       |
+------------------------------------+---------------------------------+
| Male                               | 1577 (45)                       |
+------------------------------------+---------------------------------+
| Race                               |                                 |
+------------------------------------+---------------------------------+
| Caucasian                          | 2988 (85)                       |
+------------------------------------+---------------------------------+
| Black                              | 288 (8)                         |
+------------------------------------+---------------------------------+
| Oriental                           | 48 (1)                          |
+------------------------------------+---------------------------------+
| Other                              | 183 (5)                         |
+------------------------------------+---------------------------------+
| Age                                |                                 |
+------------------------------------+---------------------------------+
| 6 - 11 yrs                         | 443 (13)                        |
+------------------------------------+---------------------------------+
| 12 - 17 yrs                        | 318 (9)                         |
+------------------------------------+---------------------------------+
| 18 - 64 yrs                        | 2595 (74)                       |
+------------------------------------+---------------------------------+
| ≥ 65 yrs                           | 151 (4)                         |
+------------------------------------+---------------------------------+
| Total IgE, IU/mL                   |                                 |
+------------------------------------+---------------------------------+
| mean                               | 212.2                           |
+------------------------------------+---------------------------------+
| range                              | 20 - 1612                       |
+------------------------------------+---------------------------------+

*Comment: Notably, approximately 75% of the safety data comes from
subjects between 18 and 64 years of age. Of concern is the limited
extent of exposure among younger subjects (approximately 300 adolescent
subjects) and geriatric subjects (approximately 150 subjects). These
considerations are important because younger subjects may ultimately
have the greatest life-long exposure to Omalizumab while the older
subjects may be at higher risk of AE because of comorbid illnesses and
other considerations unique to the elderly.*

Table 16 summarizes the Omalizumab safety database for two groups of
subjects: 1) all subjects in the safety database and 2) all subjects in
the safety database plus all subjects with some follow-up data from
on-going studies (not thoroughly verified clinical data) up to the
safety date cut-off of January 17, 2003. In general, clinical data after
52 weeks of exposure is limited to the collection of SAE reports. This
preliminary data from the on-going, open label, uncontrolled clinical
studies consist of information from 294 subjects newly exposed to
Omalizumab. However, the safety database of 3507 subjects from the
completed studies provides the basis for overall safety assessment. The
duration of Omalizumab exposure within this safety database is limited
to approximately one year.

Table 16. Drug exposure in safety database and on-going studies\*, n (%)

+--------------------+------------------------+------------------------+
| **Exposure**       | **Safety Database,**   | **Safety Database +**  |
|                    |                        |                        |
|                    | **n = 3507**           | **Preliminary Data     |
|                    |                        | from On-going          |
|                    |                        | Studies**              |
|                    |                        |                        |
|                    |                        | **n = 3790**           |
+--------------------+------------------------+------------------------+
| ≥ 8 weeks          | 3338 (94)              | 3619 (96)              |
+--------------------+------------------------+------------------------+
| ≥ 12 weeks         | 3122 (89)              | 3401 (90)              |
+--------------------+------------------------+------------------------+
| ≥ 24 weeks         | 2301 (66)              | 2590 (68)              |
+--------------------+------------------------+------------------------+
| ≥ 36 weeks         | 1305 (37)              | 1822 (48)              |
+--------------------+------------------------+------------------------+
| ≥ 52 weeks         | 715 (20)               | 1150 (30)              |
+--------------------+------------------------+------------------------+
| ≥ 76 weeks         | 0                      | 418 (11)               |
+--------------------+------------------------+------------------------+
| ≥ 100 weeks        | 0                      | 326 (9)                |
+--------------------+------------------------+------------------------+
| ≥ 124 weeks        | 0                      | 262 (7)                |
+--------------------+------------------------+------------------------+
| ≥ 148 weeks        | 0                      | 171 (5)                |
+--------------------+------------------------+------------------------+
| ≥ 156 weeks        | 0                      | 158 (4)                |
+--------------------+------------------------+------------------------+

\*includes data from all major studies and follow-up data from the
extension studies through the safety cut-off date of January 17, 2003

*Comment: The clinical data within the safety database have been audited
by the sponsor for accuracy. The clinical data from the on-going studies
are preliminary data. Nevertheless, it is notable that the sponsor has
some experience with subjects receiving Omalizumab for over three
years.*

To facilitate comparative interpretations of safety findings in all
controlled studies and the AA controlled studies, Table 17 shows the
major baseline characteristics for subjects within these two groups of
studies.

Table 17. Baseline characteristics in controlled studies

+-------------+-------------+-------------+-------------+-------------+
| **          | **All       |             | **AA        |             |
| Parameter** | controlled  |             | controlled  |             |
|             | studies**   |             | studies\*** |             |
+-------------+-------------+-------------+-------------+-------------+
|             | Omalizumab, | Cont, n =   | Omalizumab, | Cont, n =   |
|             |             | 2019        |             | 1383        |
|             | n = 3224    |             | n = 2076    |             |
+-------------+-------------+-------------+-------------+-------------+
| Sex         |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Male        | 1440 (45%)  | 905 (45%)   | 837 (40%)   | 589 (43%)   |
+-------------+-------------+-------------+-------------+-------------+
| Female      | 1784 (55%)  | 1114 (55%)  | 1239 (60%)  | 794 (57%)   |
+-------------+-------------+-------------+-------------+-------------+
| Race        |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Caucasian   | 2764 (86%)  | 1741 (86%)  | 1758 (85%)  | 1171 (85%)  |
+-------------+-------------+-------------+-------------+-------------+
| Black       | 253 (8%)    | 143 (7%)    | 158 (8%)    | 99 (7%)     |
+-------------+-------------+-------------+-------------+-------------+
| Oriental    | 44 (1%)     | 25 (1%)     | 35 (2%)     | 24 (2%)     |
+-------------+-------------+-------------+-------------+-------------+
| Other       | 165 (5%)    | 110 (5%)    | 125 (6%)    | 89 (6%)     |
+-------------+-------------+-------------+-------------+-------------+
| Age         |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| 6 - 11 yrs  | 345 (11%)   | 197 (10%)   | \-          | \-          |
+-------------+-------------+-------------+-------------+-------------+
| 12 - 17 yrs | 296 (9%)    | 190 (9%)    | 151 (7%)    | 97 (7%)     |
+-------------+-------------+-------------+-------------+-------------+
| 18 - 64 yrs | 2441 (76%)  | 1561 (77%)  | 1791 (86%)  | 1221 (88%)  |
+-------------+-------------+-------------+-------------+-------------+
| ≥ 65 yrs    | 142 (4%)    | 71 (4%)     | 134 (7%)    | 65 (5%)     |
+-------------+-------------+-------------+-------------+-------------+

\*adolescent/adult subjects (ages ≥ 12 yrs in Studies 008, 009, 011C,
012, IA04 and Q2143g)

Cont = control

*Comment: Table 17 suggests that subjects were generally well balanced
between the active treatment arm and the control arm in the controlled
studies\--for certain major baseline characteristics. In order to
interpret the AA safety findings more clearly, Table 18 shows certain
asthma-related baseline characteristics for subjects in all controlled
AA studies and all placebo controlled AA studies (adult/adolescent
subjects only).*

**Table 18. Asthma-related baseline characteristics in
adult/adolescent**

**AA controlled studies**

+--------------+-------------+-------------+-------------+-------------+
| Parameter    | AA          |             | AA placebo  |             |
|              | controlled  |             | controlled  |             |
|              | studies\*   |             | studies\*\* |             |
+--------------+-------------+-------------+-------------+-------------+
|              | Omalizumab, | Cont, n =   | Omalizumab, | Placebo, n  |
|              |             | 1383        |             | = 717       |
|              | n = 2076    |             | n = 738     |             |
+--------------+-------------+-------------+-------------+-------------+
| Any prior    | 246 (12%)   | 147 (11%)   | 44 (6%)     | 49 (7%)     |
| year         |             |             |             |             |
| overnight    |             |             |             |             |
| asthma       |             |             |             |             |
| hos          |             |             |             |             |
| pitalization |             |             |             |             |
+--------------+-------------+-------------+-------------+-------------+
| Any prior    | 96 (5%)     | 61 (4%)     | 8 (1%)      | 11 (2%)     |
| year asthma  |             |             |             |             |
| ICU adm      |             |             |             |             |
+--------------+-------------+-------------+-------------+-------------+
| No. of prior |             |             |             |             |
| year ER      |             |             |             |             |
| visits for   |             |             |             |             |
| asthma       |             |             |             |             |
+--------------+-------------+-------------+-------------+-------------+
| Only 1       | 260 (13%)   | 142 (10%)   | 68 (9%)     | 58 (8%)     |
+--------------+-------------+-------------+-------------+-------------+
| More than 1  | 258 (12%)   | 144 (10%)   | 48 (7%)     | 45 (6%)     |
+--------------+-------------+-------------+-------------+-------------+
| Any prior    | 100 (5%)    | 57 (4%)     | 11 (2%)     | 11 (2%)     |
| intubation   |             |             |             |             |
| or MV for    |             |             |             |             |
| asthma       |             |             |             |             |
+--------------+-------------+-------------+-------------+-------------+
| FEV1 %       |             |             |             |             |
| predicted    |             |             |             |             |
+--------------+-------------+-------------+-------------+-------------+
| n            | 2076        | 1383        | 738         | 717         |
+--------------+-------------+-------------+-------------+-------------+
| Mean         | 71          | 70          | 70          | 71          |
+--------------+-------------+-------------+-------------+-------------+
| Range        | (12 - 139)  | (14 - 130)  | (12 - 126)  | (22 - 127)  |
+--------------+-------------+-------------+-------------+-------------+

\*adolescent/adult subjects (ages ≥ 12 yrs in Studies 008, 009, 011C,
012, IA04 and Q2143g)

\*\*adolescent/adult subjects (ages ≥ 12 yrs in Studies 008, 009, 011C
and 012)

ICU = intensive care unit; adm = admission; MV = mechanical ventilation

*Comment: Table 18 shows that \"AA controlled studies\" provide
substantially more safety information than \"AA placebo controlled
studies\" for the subset of subjects with the most refractory forms of
AA: those with a history of overnight hospitalization or ICU admission
or \>1 ER visit in the past year for an asthma exacerbation. This is a
special concern in interpreting the AA placebo controlled studies
(mainly Studies 008 and 009) because these studies may not
comprehensively characterize the risks associated with Omalizumab among
refractory patients.*

*The safety findings from \"AA controlled studies\" (especially Studies
IA04 and Q213g) are especially important for providing information from
subjects at potentially higher risk for misadventures and these studies
may provide a more general population-applicable description of the
risks of Omalizumab than \"AA placebo controlled studies.\"*

**C. In-study characteristics:**

*Comment: One of the concerns conveyed to the sponsor in FDA\'s July,
2001 Complete Review letter related to the limited amount of clinical
data from Omalizumab-exposed subjects who received a variety of
concomitant medications. As noted above, the sponsor\'s BLA resubmission
attempts to resolve this concern by supplying additional clinical data
from studies with relatively broad eligibility criteria\--observations
evident in comparisons of concomitant medication use between \"All AA
controlled studies\" and \"AA placebo controlled studies,\" as shown in
Table 19. For example, the total number of Omalizumab-exposed subjects
receiving concomitant oral steroids is over three fold larger in the
group of \"AA controlled studies\" than \"AA placebo controlled
studies.\" The difference is also vivid for comparisons of the number of
subjects receiving leukotriene modifying agents and/or xanthines\--the
number receiving these concomitant medications is almost negligible in
\"AA placebo controlled studies.\"*

Table 19 summarizes the extent of concomitant medication exposure in the
AA controlled clinical studies.

**Table 19. Concomitant medication use in AA controlled studies**

+-------------+-------------+-------------+-------------+-------------+
| **M         | **AA        |             | **AA        |             |
| edication** | controlled  |             | placebo     |             |
|             | studies\*** |             | controlled  |             |
|             |             |             | studies**   |             |
+-------------+-------------+-------------+-------------+-------------+
|             | Omalizumab, | Control, n  | Omalizumab, | Placebo, n  |
|             |             | = 1383      |             | = 717       |
|             | n = 2076    |             | n = 738     |             |
+-------------+-------------+-------------+-------------+-------------+
| Oral        | 654 (32%)   | 514 (37%)   | 194 (36%)   | 259 (36%)   |
| steroids    |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Xanthines   | 226 (11%)   | 130 (9%)    | 6 (\<1%)    | 29 (4%)     |
+-------------+-------------+-------------+-------------+-------------+
| LTR         | 675 (33%)   | 372 (27%)   | 22 (3%)     | 34 (5%)     |
| modifiers   |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Long-acting | 1339 (65%)  | 785 (57%)   | 163 (22%)   | 191 (27%)   |
| beta        |             |             |             |             |
| agonists    |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Cromolyns   | 77 (4%)     | 43 (3%)     | 7 (\<1%)    | 8 (1%)      |
+-------------+-------------+-------------+-------------+-------------+
| Penicillins | 338 (16%)   | 221 (16%)   | 147 (20%)   | 131 (18%)   |
+-------------+-------------+-------------+-------------+-------------+
| Fluor       | 312 (15%)   | 166 (12%)   | 85 (12%)    | 75 (11%)    |
| oquinolones |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Sulfa       | 42 (2%)     | 17 (1%)     | 9 (1%)      | 4 (\<1%)    |
| Antibiotics |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| ACE         | 129 (6%)    | 72 (5%)     | 28 (4%)     | 26 (4%)     |
| inhibitors  |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| H~2~        | 129 (6%)    | 90 (7%)     | 42 (6%)     | 41 (6%)     |
| antagonists |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Calc        | 134 (7%)    | 79 (6%)     | 30 (4%)     | 29 (4%)     |
| ium-channel |             |             |             |             |
| antagonists |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Iodinated   | 6 (\< 1%)   | 1 (\< 1%)   | 1 (\< 1%)   | 0           |
| contrast    |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+

*\*adolescent/adult subjects (ages ≥ 12 yrs in Studies 008, 009, 011C,
012, IA04 and Q2143g)*

*LTR = leukotriene*

*Comment: Table 19 is also notable for showing minimal use of certain
non-steroid controller medications among subjects in the placebo
controlled studies. This is important because these studies are
described as enrolling subjects with inadequately controlled asthma
symptoms despite high doses of inhaled corticosteroids. Conceivably,
some of these subjects could have had their symptoms controlled through
concomitant use of non-steroid controller medications, such as LTR
modifiers, cromolyns and/or long acting beta blockers.*

*Another basis for emphasizing the importance of \"All AA controlled
studies\" relates to the construct of the safety database. When making
comparisons to control groups for ascertaining effects in AA, it is
important to note that the group of studies composing \"All AA
controlled studies,\" probably provides the most pertinent clinical
data, as compared to the group of \"All controlled studies\" because
\"All controlled studies\" includes several studies in which Omalizumab
exposure times are brief and uneven randomization ratios were used to
enrich the Omalizumab groups\--designs which, in the composite of \"All
controlled studies,\" may dilute safety signals when only numbers of
subjects are compared.*

**D. Disposition of subjects in Safety Database:**

**1. Controlled studies:**

Table 20 summarizes the disposition of subjects in controlled clinical
studies (shown are the numbers for all randomized subjects). Similar
data for the placebo controlled studies are shown in Table 21.
Discontinuations for AE are cited in bold text.

Table 20. Subject disposition

+--------------+-------------+------------+-------------+------------+
| **Disposit   | **All       |            | **AA        |            |
| ion/Reason** | controlled  |            | controlled  |            |
|              | studies**   |            | studies\*** |            |
+--------------+-------------+------------+-------------+------------+
|              | Omalizumab, | Control,   | Omalizumab, | Control,   |
|              |             |            |             |            |
|              | n = 3274    | n = 2054   | n = 2115    | n = 1414   |
+--------------+-------------+------------+-------------+------------+
| Completed    | 2912        | 1781       | 1835        | 1194       |
|              | (88.9%)     | (86.7%)    | (86.8%)     | (84.4%)    |
+--------------+-------------+------------+-------------+------------+
| D            | 362 (11.1%) | 273(13.3%) | 280 (13.2%) | 220        |
| iscontinued: |             |            |             | (15.6%)    |
+--------------+-------------+------------+-------------+------------+
| **AE**       | **62        | **19       | **55        | **16       |
|              | (1.9%)**    | (0.9%)**   | (2.6%)**    | (1.1%)**   |
+--------------+-------------+------------+-------------+------------+
| Abnormal lab | 3 (0.1%)    | 3 (0.1%)   | 3 (0.1%)    | 2 (0.1%)   |
| value        |             |            |             |            |
+--------------+-------------+------------+-------------+------------+
| Other        | 297 (9.1%)  | 251        | 222 (10.5%) | 202        |
| reasons      |             | (12.2%)    |             | (14.3%)    |
+--------------+-------------+------------+-------------+------------+

\*adolescent/adult subjects (ages ≥ 12 yrs in Studies 008, 009, 011C,
012, IA04 and Q2143g)

Cont = control; f/u = follow-up; Other reasons include: unsatisfactory
therapy, protocol violation, consent withdrawal, lost to follow-up,
administrative problems, death, physician\'s or sponsor\'s decision to
withdraw subject or reason not stated

*Comment: Table 20 shows more discontinuations for AE among the
Omalizumab group than the control group (especially notable within the
group of AA controlled studies). No specific AE or group of clinically
similar AE accounts for the excess among the Omalizumab group. The
larger number of Omalizumab discontinuations for AE is derived from the
open label, standard care AA controlled studies, as shown by comparisons
of Table 20 to Table 21. Conceivably, knowledge of the treatment
assignment in the open label studies may have impacted the decision to
discontinue a subject because of AE.*

Table 21. Disposition in placebo controlled studies

+--------------+-------------+------------+-------------+------------+
| **Disposit   | **All       |            | **AA        |            |
| ion/Reason** | placebo     |            | placebo     |            |
|              | controlled  |            | controlled  |            |
|              | studies**   |            | studies\*** |            |
+--------------+-------------+------------+-------------+------------+
|              | Omalizumab, | Control,   | Omalizumab, | Control,   |
|              |             |            |             |            |
|              | n = 1806    | n = 1311   | n = 740     | n = 717    |
+--------------+-------------+------------+-------------+------------+
| Completed    | 1666        | 1145       | 663 (89.6%) | 594        |
|              | (92.2%)     | (87.3%)    |             | (82.8%)    |
+--------------+-------------+------------+-------------+------------+
| D            | 140 (7.8%)  | 166        | 77 (10.4%)  | 123        |
| iscontinued: |             | (12.7%)    |             | (17.2%)    |
+--------------+-------------+------------+-------------+------------+
| **AE**       | **13        | **15       | **6         | **12       |
|              | (0.7%)**    | (1.1%)**   | (0.8%)**    | (1.7%)**   |
+--------------+-------------+------------+-------------+------------+
| Abn lab      | 3 (0.2%)    | 3 (0.2%)   | 3 (0.4%)    | 2 (0.3%)   |
| value        |             |            |             |            |
+--------------+-------------+------------+-------------+------------+
| Other        | 124 (6.9%)  | 148        | 68 (9.2%)   | 109        |
| reasons      |             | (11.3%)    |             | (15.2%)    |
+--------------+-------------+------------+-------------+------------+

\*adolescent/adult subjects (ages ≥ 12 yrs in Studies 008, 009, 011C and
012)

Abn = abnormal; Cont = control; f/u = follow-up

Within the group of all controlled studies, the specific AE prompting
study discontinuation was known for 54 Omalizumab subjects and 16
control subjects. The AE that prompted study discontinuation in more
than one of the Omalizumab group subjects within the group of all
controlled studies are summarized in Table 22, along similar data for AA
controlled studies.

**Table 22. AE leading to study discontinuation in \> 1 Omalizumab
subjects**

**in controlled studies (number of subjects with AE)**

+-------------------------------------+--------+--------+------+------+
| **Main clinical AE\***              | **All  |        | **AA |      |
|                                     | cont   |        | co   |      |
|                                     | rolled |        | ntro |      |
|                                     | stu    |        | lled |      |
|                                     | dies** |        | s    |      |
|                                     |        |        | tudi |      |
|                                     |        |        | es** |      |
+-------------------------------------+--------+--------+------+------+
|                                     | **O    | **Con  | **O  | **C  |
|                                     | ma-liz | trol** | ma-l | ontr |
|                                     | umab** |        | izum | ol** |
|                                     |        | **n**  | ab** |      |
|                                     | **n**  |        |      | *    |
|                                     |        |        | *    | *n** |
|                                     |        |        | *n** |      |
+-------------------------------------+--------+--------+------+------+
| Rash (including urticaria,          | 10     | 0      | 8    | 0    |
| dermatitis, facial rash, etc)       |        |        |      |      |
+-------------------------------------+--------+--------+------+------+
| Pregnancy                           | 6      | 1      | 5    | 1    |
+-------------------------------------+--------+--------+------+------+
| Injection site reaction             | 4      | 0      | 3    | 0    |
+-------------------------------------+--------+--------+------+------+
| Fatigue                             | 3      | 1      | 3    | 0    |
+-------------------------------------+--------+--------+------+------+
| Diarrhea, vomiting, gastroenteritis | 3      | 0      | \-   | \-   |
+-------------------------------------+--------+--------+------+------+
| Asthma exacerbation                 | 2      | 0      | \-   | \-   |
+-------------------------------------+--------+--------+------+------+
| Upper respiratory infection         | 2      | 0      | 2    | 0    |
+-------------------------------------+--------+--------+------+------+
| Pneumonia                           | 2      | 1      | \-   | \-   |
+-------------------------------------+--------+--------+------+------+
| Anaphylaxis                         | 2      | 0      | 2    | 0    |
+-------------------------------------+--------+--------+------+------+
| Headache                            | 2      | 2      | \-   | \-   |
+-------------------------------------+--------+--------+------+------+
| Ischemic heart disease              | 2      | 2      | \-   | \-   |
+-------------------------------------+--------+--------+------+------+
| Atrial fibrillation                 | 2      | 0      | 2    | 0    |
+-------------------------------------+--------+--------+------+------+
| Cancer                              | 2      | 0      | \-   | \-   |
+-------------------------------------+--------+--------+------+------+
| Dry mouth                           | 2      | 0      | 2    | 0    |
+-------------------------------------+--------+--------+------+------+
| Rhinitis                            | 2      | 0      | 2    | 0    |
+-------------------------------------+--------+--------+------+------+
| Eye edema                           | 2      | 0      | 2    | 0    |
+-------------------------------------+--------+--------+------+------+

\*several subjects had preferred term AE that represented multiple
manifestations of what may be regarded as the main clinical AE; the
table lists the main clinical AE that appears most clinically pertinent
to this reviewer; the symbol \"-\" notes where no more than 1 OMALIZUMAB
subject experienced the AE

*Comment: Table 22 shows the AE of rash and injection site reaction
appearing notably more commonly among discontinuing Omalizumab subjects
than control subjects\--a pattern not found when the analysis is limited
to subjects within only the placebo controlled studies. However, this
numeric excess (alone) does not account for the larger number of
Omalizumab subjects discontinuing in non-placebo controlled studies than
in the placebo controlled studies. Table 22 also illustrates the
relatively broad spectrum of AE among discontinuing subjects in all
controlled and AA controlled studies. No single AE other than rash and
injection site reaction appears prominent in frequency. Consequently, it
appears that Omalizumab group discontinuations due to AE within the
non-placebo controlled studies were related to a very broad variety of
AE, but especially prominent are rash and injection site reactions.*

**2. Uncontrolled studies:**

Three major studies were uncontrolled: Studies 10E, ,Q2195g and 006E.
Together, these three studies enrolled 1209 subjects and 1137 (94%)
completed the studies. The reasons for study discontinuation included:

-AE in 17 subjects (5 from Study 006E, 12 from Q2195g)

> -Other reasons in 55 subjects

Of the five AE prompting discontinuation from Study 006E, two are
especially notable because of their temporal associated with Omalizumab
administration and the investigators\' assessment of suspected
association with the Omalizumab injection. Both AE consisted of facial
flushing and skin erythema shortly following the Omalizumab injection.
Both AE resolved with antihistamine therapy.

Of the 12 AE prompting discontinuation from Study Q2195g, four are
especially notable because of cancer (discussed in the malignancy
section of this document). Most other discontinuations were related to
asthma exacerbations.

*Comment: The overall pattern of study discontinuations suggests that
Omalizumab was associated with more AE prompting study discontinuation
when compared to a control group. Chief among the specific types of AE
prompting discontinuation were rash and injection site reaction.*

**9. Serious adverse events (SAE):**

**A. Deaths:**

No deaths occurred during the exploratory studies. During the major
studies, three subjects died, as summarized below:

-Subject 4145 (Omalizumab) in Study 014 died after a motor vehicle
accident

-Subject 11 (Omalizumab) in Study IA04 died of ischemic heart disease

-Subject 2581 (Placebo) in Study 008 died of cardiac arrest.

One additional Omalizumab subject died during an on-going study. Subject
5613 died of meningococcal sepsis after receiving approximately one year
of Omalizumab administrations within Study 011Ext.

One placebo subject also died during a post-study follow-up period.
Subject 2322 (Placebo) died after a motor vehicle accident, an event
occurring during the 12 weeks of observation after the completion of the
study.

**B. Nonfatal SAE:**

**1. Major studies:**

Table 23 summarizes SAE in all controlled and all AA controlled studies.
Hospitalizations for asthma-related events were efficacy endpoints in
most placebo controlled studies and were not recorded as SAE.

Table 23. SAE in controlled studies

  ------------------- ---------------- ------------- ---------------- -------------
  **Study group**     **Placebo and                  **Placebo        
                      standard therapy               controlled       
                      controlled                     studies**        
                      studies**                                       

                      **Omalizumab**   **Control**   **Omalizumab**   **Control**

  **All controlled                                                    
  studies**                                                           

  Total n             3224             2019          1801             1310

  Subjects with SAE,  135 (4.2)        76 (3.8)      44 (2.4)         35 (2.7)
  n (%)                                                               

  **AA                                                                
  adolescent/adult                                                    
  studies\***                                                         

  Total n             2076             1383          738              717

  Subjects with SAE,  117 (5.6)        64 (4.6)      32 (4.3)         25 (3.5)
  n (%)                                                               
  ------------------- ---------------- ------------- ---------------- -------------

\*adolescent/adult female subjects (ages ≥ 12 yrs in Studies 008, 009,
011C, 012, IA04 and Q2143g)

*Comment: Table 23 shows a small excess of Omalizumab subjects with SAE
when compared to all control subjects, an observation that, for the AA
studies was present in both the placebo controlled and non-placebo
controlled studies.*

Table 24 summarizes the SAE by body system clusters.

**Table 24.** SAE by body system in controlled studies

+-------------------+---+----------+---+------------+---+-----------+---+------------+
| **System**        |   | **All    |   |            |   | **AA      |   |            |
|                   |   | co       |   |            |   | c         |   |            |
|                   |   | ntrolled |   |            |   | ontrolled |   |            |
|                   |   | studies, |   |            |   | s         |   |            |
|                   |   | n (%)**  |   |            |   | tudies\*, |   |            |
|                   |   |          |   |            |   | n (%)**   |   |            |
+-------------------+---+----------+---+------------+---+-----------+---+------------+
|                   |   | Om       |   | Control    |   | O         |   | Control    |
|                   |   | alizumab |   |            |   | malizumab |   |            |
|                   |   |          |   | n = 2019   |   |           |   | n = 1383   |
|                   |   | n = 3224 |   |            |   | n = 2076  |   |            |
+-------------------+---+----------+---+------------+---+-----------+---+------------+
| Any event         | 1 |          | 7 |            | 1 |           | 6 |            |
|                   | 3 |          | 6 |            | 1 |           | 4 |            |
|                   | 5 |          | ( |            | 7 |           | ( |            |
|                   | ( |          | 3 |            | ( |           | 4 |            |
|                   | 4 |          | . |            | 5 |           | . |            |
|                   | . |          | 8 |            | . |           | 6 |            |
|                   | 2 |          | ) |            | 6 |           | ) |            |
|                   | ) |          |   |            | ) |           |   |            |
+-------------------+---+----------+---+------------+---+-----------+---+------------+
| Body as a whole   | 1 |          | 7 |            | 1 |           | 7 |            |
|                   | 7 |          | ( |            | 5 |           | ( |            |
|                   | ( |          | 0 |            | ( |           | 0 |            |
|                   | 0 |          | . |            | 0 |           | . |            |
|                   | . |          | 3 |            | . |           | 5 |            |
|                   | 5 |          | ) |            | 7 |           | ) |            |
|                   | ) |          |   |            | ) |           |   |            |
+-------------------+---+----------+---+------------+---+-----------+---+------------+
| CV system         | 1 |          | 8 |            | 1 |           | 8 |            |
|                   | 3 |          | ( |            | 2 |           | ( |            |
|                   | ( |          | 0 |            | ( |           | 0 |            |
|                   | 0 |          | . |            | 0 |           | . |            |
|                   | . |          | 4 |            | . |           | 6 |            |
|                   | 4 |          | ) |            | 6 |           | ) |            |
|                   | ) |          |   |            | ) |           |   |            |
+-------------------+---+----------+---+------------+---+-----------+---+------------+
| Digestive system  | 3 |          | 1 |            | 2 |           | 8 |            |
|                   | 0 |          | 0 |            | 3 |           | ( |            |
|                   | ( |          | ( |            | ( |           | 0 |            |
|                   | 0 |          | 0 |            | 1 |           | . |            |
|                   | . |          | . |            | . |           | 6 |            |
|                   | 9 |          | 5 |            | 1 |           | ) |            |
|                   | ) |          | ) |            | ) |           |   |            |
+-------------------+---+----------+---+------------+---+-----------+---+------------+
| Endocrine         | 0 |          | 1 |            | 0 |           | 1 |            |
|                   |   |          |   |            |   |           | ( |            |
|                   |   |          |   |            |   |           | 0 |            |
|                   |   |          |   |            |   |           | . |            |
|                   |   |          |   |            |   |           | 1 |            |
|                   |   |          |   |            |   |           | ) |            |
+-------------------+---+----------+---+------------+---+-----------+---+------------+
| Fetal/neonatal    | 1 |          | 2 |            | 1 |           | 2 |            |
|                   | ( |          | ( |            | ( |           | ( |            |
|                   | 0 |          | 0 |            | 0 |           | 0 |            |
|                   | ) |          | . |            | ) |           | . |            |
|                   |   |          | 1 |            |   |           | 1 |            |
|                   |   |          | ) |            |   |           | ) |            |
+-------------------+---+----------+---+------------+---+-----------+---+------------+
| Hemic and         | 1 |          | 0 |            | 1 |           | 0 |            |
| Lymphatic         | ( |          |   |            | ( |           |   |            |
|                   | 0 |          |   |            | 0 |           |   |            |
|                   | ) |          |   |            | ) |           |   |            |
+-------------------+---+----------+---+------------+---+-----------+---+------------+
| Infect            | 3 |          | 2 |            | 2 |           | 2 |            |
| ions/infestations | ( |          | ( |            | ( |           | ( |            |
|                   | 0 |          | 0 |            | 0 |           | 0 |            |
|                   | . |          | . |            | . |           | . |            |
|                   | 1 |          | 1 |            | 1 |           | 1 |            |
|                   | ) |          | ) |            | ) |           | ) |            |
+-------------------+---+----------+---+------------+---+-----------+---+------------+
| Lab abnormality   | 3 |          | 2 |            | 2 |           | 2 |            |
|                   | ( |          | ( |            | ( |           | ( |            |
|                   | 0 |          | 0 |            | 0 |           | 0 |            |
|                   | . |          | . |            | . |           | . |            |
|                   | 1 |          | 1 |            | 1 |           | 1 |            |
|                   | ) |          | ) |            | ) |           | ) |            |
+-------------------+---+----------+---+------------+---+-----------+---+------------+
| Meta              | 1 |          | 0 |            | 1 |           | 0 |            |
| bolic/nutritional | ( |          |   |            | ( |           |   |            |
|                   | 0 |          |   |            | 0 |           |   |            |
|                   | ) |          |   |            | ) |           |   |            |
+-------------------+---+----------+---+------------+---+-----------+---+------------+
| Musculoskeletal   | 1 |          | 1 |            | 9 |           | 7 |            |
|                   | 0 |          | 0 |            | ( |           | ( |            |
|                   | ( |          | ( |            | 0 |           | 0 |            |
|                   | 0 |          | 0 |            | . |           | . |            |
|                   | . |          | . |            | 4 |           | 5 |            |
|                   | 3 |          | 5 |            | ) |           | ) |            |
|                   | ) |          | ) |            |   |           |   |            |
+-------------------+---+----------+---+------------+---+-----------+---+------------+
| Nervous           | 7 |          | 4 |            | 7 |           | 4 |            |
|                   | ( |          | ( |            | ( |           | ( |            |
|                   | 0 |          | 0 |            | 0 |           | 0 |            |
|                   | . |          | . |            | . |           | . |            |
|                   | 2 |          | 2 |            | 3 |           | 3 |            |
|                   | ) |          | ) |            | ) |           | ) |            |
+-------------------+---+----------+---+------------+---+-----------+---+------------+
| Respiratory       | 2 |          | 1 |            | 2 |           | 1 |            |
|                   | 4 |          | 8 |            | 3 |           | 3 |            |
|                   | ( |          | ( |            | ( |           | ( |            |
|                   | 0 |          | 0 |            | 1 |           | 0 |            |
|                   | . |          | . |            | . |           | . |            |
|                   | 7 |          | 9 |            | 1 |           | 9 |            |
|                   | ) |          | ) |            | ) |           | ) |            |
+-------------------+---+----------+---+------------+---+-----------+---+------------+
| Skin and          | 1 |          | 2 |            | 1 |           | 2 |            |
| appendages        | ( |          | ( |            | ( |           | ( |            |
|                   | 0 |          | 0 |            | 0 |           | 0 |            |
|                   | ) |          | . |            | ) |           | . |            |
|                   |   |          | 1 |            |   |           | 1 |            |
|                   |   |          | ) |            |   |           | ) |            |
+-------------------+---+----------+---+------------+---+-----------+---+------------+
| Special senses    | 6 |          | 2 |            | 4 |           | 1 |            |
|                   | ( |          | ( |            | ( |           | ( |            |
|                   | 0 |          | 0 |            | 0 |           | 0 |            |
|                   | . |          | . |            | . |           | . |            |
|                   | 2 |          | 1 |            | 2 |           | 1 |            |
|                   | ) |          | ) |            | ) |           | ) |            |
+-------------------+---+----------+---+------------+---+-----------+---+------------+
| Med/surg          | 1 |          | 5 |            | 1 |           | 5 |            |
| procedures        | 5 |          | ( |            | 4 |           | ( |            |
|                   | ( |          | 0 |            | ( |           | 0 |            |
|                   | 0 |          | . |            | 0 |           | . |            |
|                   | . |          | 2 |            | . |           | 4 |            |
|                   | 5 |          | ) |            | 7 |           | ) |            |
|                   | ) |          |   |            | ) |           |   |            |
+-------------------+---+----------+---+------------+---+-----------+---+------------+
| GU and            | 1 |          | 9 |            | 1 |           | 8 |            |
| reproductive      | 5 |          | ( |            | 4 |           | ( |            |
|                   | ( |          | 0 |            | ( |           | 0 |            |
|                   | 0 |          | . |            | 0 |           | . |            |
|                   | . |          | 4 |            | . |           | 6 |            |
|                   | 5 |          | ) |            | 7 |           | ) |            |
|                   | ) |          |   |            | ) |           |   |            |
+-------------------+---+----------+---+------------+---+-----------+---+------------+

\*adolescent/adult female subjects (ages ≥ 12 yrs in Studies 008, 009,
011C, 012, IA04 and Q2143g)

CV = cardiovascular, Med/surg = medical or surgical procedures; GU =
genitourinary

*Comment: Table 24 suggests no single body system cluster of SAE
accounts for the excess of Omalizumab subjects with SAE, although
subjects with digestive system SAE appear to account for a large portion
of the excess. The broad variety of SAE are illustrated by the preferred
term mappings, as shown in Table 25 for subjects in all controlled
studies.*

Table 25 summarizes the most common SAE (by preferred term) for subjects
in all controlled studies.

**Table 25. SAE (other than asthma-related events) occurring in ** 3
subjects within any group, by preferred term, all controlled studies, n

+-------------------------------+------------------+------------------+
| **Term**                      | **Omalizumab,**  | **Control, n =   |
|                               |                  | 76**             |
|                               | **n = 135**      |                  |
+-------------------------------+------------------+------------------+
| Surgery                       | 15               | 5                |
+-------------------------------+------------------+------------------+
| Pneumonia                     | 8                | 2                |
+-------------------------------+------------------+------------------+
| Fracture                      | 6                | 5                |
+-------------------------------+------------------+------------------+
| Pregnancy                     | 6                | 1                |
+-------------------------------+------------------+------------------+
| Appendicitis                  | 5                | 3                |
+-------------------------------+------------------+------------------+
| Cholelithiasis                | 4                | 0                |
+-------------------------------+------------------+------------------+
| Chest infection               | 4                | 1                |
+-------------------------------+------------------+------------------+
| Anaphylaxis                   | 3                | 1                |
+-------------------------------+------------------+------------------+
| Abdominal pain                | 3                | 0                |
+-------------------------------+------------------+------------------+
| Chest pain                    | 3                | 1                |
+-------------------------------+------------------+------------------+
| Supraventricular tachycardia  | 3                | 0                |
+-------------------------------+------------------+------------------+
| Bronchospasm                  | 2                | 4                |
+-------------------------------+------------------+------------------+
| Cholecystitis                 | 0                | 4                |
+-------------------------------+------------------+------------------+
| Bronchitis                    | 0                | 4                |
+-------------------------------+------------------+------------------+

*Comment: Table 25 suggests that the specific types of SAE within the
controlled studies covered a broad range of events, with the number of
subjects experiencing any single type of SAE very small. No single type
of SAE appears to account for the excess of Omalizumab subjects with SAE
but surgeries, pneumonia, pregnancy and cholelithiasis were the most
disparate.*

Appendix A summarizes the asthma-related hospitalizations within the AA
controlled studies, including those studies where asthma-related
hospitalizations were recorded as efficacy endpoints and not AE.

*Comment: Few subjects (\< 3%) were hospitalized for asthma in the
controlled studies. However, a larger proportion of control subjects
required hospitalization for asthma than Omalizumab subjects. This
pattern was present both in the placebo controlled AA studies and the
standard therapy AA controlled studies.*

**2. Exploratory studies:**

In the phase 1/2 studies, 16 subjects experienced SAE, nine in the
Omalizumab group and seven in the control groups. Most had SAE related
to asthma exacerbations (7 Omalizumab subjects and 4 control subjects).
Other SAE were isolated events consistent with the subjects\' other
underlying diseases.

**3. Uncontrolled studies:**

Three of the 15 major studies examined Omalizumab use in an uncontrolled
study design (Studies Q2195g, 006E and 010E). No SAE were reported in
Study 010E and the only SAE reported in Study 006E was appendicitis.
Consequently, Study Q2195g provided the most notable SAE findings. SAE
were reported for 39 of the 609 (6%) treated subjects within Study
Q2195g (eight subjects in the new Omalizumab treatment group and 31
subjects in the continued Omalizumab treatment group). None of the SAE
were assessed as related to Omalizumab by the site investigators. The
most remarkable SAE related to the reporting of nine malignancies among
seven subjects (as reviewed subsequently).

**4. On-going studies:**

The sponsor had eight on-going studies (and one recently discontinued
study) at the time of the BLA CR amendment submission (December, 2002).
Most of these studies are uncontrolled. A 120 day safety update was
submitted to the BLA with a safety cut-off date of January 17, 2003. As
of this cut-off date, all eight studies were still on-going. From these
studies, the sponsor received reports of SAE among 154
Omalizumab-exposed subjects (out of a known, on-going Omalizumab
exposure database of 1,184 subjects). Three of the on-going studies are
double blinded studies and the treatment assignment of subjects with SAE
in these studies has not been unblinded.

SAE related to the respiratory system accounted for almost half of the
SAE. Most (nearly three-quarters) of the respiratory system SAE related
to asthma exacerbations. GU system SAE were the second most frequently
involved body system and most of these events related to pregnancies. Of
the 15 GU SAE, 12 were pregnancies. Other GU events included isolated
cases of kidney calculus, hysterectomy and prostate cancer. Digestive
system SAE accounted for the third most frequently involved body system.
Except for three cases of appendicitis, specific digestive system SAE
covered a broad range with no more than two subjects experiencing any
specific preferred term event (e.g., abdominal pain, vomiting,
cholecystitis, nausea, etc).

SAE of special note from on-going studies include four cases of
malignancy and one case of meningococcal sepsis. Malignancy was
diagnosed within one subject each, as follows: prostate cancer, colon
adenocarcinoma, basal cell skin cancer and squamous cell skin cancer.
These events are summarized within the Neoplasia section of this review.

**C. Neoplasia (malignant and benign):**

This section will summarize all benign and malignant neoplasia events.

**1. Malignancies:**

*Comment: In reviewing the malignancy data, it is important to note that
subjects with a history of malignancy (more than 3 months prior to
enrollment) were not excluded from the sponsor\'s clinical studies.
Consequently, some of the cases of malignancy represent recurrent
disease.*

Among all completed studies, malignant neoplasms occurred in 20/4127
(0.5%) Omalizumab subjects compared to 5/2236 (0.2%) control subjects.
Among the 20 Omalizumab subjects with malignancies, one subject
(#21/4005) was determined, after discontinuation from the study, to have
had a breast lump present prior to study entry (although the malignancy
diagnosis was unknown) and another subject (#1230/10045) was suspected
of having had a diagnosis of recurrent thyroid cancer made in error
during the clinical study.

*Comment: There were special circumstances cited for three Omalizumab
malignancy subjects. One subject, an Omalizumab subject who was
suspected of having a recurrent optic glioma, had the event clarified
when recurrent follow-up imaging studies documented no recurrence. The
two other special Omalizumab subjects included the woman who, following
study enrollment, reported that she had noted a breast lump prior to
enrollment and another subject who, according to a reviewing physician,
may not have had a correct diagnosis of recurrent thyroid cancer (see
Appendix E). These two subjects are counted as having malignancies
because the cancer diagnosis was made in the breast cancer subject only
after Omalizumab exposure and, for the thyroid cancer subject,
Omalizumab administration was followed by the development of evidence
(but not histological confirmation) of recurrent thyroid cancer, a
finding that prompted radiation therapy.*

Table 26 summarizes the subjects with a malignancy diagnosis within all
completed clinical studies (the major studies plus exploratory studies).

Table 26. Malignant neoplasms in all completed studies, n (%)

+------------------------------+-----------------+---------------------+
| **Neoplasm**                 | **Omalizumab n  | **Control,**        |
|                              | = 4127**        |                     |
|                              |                 | **n = 2236**        |
+------------------------------+-----------------+---------------------+
| Any event                    | 20 (0.5)\*      | 5 (0.2)             |
+------------------------------+-----------------+---------------------+
| Skin, non-melanoma           | 5               | 3                   |
+------------------------------+-----------------+---------------------+
| Breast                       | 5               | 0                   |
+------------------------------+-----------------+---------------------+
| Prostate                     | 2               | 0                   |
+------------------------------+-----------------+---------------------+
| Melanoma                     | 2               | 0                   |
+------------------------------+-----------------+---------------------+
| Bladder                      | 1               | 0                   |
+------------------------------+-----------------+---------------------+
| Glioma                       | 0               | 1                   |
+------------------------------+-----------------+---------------------+
| Non-Hodgkin\'s lymphoma      | 1               | 0                   |
+------------------------------+-----------------+---------------------+
| Pancreas                     | 1               | 0                   |
+------------------------------+-----------------+---------------------+
| Rectum                       | 1               | 0                   |
+------------------------------+-----------------+---------------------+
| Parotid gland                | 2               | 0                   |
+------------------------------+-----------------+---------------------+
| Thyroid                      | 1               | 0                   |
+------------------------------+-----------------+---------------------+
| Testis                       | 0               | 1                   |
+------------------------------+-----------------+---------------------+

\*One subject with melanoma also had a basal cell skin cancer and
appears in both the Skin, non-melanoma and Melanoma rows. This subject
is counted only once in the total number of subjects with any event.

Excluding locally resected squamous or basal cell carcinomas,
malignancies were detected in 16 (0.4%) Omalizumab group subjects and 2
(0.1%) control subjects. Due to variation in Omalizumab exposure times
between the study groups, the occrrence data are best

expressed in terms of Omalizumab exposure duration (Table 27). The table
refers to first malignancy because some subjects with non-melanoma skin
cancer had multiple skin cancers.

Table 27. Malignancy rates (events/1000 patient year) in all complete
studies

+--------------------------+----------+--------+------------+---------+
| **Malignancy type**      | **Omal   | **Con  | **Rate     | **Rate  |
|                          | izumab** | trol** | di         | ratio** |
|                          |          |        | fference** |         |
|                          | **(n =   | **(n = |            | **(95%  |
|                          | 4127)**  | 2      | **(95%     | CI)**   |
|                          |          | 236)** | CI)**      |         |
+--------------------------+----------+--------+------------+---------+
| First malignancy         | 6.3      | 3.3    | 3.0        | 1.9     |
|                          |          |        |            |         |
| (event/patient years)    | 20/3160  | (5     | (-1.0,     | (0.7,   |
|                          |          | /1513) | 7.0)       | 6.5)    |
+--------------------------+----------+--------+------------+---------+
| First malignancy         | 5.1      | 1.3    | 3.7        | 3.8     |
|                          |          |        |            |         |
| excluding non-melanoma   | (        | (2     | (0.7, 6.8) | (0.9,   |
| skin cancer              | 16/3160) | /1513) |            | 34.3)   |
|                          |          |        |            |         |
| (event/patient years)    |          |        |            |         |
+--------------------------+----------+--------+------------+---------+

\*all rates and their differences are calculated as per 1000 patient
years

In addition to these malignancies, two Omalizumab-exposed subjects
(2/1420 patient years of exposure) in on-going clinical studies have
been diagnosed with malignancies (colon cancer, prostate cancer).
Because most of the on-going studies are uncontrolled, the corresponding
exposure time for controls was only 374 additional patient years.

*Comment: The Omalizumab group experienced an absolute 0.3 percentage
point increase in the rate of malignancy per year. Table 27 suggests
that the cancer rate might double with Omalizumab exposure. However, the
confidence intervals are broad and exclude neither no increase nor an
increase of many fold. Most concerning is the comparison of rates for
malignancies exclusive of non-melanoma skin cancer. Table 27 suggests
that the cancer rate for these types of malignancies might increase
considerably. The numbers of subjects with malignancy in the studies was
very small such that it is very difficult to form conclusions.*

The National Cancer Institute\'s (NCI) SEER (Surveillance, Epidemiology
and End Results) database was used to compare the incidence of
malignancy in the Omalizumab clinical studies to the expected incidence
within the general USA population. SEER is a continuing project of NCI
in which cancer statistics are collected from approximately 14% of the
US population. These statistics are used to estimate overall cancer
statistics in the USA. The SEER database provides cancer incidence rates
adjusted for age, sex and race. Demographics of the SEER database are
generally thought to parallel the demographics for the USA as a whole.
The sponsor\'s comparisons to the SEER data were age and gender-adjusted
and included calculation of the SIR (standardized incidence ratio), a
ratio comparing the observed number of cases to the expected number. The
sponsor\'s comparisons to SEER were not adjusted for race. Notably,
non-melanoma skin cancers are excluded from these analyses because SEER
doesn\'t contain comparison data. Table 28 summarizes the sponsor\'s SIR
findings for the group of all completed controlled studies and all
completed studies (some controlled, some uncontrolled).

**Table 28. Observed and expected number of malignancies**

(excluding non-melanoma skin cancer) in completed studies

+----------+--------+--------+---------+--------+--------+---------+
| **Study  | **     |        |         | **Con  |        |         |
| group**  | Omaliz |        |         | trol** |        |         |
|          | umab** |        |         |        |        |         |
+----------+--------+--------+---------+--------+--------+---------+
|          | No. of |        | SIR     | No. of |        | SIR     |
|          | events |        |         | events |        |         |
|          |        |        | (95%CI) |        |        | (95%    |
|          |        |        |         |        |        | CI)     |
+----------+--------+--------+---------+--------+--------+---------+
|          | ob     | ex     |         | ob     | ex     |         |
|          | served | pected |         | served | pected |         |
+----------+--------+--------+---------+--------+--------+---------+
| ***All   |        |        |         |        |        |         |
| c        |        |        |         |        |        |         |
| ompleted |        |        |         |        |        |         |
| co       |        |        |         |        |        |         |
| ntrolled |        |        |         |        |        |         |
| st       |        |        |         |        |        |         |
| udies*** |        |        |         |        |        |         |
+----------+--------+--------+---------+--------+--------+---------+
| Female   | 4      | 4.1    | 1.0     | 1.0    | 2.8    | 0.4     |
|          |        |        |         |        |        |         |
|          |        |        | (0.3 -  |        |        | (0.0 -  |
|          |        |        | 2.5)    |        |        | 2.0)    |
+----------+--------+--------+---------+--------+--------+---------+
| Males    | 6      | 3.1    | 2.0     | 1.0    | 2.0    | 0.5     |
|          |        |        |         |        |        |         |
|          |        |        | (0.7 -  |        |        | (0.0 -  |
|          |        |        | 4.3)    |        |        | 2.9)    |
+----------+--------+--------+---------+--------+--------+---------+
| Total    | 10     | 7.1    | 1.4     | 2.0    | 4.7    | 0.4     |
|          |        |        |         |        |        |         |
|          |        |        | (0.7 -  |        |        | (0.1 -  |
|          |        |        | 2.6)    |        |        | 1.6)    |
+----------+--------+--------+---------+--------+--------+---------+
| ***All   |        |        |         |        |        |         |
| c        |        |        |         |        |        |         |
| ompleted |        |        |         |        |        |         |
| st       |        |        |         |        |        |         |
| udies*** |        |        |         |        |        |         |
+----------+--------+--------+---------+--------+--------+---------+
| Female   | 7      | 5.3    | 1.3     | 1.0    | 2.8    | 0.4     |
|          |        |        |         |        |        |         |
|          |        |        | (0.5 -  |        |        | (0.0 -  |
|          |        |        | 2.8)    |        |        | 2.0)    |
+----------+--------+--------+---------+--------+--------+---------+
| Male     | 9      | 3.9    | 2.3     | 1.0    | 2.0    | 0.5     |
|          |        |        |         |        |        |         |
|          |        |        | (1.1 -  |        |        | (0.0 -  |
|          |        |        | 4.4)    |        |        | 2.9)    |
+----------+--------+--------+---------+--------+--------+---------+
| Total    | 16     | 9      | 1.8     | 2.0    | 4.7    | 0.4     |
|          |        |        |         |        |        |         |
|          |        |        | (1.0 -  |        |        | (0.1 -  |
|          |        |        | 2.9)    |        |        | 1.6)    |
+----------+--------+--------+---------+--------+--------+---------+

*Comment: The SEER comparisons suggest, on average, the Omalizumab group
had a higher number of malignancies than might be expected while the
control group had a lower number than might be expected. These data
support the concerns raised by direct comparisons of cancer rates
between the study groups. However, several limitations are pertinent to
interpreting the malignancy comparisons to the SEER database, as
follows:*

*a. Demographics of subjects within the SEER database may be
meaningfully different from demographics within the sponsor\'s safety
and efficacy studies. The sponsor\'s two longest duration clinical
studies assessing safety and efficacy (Studies 008 and 009) used
eligibility criteria that were rigorous in eliminating subjects at
substantial risk for co-morbidities, including malignancy. The subject
demographics within these two studies also appear substantially
different from those of the general USA population for certain notable
characteristics. For example, the USA Census Bureau estimates that
approximately 75% of the USA population is Caucasian and 12% Black.
Within Studies 008 and 009, approximately 90% were Caucasian and 7%
Black. This racial distribution is similarly different for comparisons
within the entire safety database. Additionally, the American Lung
Association estimates that approximately 25% of the USA population may
be current cigarette smokers. Current smokers were excluded from
enrollment in eight of the sponsor\'s major studies (including the main
safety and efficacy studies). Consequently, substantial numbers of
subjects at increased risk for malignancy based upon cigarette exposure
may have been eliminated from the sponsor\'s studies. The possibility of
discrepant demographics between the sponsor\'s studies and the USA
population (the SEER demographic) is emphasized by the finding that:*

*-only three of the 16 subjects with non-melanoma/skin cancer
malignancies were*

> *enrolled in Studies 008 and 009. Most reports of malignancies are
> from the safety studies (Studies Q2143g and Q2195g).*

*-the number of expected malignancies within the control groups appears
less than*

> *that predicted by SEER data*

*b. The applicability of SEER data to the population of AA subjects in
unknown; the expected malignancy rate within AA subjects can not be
accurately estimated. However, some studies suggest that atopic
individuals have lower malignancy rates and this database control group
is fully compatable with that hypothesis.*

*These limitations suggest comparisons to SEER should be regarded as
very exploratory analyses.*

Features of Omalizumab-exposed subjects with malignancies are summarized
in Table 29.

Table 29. Characteristics of Omalizumab-exposed subjects with
malignancies\*

+----------------------------+-------------------+--------------------+
| **Parameter**              | **Excluding       | **Non-melanoma     |
|                            | non-melanoma skin | skin cancer,**     |
|                            | cancer, n = 16**  |                    |
|                            |                   | **n = 5**          |
+----------------------------+-------------------+--------------------+
| Sex                        |                   |                    |
+----------------------------+-------------------+--------------------+
| Male n (%)                 | 9 (56)            | 1 (20)             |
+----------------------------+-------------------+--------------------+
| Female n (%)               | 7 (44)            | 4 (80)             |
+----------------------------+-------------------+--------------------+
| Age, yrs, mean ± SD        | 52 ± 10 (40 - 74) | 57 ± 19 (30 - 75)  |
| (range)                    |                   |                    |
+----------------------------+-------------------+--------------------+
| Recurrence, n (%)          | 4 (25%)           | 3 (60)             |
+----------------------------+-------------------+--------------------+
| Weeks of Omalizumab        | 24.0 (4 - 61)     | 25.0 (2 - 43)      |
| exposure prior to          |                   |                    |
| malignancy diagnosis,      |                   |                    |
| median (range)             |                   |                    |
+----------------------------+-------------------+--------------------+

> \*one subject had both a melanoma and a non-melanoma skin cancer

*Comment: Omalizumab subjects with cancer were middle age or older and
had the malignancy diagnosed following a fairly wide range of Omalizumab
exposure times although eight of the 16 non-skin cancer malignancies
were diagnosed within 24 weeks of initial Omalizumab exposure, an
observation suggesting that a number of the malignancies were probably
present prior to receipt of Omalizumab. The median Omalizumab exposure
time prior to diagnosis of the malignancies was similar to the median
exposure time of the entire population of Omalizumab-exposed subjects
(24 - 25 weeks). The clinical data are insufficient to assess whether
Omalizumab accelerated the growth of any pre-existing malignancies. The
overall pattern of malignancies within the Omalizumab group is
remarkable for a predominance of epithelial/solid organ cancers and only
one case of a hematological/lymphatic cancer.*

The very small number of malignancy events and the relatively short
period of observation in the studies limit the ability to assess changes
in the rate of cancer diagnosis over time. Nevertheless, the rate of
cancer diagnosis over time is summarized in Table 30 (first malignancy,
including non-melanoma skin cancer) and Table 31 (first malignancy,
excluding non-melanoma skin cancer).

**Table 30. First malignancy by exposure interval in all completed
studies**

(rates expressed as number of events per 1,000 patient years)

+---------------------+------------------------+-----------------------+
| **Weeks of study**  | **Event rate**         |                       |
|                     |                        |                       |
|                     | **(# events/patient    |                       |
|                     | years exposure)**      |                       |
+---------------------+------------------------+-----------------------+
|                     | Omalizumab,            | Control, n = 2236     |
|                     |                        |                       |
|                     | n = 4127               |                       |
+---------------------+------------------------+-----------------------+
| 1 - ≤ 13 weeks      | 5.9 (6/1017)           | 1.8 (1/556)           |
+---------------------+------------------------+-----------------------+
| 13 - ≤ 26 weeks     | 6.8 (6/876)            | 6.2 (3/482)           |
+---------------------+------------------------+-----------------------+
| 26 - ≤ 39 weeks     | 5.7 (3/527)            | 4.6 (1/216)           |
+---------------------+------------------------+-----------------------+
| 39 - ≤ 52 weeks     | 7.6 (3/395)            | 0 (0/147)             |
+---------------------+------------------------+-----------------------+
| \> 52 weeks         | 5.8 (2/344)            | 0 (0/111)             |
+---------------------+------------------------+-----------------------+
| Overall             | 6.3 (20/3160)          | 3.3 (5/1513)          |
+---------------------+------------------------+-----------------------+

**Table 31. First malignancy by exposure interval in all completed
studies,**

**excluding non-melanoma skin cancer**

(rates expressed as number of events per 1,000 patient years)

+---------------------+------------------------+-----------------------+
| **Weeks of study**  | **Event rate**         |                       |
|                     |                        |                       |
|                     | **(# events/patient    |                       |
|                     | years exposure)**      |                       |
+---------------------+------------------------+-----------------------+
|                     | Omalizumab,            | Control, n = 2236     |
|                     |                        |                       |
|                     | n = 4127               |                       |
+---------------------+------------------------+-----------------------+
| 1 - ≤ 13 weeks      | 4.9 (5/1017)           | 0 (0/556)             |
+---------------------+------------------------+-----------------------+
| 13 - ≤ 26 weeks     | 4.6 (4/876)            | 2.1 (1/482)           |
+---------------------+------------------------+-----------------------+
| 26 - ≤ 39 weeks     | 3.8 (2/527)            | 4.6 (1/216)           |
+---------------------+------------------------+-----------------------+
| 39 - ≤ 52 weeks     | 7.6 (3/395)            | 0 (0/147)             |
+---------------------+------------------------+-----------------------+
| \> 52 weeks         | 5.8 (2/344)            | 0 (0/111)             |
+---------------------+------------------------+-----------------------+
| Overall             | 5.1 (16/3160)          | 1.3 (2/1513)          |
+---------------------+------------------------+-----------------------+

*Comment: Tables 30 and 31 suggest that the cancer diagnosis rate was
not increasing or decreasing dramatically during the time lines of the
studies. This suggests that the Omalizumab group\'s higher rate was not
a transient unmasking effect and that the imbalance of cancer diagnosis
may continue with prolonged use of the drug.*

*Overall, there was a numeric excess of malignancies among
Omalizumab-exposed subjects\--raising the concern the excess may be
Omalizumab-related.*

**2. Benign neoplasms:**

In all controlled studies, the incidence of benign neoplasms was
approximately 1% in both Omalizumab (28/3224) and control (11/2019)
subjects. Benign neoplasms recorded among ≥ 2 subjects are summarized in
Table 32.

**Table 32. Benign neoplasms in all controlled studies (affecting ** 2
subjects)

+---------------------------------------+------------------------------+
| **Omalizumab group**                  | **Control**                  |
+---------------------------------------+------------------------------+
| -nasal polyp (n = 7)                  | -nasal polyp (n = 8)         |
|                                       |                              |
| -uterine fibroid (n = 6)              | -uterine fibroid (n = 2)     |
|                                       |                              |
| -colon polyp (n = 3)                  |                              |
|                                       |                              |
| -benign nevus (n = 3)                 |                              |
|                                       |                              |
| -breast adenoma (n = 2)               |                              |
|                                       |                              |
| -neuroma (n = 2)                      |                              |
|                                       |                              |
| -unspecified benign tumor (n = 2)     |                              |
+---------------------------------------+------------------------------+

*Comment: Given that the incidence of benign neoplasia is similar
between the two groups and the total exposure time for the Omalizumab
group is approximately twice that of the control group, the data do not
appear to signal a concern regarding a potential Omalizumab association
with benign neoplasia. A broader range of benign types of neoplasia
occurred among the Omalizumab-exposed subjects than among the control
subjects\--a findings perhaps related to the larger number of events.
The finding of similar rates of benign neoplasms between the study
groups but a disproportion in the malignancy rates may underscore the
meaningfulness of the malignancy findings.*

**10. Adverse Events:**

**A. Survey of all AE by body system and preferred term:**

Table 33 summarizes the study groups of all controlled and AA controlled
studies by AE body system while Table 34 summarizes the findings of AA
controlled studies and AA placebo controlled studies by AE preferred
term. Additional AE tables are shown in Appendix A.

**Table 33. Number of subjects with AE in the most frequently affected
body systems**

**(** 5% any group)

+------------------+-----------+-----------+-----------+-------------+
| **Body system**  | **All     |           | **AA      |             |
|                  | c         |           | c         |             |
|                  | ontrolled |           | ontrolled |             |
|                  | studies** |           | st        |             |
|                  |           |           | udies\*** |             |
+------------------+-----------+-----------+-----------+-------------+
|                  | Om        | Control,  | Om        | Control,    |
|                  | alizumab, |           | alizumab, |             |
|                  |           | n = 2019  |           | n = 1383    |
|                  | n = 3224  |           | n = 2076  |             |
+------------------+-----------+-----------+-----------+-------------+
| Any AE/any       | 2411      | 1530      | 1672      | 1080 (78%)  |
| system           | (75%)     | (76%)     | (81%)     |             |
+------------------+-----------+-----------+-----------+-------------+
| Respiratory      | 1482      | 1022      | 1086      | 767 (56%)   |
| system           | (46%)     | (51%)     | (52%)     |             |
+------------------+-----------+-----------+-----------+-------------+
| Infections &     | 759 (24%) | 557 (28%) | 577 (28%) | 439 (32%)   |
| infestations     |           |           |           |             |
+------------------+-----------+-----------+-----------+-------------+
| Nervous system   | 744 (23%) | 458 (23%) | 492 (24%) | 303 (22%)   |
+------------------+-----------+-----------+-----------+-------------+
| Body as a whole  | 681 (21%) | 375 (19%) | 493 (24%) | 272 (20%)   |
+------------------+-----------+-----------+-----------+-------------+
| Digestive system | 612 (19%) | 360 (18%) | 444 (21%) | 260 (19%)   |
+------------------+-----------+-----------+-----------+-------------+
| Musculoskeletal  | 569 (18%) | 357 (18%) | 448 (22%) | 286 (21%)   |
| system           |           |           |           |             |
+------------------+-----------+-----------+-----------+-------------+
| Special senses   | 296 (9%)  | 189 (9%)  | 202 (10%) | 132 (10%)   |
+------------------+-----------+-----------+-----------+-------------+
| Skin &           | 412 (13%) | 195 (10%) | 303 (15%) | 136 (10%)   |
| appendages       |           |           |           |             |
+------------------+-----------+-----------+-----------+-------------+
| GU & repro       | 216 (7%)  | 124 (6%)  | 185 (9%)  | 110 (8%)    |
| system           |           |           |           |             |
+------------------+-----------+-----------+-----------+-------------+
| CV system        | 105 (3%)  | 68 (3%)   | 90 (4%)   | 55 (4%)     |
+------------------+-----------+-----------+-----------+-------------+

\*adolescent/adult subjects (ages ≥ 12 yrs in Studies 008, 009, 011C,
012, IA04 and Q2143g)

GU = genitourinary; CV = cardiovascular

*Comment: Table 33 shows a slight excess in the Omalizumab rates for
\"body as a whole,\" digestive, GU and skin AE within both groups of
studies (the differences more evident in the AA controlled studies).*

*As shown in Table 34,* *rates of frequent (specific) AE are generally
similar between the AA study groups. A small excess of the following AE
within the Omalizumab group are notable: injection site reactions, rash,
fatigue, arthralgia, diarrhea and nausea. As will be shown subsequently,
all these excess events are generally related to AE of mild severity
(except for rash). When comparing the injection site reaction rates, it
is important to note that some control subjects within the group of all
AA controlled studies received no study agent injections (because they
were standard care therapy controls). Hence, these control subjects had
no potential to experience injection site reactions. Additionally,
injection site reactions within some of the placebo controlled AA
studies were graded on special case report forms designed to assess all
injections. Hence, injection site reactions may not have as readily been
recorded as AE\--possibly contributing to the much lower injection site
AE rates in the AA placebo controlled studies compared to the group of
all AA controlled studies. Injection site reactions are reviewed in
detail subsequently.*

**Table 34. Most common AE (≥ 3% in any group) in AA controlled
studies\***

n (%) of subjects

+--------------------+-----------+------------+----------+------------+
| **Preferred term** | **AA      |            | **AA     |            |
|                    | c         |            | placebo  |            |
|                    | ontrolled |            | co       |            |
|                    | studies** |            | ntrolled |            |
|                    |           |            | s        |            |
|                    |           |            | tudies** |            |
+--------------------+-----------+------------+----------+------------+
|                    | O         | Control    | Om       | Placebo    |
|                    | malizumab |            | alizumab |            |
|                    |           | N = 1383   |          | N = 717    |
|                    | N = 2076  |            | N = 738  |            |
+--------------------+-----------+------------+----------+------------+
| **Infections &     |           |            |          |            |
| infestations**     |           |            |          |            |
+--------------------+-----------+------------+----------+------------+
| Viral infection    | 484       | 364 (26.3) | 275      | 280 (39.1) |
|                    | (23.3)    |            | (37.3)   |            |
+--------------------+-----------+------------+----------+------------+
| Moniliasis         | 48 (2.3)  | 41 (3.0)   | 29 (3.9) | 26 (3.6)   |
+--------------------+-----------+------------+----------+------------+
| **Respiratory      |           |            |          |            |
| system**           |           |            |          |            |
+--------------------+-----------+------------+----------+------------+
| URI                | 415       | 284 (20.5) | 195      | 196 (27.3) |
|                    | (20.0)    |            | (26.4)   |            |
+--------------------+-----------+------------+----------+------------+
| Sinusitis          | 341       | 244 (17.6) | 142      | 157 (21.9) |
|                    | (16.4)    |            | (19.2)   |            |
+--------------------+-----------+------------+----------+------------+
| Pharyngitis        | 221       | 143 (10.3) | 126      | 120 (16.7) |
|                    | (10.7)    |            | (17.1)   |            |
+--------------------+-----------+------------+----------+------------+
| Rhinitis           | 188 (9.1) | 147(10.6)  | 107      | 101 (14.1) |
|                    |           |            | (14.5)   |            |
+--------------------+-----------+------------+----------+------------+
| Bronchitis         | 182 (8.8) | 142 (10.3) | 75       | 87 (12.1)  |
|                    |           |            | (10.2)   |            |
+--------------------+-----------+------------+----------+------------+
| Coughing           | 135 (6.5) | 101 (7.3)  | 74       | 88 (12.3)  |
|                    |           |            | (10.0)   |            |
+--------------------+-----------+------------+----------+------------+
| Sinus headache     | 28 (1.4)  | 27 (2.0)   | 16(2.2)  | 24 (3.4)   |
+--------------------+-----------+------------+----------+------------+
| **Nervous system** |           |            |          |            |
+--------------------+-----------+------------+----------+------------+
| Headache           | 320       | 215 (15.6) | 196      | 190 (26.5) |
|                    | (15.4)    |            | (26.6)   |            |
+--------------------+-----------+------------+----------+------------+
| Insomnia           | 42 (2.0)  | 38 (2.8)   | 28 (3.8) | 34 (4.7)   |
+--------------------+-----------+------------+----------+------------+
| **Digestive        |           |            |          |            |
| system**           |           |            |          |            |
+--------------------+-----------+------------+----------+------------+
| Diarrhea           | 90 (4.3)  | 49 (3.5)   | 48 (6.5) | 44 (6.1)   |
+--------------------+-----------+------------+----------+------------+
| Nausea             | 88 (4.2)  | 47 (3.4)   | 42 (5.7) | 39 (5.4)   |
+--------------------+-----------+------------+----------+------------+
| Gastroenteritis    | 68 (3.3)  | 40 (2.9)   | 40 (5.4) | 32 (4.5)   |
+--------------------+-----------+------------+----------+------------+
| Dyspepsia          | 58 (2.8)  | 62 (4.5)   | 42 (5.7) | 60 (8.4)   |
+--------------------+-----------+------------+----------+------------+
| Abdominal pain     | 58 (2.8)  | 40 (2.9)   | 32 (4.3) | 36 (5.0)   |
+--------------------+-----------+------------+----------+------------+
| Tooth ache         | 39 (1.9)  | 30 (2.2)   | 34 (4.6) | 27 (3.8)   |
+--------------------+-----------+------------+----------+------------+
| Vomiting           | 39 (1.9)  | 19 (1.4)   | 22 (3.0) | 17 (2.4)   |
+--------------------+-----------+------------+----------+------------+
| **Musculoskeletal  |           |            |          |            |
| system**           |           |            |          |            |
+--------------------+-----------+------------+----------+------------+
| Back pain          | 143 (6.9) | 97 (7.0)   | 92       | 86 (12.0)  |
|                    |           |            | (12.5)   |            |
+--------------------+-----------+------------+----------+------------+
| Arthralgia         | 98 (4.7)  | 50 (3.6)   | 57 (7.7) | 46 (6.4)   |
+--------------------+-----------+------------+----------+------------+
| Sprains & strains  | 71 (3.4)  | 47 (3.4)   | 42 (5.7) | 34 (4.8)   |
+--------------------+-----------+------------+----------+------------+
| Myalgia            | 69 (3.3)  | 46 (3.3)   | 47 (6.4) | 43 (6.0)   |
+--------------------+-----------+------------+----------+------------+
| Leg pain           | 33 (1.6)  | 15 (1.1)   | 26 (3.5) | 13 (1.8)   |
+--------------------+-----------+------------+----------+------------+
| **Body as a        |           |            |          |            |
| whole**            |           |            |          |            |
+--------------------+-----------+------------+----------+------------+
| Pain               | 72 (3.5)  | 44 (3.2)   | 48 (6.5) | 39 (5.4)   |
+--------------------+-----------+------------+----------+------------+
| Injection site     | 69 (3.3)  | 1 (0.1)    | 2 (0.3)  | 1 (0.1)    |
| reaction           |           |            |          |            |
+--------------------+-----------+------------+----------+------------+
| Injury             | 65 (3.1)  | 39 (2.8)   | 28 (3.8) | 26 (3.6)   |
+--------------------+-----------+------------+----------+------------+
| Fatigue            | 54 (2.6)  | 17 (1.2)   | 23 (3.1) | 14 (2.0)   |
+--------------------+-----------+------------+----------+------------+
| Fever              | 51 (2.5)  | 40 (2.9)   | 38 (5.2) | 36 (5.0)   |
+--------------------+-----------+------------+----------+------------+
| **Skin &           |           |            |          |            |
| appendages**       |           |            |          |            |
+--------------------+-----------+------------+----------+------------+
| Rash               | 69 (3.3)  | 28 (2.0)   | 29 (3.9) | 23 (3.2)   |
+--------------------+-----------+------------+----------+------------+
| **Special senses** |           |            |          |            |
+--------------------+-----------+------------+----------+------------+
| Conjunctivitis     | 29 (1.4)  | 33 (2.4)   | 18 (2.4) | 25 (3.5)   |
+--------------------+-----------+------------+----------+------------+
| **GU &             |           |            |          |            |
| reproductive       |           |            |          |            |
| system**           |           |            |          |            |
+--------------------+-----------+------------+----------+------------+
| Dysmenorrhea       | 35 (1.7)  | 33 (2.4)   | 28 (3.8) | 31 (4.3)   |
+--------------------+-----------+------------+----------+------------+

\*adolescent/adult subjects (ages ≥ 12 yrs in Studies 008, 009, 011C,
012, IA04 and Q2143g)

**B. AE by severity:**

Within the controlled studies, the Omalizumab and control groups had
similar rates of AE when the events were analyzed according to severity
grade. These findings are summarized in Appendix A. Severe grade AE are
analyzed in more detail below.

Tables 35 and 36 summarize the severe grade AE by body system and
preferred term, respectively. The \" skin and appendages\" system is
highlighted in bold text because of its higher Omalizumab/control rate
difference.

**Table 35.** Severe AE by body system

+------------------------+----------+----------+----------+-----------+
| **Body system**        | **All    |          | **AA     |           |
|                        | co       |          | co       |           |
|                        | ntrolled |          | ntrolled |           |
|                        | studies, |          | st       |           |
|                        | n (%)**  |          | udies\*, |           |
|                        |          |          | n (%)**  |           |
+------------------------+----------+----------+----------+-----------+
|                        | Om       | Control  | Om       | Control   |
|                        | alizumab |          | alizumab |           |
|                        |          | n = 2019 |          | n = 1383  |
|                        | n = 3224 |          | n = 2076 |           |
+------------------------+----------+----------+----------+-----------+
| Any system             | 372      | 274      | 294      | 215       |
|                        | (11.5)   | (13.6)   | (14.2)   | (15.5)    |
+------------------------+----------+----------+----------+-----------+
| Body as a whole        | 63 (2.0) | 36 (1.8) | 55 (2.6) | 28 (2.0)  |
+------------------------+----------+----------+----------+-----------+
| CV system              | 13 (0.4) | 6 (0.3)  | 12 (0.6) | 5 (0.4)   |
+------------------------+----------+----------+----------+-----------+
| Digestive system       | 68 (2.1) | 44 (2.2) | 53 (2.6) | 34 (2.5)  |
+------------------------+----------+----------+----------+-----------+
| Infections and         | 30 (0.9) | 40 (2.0) | 18 (0.9) | 34 (2.5)  |
| infestations           |          |          |          |           |
+------------------------+----------+----------+----------+-----------+
| Musculoskeletal system | 63 (2.0) | 47 (2.2) | 53 (2.6) | 37 (2.7)  |
+------------------------+----------+----------+----------+-----------+
| Nervous system         | 81 (2.5) | 54 (2.7) | 65 (3.1) | 43 (3.1)  |
+------------------------+----------+----------+----------+-----------+
| Respiratory system     | 105      | 101      | 83 (4.0) | 80 (5.8)  |
|                        | (3.3)    | (5.0)    |          |           |
+------------------------+----------+----------+----------+-----------+
| **Skin and             | **25     | **9      | **23     | **9       |
| appendages**           | (0.8)**  | (0.4)**  | (1.1)**  | (0.7)**   |
+------------------------+----------+----------+----------+-----------+
| Special senses         | 28 (0.9) | 10 (0.5) | 21 (1.0) | 8 (0.6)   |
+------------------------+----------+----------+----------+-----------+
| Surgical/medical       | 6 (0.2)  | 4 (0.2)  | 5 (0.2)  | 3 (0.2)   |
| procedures             |          |          |          |           |
+------------------------+----------+----------+----------+-----------+
| GU and reproductive    | 21 (0.7) | 11 (0.5) | 21 (1.0) | 10 (0.7)  |
+------------------------+----------+----------+----------+-----------+

\*adolescent/adult subjects (ages ≥ 12 yrs in Studies 008, 009, 011C,
012, IA04 and Q2143g)

*Comment: Table 35 shows a higher rate of severe skin and appendages AE
among the Omalizumab group. However, the number of subjects experiencing
these reactions is small (\< 1%). In general, the AE preferred terms for
these \"skin and appendages\" events refer to various forms of rash. The
proportions of subjects with severe skin and appendage system AE in the
placebo controlled studies were similar between the Omalizumab and
control groups (data not shown). Consequently, the higher rate of severe
skin reactions was mainly a result of observations from the open label
studies.*

*Table 35 also shows a somewhat higher rate of \"special senses\" AE
among Omalizumab subjects. The preferred term for these events referred
to a very broad group of AE involving either the eyes or ears, e.g.,
conjunctivitis, ear infection, cataracts, earache. In general, no more
than two subjects experienced any one of these specific events.*

Table 36 summarizes the most common severe grade AE by preferred term.

**Table 36. Most common severe AE (** 1% any group) in controlled
studies

+-------------+-------------+-------------+-------------+-------------+
| **Preferred | **All       |             | **AA        |             |
| term**      | controlled  |             | controlled  |             |
|             | studies, n  |             | studies\*,  |             |
|             | (%)**       |             | n (%)**     |             |
+-------------+-------------+-------------+-------------+-------------+
|             | Omalizumab  | Control     | Omalizumab  | Control     |
|             |             |             |             |             |
|             | n = 3224    | n = 2019    | n = 2076    | n = 1383    |
+-------------+-------------+-------------+-------------+-------------+
| Any severe  | 372 (11.5)  | 274 (13.6)  | 294 (14.2)  | 215 (15.5)  |
| AE          |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Headache    | 54 (1.7)    | 37 (1.8)    | 44 (2.1)    | 30 (2.2)    |
+-------------+-------------+-------------+-------------+-------------+
| URI         | 29 (0.9)    | 18 (0.9)    | 19 (0.9)    | 13 (0.9)    |
+-------------+-------------+-------------+-------------+-------------+
| Viral       | 21 (0.7)    | 31 (1.5)    | 12 (0.6)    | 26 (1.9)    |
| infection   |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Sinusitis   | 21 (0.7)    | 26 (1.3)    | 19 (0.9)    | 23 (1.7)    |
+-------------+-------------+-------------+-------------+-------------+

\*adolescent/adult subjects (ages ≥ 12 yrs in Studies 008, 009, 011C,
012, IA04 and Q2143g)

URI = upper respiratory tract infection

*Comment: In general, the study groups have similar rates of the most
common severe grade AE. An uncommon (\< 1% subjects) group of severe
grade AE (\"skin and appendages\") occurred at a higher rate in the
Omalizumab group than controls (Table 35). The excess in this group is
related to an excess number of subjects with rash (as described
subsequently).*

**C. Digestive, respiratory and GU system AE:**

*Comment: Because certain publications suggest IgE may function in
mucosal immunity, AE that occur in body systems potentially altered by
anti-IgE therapy are highlighted for review below. Specifically, the
following systems are examined: digestive, respiratory and GU system.*

**1. Digestive AE, including appendicitis:**

Table 37 summarizes the digestive system AE by severity grade within
both the AA controlled studies and the group of all controlled studies.

Table 37. Digestive system AE by severity grade

+-------------+-------------+-------------+-------------+-------------+
| **Severity  | **All       |             | **AA        |             |
| grade**     | controlled  |             | controlled  |             |
|             | studies, n  |             | studies\*,  |             |
|             | (%)**       |             | n (%)**     |             |
+-------------+-------------+-------------+-------------+-------------+
|             | Omalizumab  | Control     | Omalizumab  | Control     |
|             |             |             |             |             |
|             | n = 3224    | n = 2019    | n = 2076    | n = 1383    |
+-------------+-------------+-------------+-------------+-------------+
| Any event   | 612 (19.0)  | 360 (17.8)  | 444 (21.4)  | 260 (18.8)  |
+-------------+-------------+-------------+-------------+-------------+
| Mild        | 273 (8.5)   | 163 (8.1)   | 201 (9.7)   | 117 (8.5)   |
+-------------+-------------+-------------+-------------+-------------+
| Moderate    | 271 (8.4)   | 153 (7.6)   | 190 (9.2)   | 109 (7.9)   |
+-------------+-------------+-------------+-------------+-------------+
| Severe      | 68 (2.1)    | 44 (2.2)    | 53 (2.6)    | 34 (2.5)    |
+-------------+-------------+-------------+-------------+-------------+

\*adolescent/adult subjects (ages ≥ 12 yrs in Studies 008, 009, 011C,
012, IA04 and Q2143g)

*Comment: Table 37 shows a small excess of mild and moderate severity
digestive system AE among Omalizumab subjects. When the comparisons were
limited to placebo controlled studies, only moderate grade digestive
system AE occurred at a higher rate than in the control group (15% vs
13% in AA placebo controlled studies, 10.2% vs 9.9% in all placebo
controlled studies).*

*As shown in Tables 38 and 39, the Omalizumab group\'s excess of mild
and moderate digestive system AE appears related to a broad group of
specific AE with no single AE manifestation especially prominent.*

Table 38 summarizes AE by preferred term and severity within the group
of all controlled studies.

**Table 38. Common digestive system AE (≥ 1% any group) by severity**

in all controlled studies

  ----------------- --------------- --------- --------- ------------ --------- ---------
  **Preferred       **Omalizumab, n                     **Control, n           
  term**            = 3224, n (%)**                     = 2019, n              
                                                        (%)**                  

                    Mild            Mod.      Sev.      Mild         Mod.      Sev.

  Nausea            72 (2.2)        42 (1.3)  4 (0.1)   34 (1.7)     23 (1.1)  7 (0.3)

  Diarrhea          62 (1.9)        43 (1.3)  8 (0.2)   39 (1.9)     22 (1.1)  3 (0.1)

  Abdominal pain    46 (1.4)        52 (1.6)  10 (0.3)  27 (1.3)     27 (1.3)  9 (0.4)

  Dyspepsia         47 (1.5)        30 (0.9)  2 (0.1)   49 (2.4)     21 (1.0)  4 (0.2)

  Gastroenteritis   33 (1.0)        42 (1.3)  10 (0.3)  18 (0.9)     31 (1.5)  5 (0.2)

  Vomiting          28 (0.9)        32 (1.0)  5 (0.2)   20 (1.0)     14 (0.7)  3 (0.1)

  Toothache         17 (0.5)        30 (0.9)  4 (0.1)   14 (0.7)     20 (1.0)  2 (0.1)
  ----------------- --------------- --------- --------- ------------ --------- ---------

Table 39 summarizes AE by preferred term and severity within the group
of AA controlled studies.

**Table 39. Common digestive system AE (≥ 1% any group) by severity**

in AA controlled studies\*

  ----------------- --------------- --------- --------- ------------ --------- ---------
  **Preferred       **Omalizumab, n                     **Control, n           
  term**            = 2076, n (%)**                     = 1383, n              
                                                        (%)**                  

                    Mild            Mod.      Sev.      Mild         Mod.      Sev.

  Nausea            57 (2.7)        28 (1.3)  3 (0.1)   26 (1.9)     16 (1.2)  5 (0.4)

  Diarrhea          50 (2.4)        33 (1.6)  7 (0.3)   29 (2.1)     18 (1.3)  2 (0.1)

  Abdominal pain    24 (1.2)        29 (1.4)  5 (0.2)   15 (1.1)     19 (1.4)  6 (0.4)

  Dyspepsia         36 (1.7)        21 (1.0)  1 (0)     41 (3.0)     18 (1.3)  3 (0.2)

  Gastroenteritis   29 (1.4)        31 (1.5)  8 (0.4)   15 (1.1)     20 (1.4)  5 (0.4)

  Vomiting          16 (0.8)        19 (0.9)  4 (0.2)   8 (0.6)      9 (0.7)   2 (0.1)

  Toothache         13 (0.6)        22 (1.1)  4 (0.2)   13 (0.9)     15 (1.1)  2 (0.1)
  ----------------- --------------- --------- --------- ------------ --------- ---------

\*adolescent/adult subjects (ages ≥ 12 yrs in Studies 008, 009, 011C,
012, IA04 and Q2143g)

Within the original BLA filing, the occurrence of appendicitis was very
rare but a slight excess appeared among the Omalizumab subjects. Within
the new database of all controlled studies, appendicitis was recorded
for six (0.2%) Omalizumab group subjects and three (0.1%) control
subjects. These subjects are summarized in Table 40.

Table 40. Appendicitis in all controlled studies

+-----+-----+-------+---+----+-----------+--------------------------+
| **S | **G | *     | * | *  | **Time    | **Pathology**            |
| tud | rou | *Subj | * | *S | post**    |                          |
| y** | p** | ect** | A | ex |           |                          |
|     |     |       | g | ** | **random  |                          |
|     |     |       | e |    | ization** |                          |
|     |     |       | ( |    |           |                          |
|     |     |       | y |    |           |                          |
|     |     |       | r |    |           |                          |
|     |     |       | s |    |           |                          |
|     |     |       | ) |    |           |                          |
|     |     |       | * |    |           |                          |
|     |     |       | * |    |           |                          |
+-----+-----+-------+---+----+-----------+--------------------------+
| 006 | O   | 1279  | 4 | M  | 17 days   | Normal appendix          |
|     |     |       | 5 |    |           |                          |
+-----+-----+-------+---+----+-----------+--------------------------+
| 006 | O   | 1083  | 2 | F  | 12 days   | Normal appendix          |
|     |     |       | 4 |    |           |                          |
+-----+-----+-------+---+----+-----------+--------------------------+
| 009 | O   | 4675  | 3 | F  | 11 hours  | Appendicitis             |
|     |     |       | 8 |    |           |                          |
+-----+-----+-------+---+----+-----------+--------------------------+
| 010 | O   | 4329  | 1 | F  | 6 months  | Normal appendix          |
|     |     |       | 2 |    |           |                          |
+-----+-----+-------+---+----+-----------+--------------------------+
| 21  | O   | 10558 | 4 | M  | 1 month   | Normal appendix /        |
| 43g |     |       | 4 |    |           | lymphadenitis            |
+-----+-----+-------+---+----+-----------+--------------------------+
| 21  | O   | 12643 | 3 | M  | 4 days    | Periappendiceal serosal  |
| 43g |     |       | 7 |    |           | inflammation             |
+-----+-----+-------+---+----+-----------+--------------------------+
| 006 | C   | 2264  | 2 | M  | 2.5       | Appendicitis             |
|     | ont |       | 8 |    | months    |                          |
|     | rol |       |   |    |           |                          |
+-----+-----+-------+---+----+-----------+--------------------------+
| 008 | C   | 4784  | 2 | F  | 4 months  | Not available            |
|     | ont |       | 9 |    |           |                          |
|     | rol |       |   |    |           |                          |
+-----+-----+-------+---+----+-----------+--------------------------+
| 014 | C   | 2004  | 2 | M  | 12 days   | Appendicitis             |
|     | ont |       | 5 |    |           |                          |
|     | rol |       |   |    |           |                          |
+-----+-----+-------+---+----+-----------+--------------------------+

O = Omalizumab

Within the uncontrolled major studies, two Omalizumab-exposed subjects
developed abdominal pain and appendectomy disclosed appendicitis in both
subjects (confirmed by pathology).

Within the 120 day safety update to the BLA CR amendment, the sponsor
reports that three (0.3%) Omalizumab subjects experienced appendicitis
in on-going clinical studies (out of 1184 unblinded Omalizumab
subjects). The pathological diagnosis was not reported but all three
subjects appeared to have gross surgical evidence of appendicitis.
Additionally, one subject in the on-going studies was hospitalized with
abdominal pain and suspected appendicitis, but the subject was observed
in the hospital and the abdominal pain resolved (no surgery performed).

*Comment: While the number of subjects undergoing appendectomy is very
small, the finding that twice as many Omalizumab-exposed subjects
underwent appendectomy as control subjects appears notable. A similar
rate of appendectomies among Omalizumab-treated patients is
recapitulated in the uncontrolled patient experience. Also somewhat
notable is the finding of a pathologically normal appendix in four of
the six Omalizumab subjects. As summarized in Appendix D, the narratives
for all eight subjects from the controlled studies suggest no unusual or
unique features for the abdominal pain.*

*Overall, the database suggests Omalizumab subjects, when compared to
control groups, experienced a slight excess in a broad range of mild to
moderate severity digestive system AE. However, no specific AE or set of
AE appears at a remarkably higher rate among the Omalizumab-exposed
subjects than controls. Hence, the meaningfulness of the slight excess
in mild to moderate severity digestive system AE is unclear.
Appendicitis was uncommon in the clinical studies, but occurred among
more Omalizumab subjects than control subjects. Altered mucosal immunity
by anti-IgE therapy may have special implications for the appendix
because of the extent of immune effector cells within the appendiceal
wall and the organ\'s vulnerability to inflammation.*

**2. Respiratory AE:**

A broad range of respiratory system AE occurred at similar rates between
Omalizumab and control groups in the clinical studies (Appendix A).

Asthma exacerbations were efficacy endpoints within Studies 008, 009,
and 010 and certain \"protocol defined\" asthma exacerbations were
efficacy endpoints within Study Q2143g. These exacerbations were not
routinely recorded as AE within these studies. Consequently, the summary
of asthma exacerbation AE from all the controlled AA studies are largely
derived from Studies 011, 012, Q2143g and IA04. The overall frequency of
an asthma exacerbation AE was 9% for both study groups within these AA
controlled studies.

*Comment: The severity grading of asthma exacerbation AE within the AA
controlled studies shows a similar distribution of the grades between
Omalizumab and control subjects (Appendix A). This is especially notable
because much of this information comes from the open label studies that
allowed enrollment of subjects receiving relatively complex medical
regimens for asthma management. In general, these data suggest that
Omalizumab administration was not associated with an excessive severity
or incidence of asthma exacerbations. The totality of the respiratory
system AE data generally suggests no remarkable differences between
control subjects and those receiving Omalizumab.*

**3. Female genitourinary (GU) and reproductive AE:**

Table 41 summarizes the female GU and reproductive system AE by severity
grade within both the AA controlled studies and the group of all
controlled studies.

**Table 41. Female GU and reproductive system AE (females ≥ 12 years)**

by severity grade

+-------------+-------------+-------------+-------------+-------------+
| **Severity  | **All       |             | **AA        |             |
| grade**     | controlled  |             | controlled  |             |
|             | studies, n  |             | studies\*,  |             |
|             | (%)**       |             | n (%)**     |             |
+-------------+-------------+-------------+-------------+-------------+
|             | Omalizumab  | Control     | Omalizumab  | Control     |
|             |             |             |             |             |
|             | n = 1662    | n = 1042    | n = 1239    | n = 794     |
+-------------+-------------+-------------+-------------+-------------+
| Any event   | 187 (11.3)  | 108 (10.4)  | 162 (13.1)  | 98 (12.3)   |
+-------------+-------------+-------------+-------------+-------------+
| Mild        | 78 (4.7)    | 33 (3.2)    | 66 (5.3)    | 27 (3.4)    |
+-------------+-------------+-------------+-------------+-------------+
| Moderate    | 93 (5.6)    | 68 (6.5)    | 80 (6.5)    | 64 (8.1)    |
+-------------+-------------+-------------+-------------+-------------+
| Severe      | 16 (1.0)    | 7 (0.7)     | 16 (1.3)    | 7 (0.9)     |
+-------------+-------------+-------------+-------------+-------------+

\*adolescent/adult female subjects (ages ≥ 12 yrs in Studies 008, 009,
011C, 012, IA04 and Q2143g)

*Comment: Table 41 shows a small excess of mild and severe
GU/reproductive system AE among Omalizumab subjects. When the comparison
is limited to placebo controlled studies, a similar difference for mild
and severe events is seen between the study groups (data not shown). As
shown in Tables 42 and 43, the Omalizumab excess appears associated, in
part, with an excessive number of severe dysmenorrhea and urinary tract
infection AE. The small excess in mild GU AE among Omalizumab subjects
was related to a broad range of events in which no single event appeared
especially prominent in frequency.*

**Table 42. Common female GU and reproductive system AE females  12
years) (** 1% in any group), by preferred term and severity in all
controlled studies

  ---------------- --------------- -------- -------- ------------ --------- ---------
  **Term**         **Omalizumab, n                   **Control, n           
                   = 1662, n (%)**                   = 1042, n              
                                                     (%)**                  

                   Mild            Mod.     Sev.     Mild         Mod.      Sev.

  Dysmenorrhea     19 (1.1)        22 (1.3) 4 (0.2)  18 (1.7)     21 (2.0)  0

  Urinary tract    14 (0.8)        24 (1.4) 3 (0.2)  8 (0.8)      21 (2.0)  0
  infection                                                                 

  Other genital    11 (0.7)        12 (0.7) 0        6 (0.6)      11 (1.1)  1 (0.1)
  disorder                                                                  
  ---------------- --------------- -------- -------- ------------ --------- ---------

Mod = moderate, Sev = severe

**Table 43. Common female GU and reproductive system AE (females  12
years) (** 1% in any group), by preferred term and severity in AA
controlled studies\*

  ---------------- --------------- -------- -------- ------------ --------- ---------
  **Term**         **Omalizumab, n                   **Control, n           
                   = 1239, n (%)**                   = 794, n               
                                                     (%)**                  

                   Mild            Mod.     Sev.     Mild         Mod.      Sev

  Dysmenorrhea     14 (1.1)        17 (1.4) 4 (0.3)  14 (1.8)     19 (2.4)  0

  Urinary tract    12 (1.0)        22 (1.8) 3 (0.2)  8 (1.0)      20 (2.5)  0
  infection                                                                 

  Cystitis         11 (0.9)        8 (0.6)  0        5 (0.6)      9 (1.1)   0

  Other genital    11 (0.9)        11 (0.9) 0        6 (0.8)      11 (1.4)  1 (0.1)
  disorder                                                                  
  ---------------- --------------- -------- -------- ------------ --------- ---------

\*adolescent/adult female subjects (ages ≥ 12 yrs in Studies 008, 009,
011C, 012, IA04 and Q2143g)

*Comment: Overall, the data suggest that Omalizumab-exposed women
experienced an increased number of severe grade GU system
AE\--especially dysmenorrhea and urinary tract infection, although the
total numbers of subjects was relatively small.*

**D. Hypersensitivity AE:**

Analyses of hypersensitivity AE consist of examination of the following
outcomes:

1\) Anaphylaxis

2\) Skin rash (including urticaria)

3\) Urticaria concomitant with bronchospasm

4\) Serum sickness and an AE cluster compatible with serum sickness-like
syndrome

**1. Anaphylaxis:**

Overall, anaphyalxis or anaphylactoid reactions were experienced by four
subjects exposed to Omalizumab: three subjects within the major studies
and one subject within an exploratory study of IV Omalizumab. Clinical
features of these four subjects are summarized in Table 44 and more
detailed narratives are described in Appendix B.

Table 44. Anaphylaxis or anaphylactoid reactions following Omalizumab
exposure

+--------+--------+---------------------------------------+-----------+
| **Sub  | **S    | **Features**                          | **        |
| ject** | tudy** |                                       | Outcome** |
+--------+--------+---------------------------------------+-----------+
| 2712   | Q0694  | 30 y o male experienced anaphylactoid | dis       |
|        |        | reactions 1.5 hours after first       | continued |
|        |        | Omalizumab dose (IV)                  | Om        |
|        |        |                                       | alizumab; |
+--------+--------+---------------------------------------+-----------+
| 4621   | 008    | 39 y o female with a history of       | continued |
|        |        | penicillin and trimethoprim-sulfa     |           |
|        |        | allergy developed facial edema,       | Om        |
|        |        | hives, dyspnea 30 minutes after a     | alizumab; |
|        |        | Levaquin tablet ingestion and 21     |           |
|        |        | days after last Omalizumab dose       |           |
+--------+--------+---------------------------------------+-----------+
| 12411  | Q2143g | 19 y o female developed hives,        | dis       |
|        |        | itching and dyspnea 90 minutes after  | continued |
|        |        | her first Omalizumab dose             | Om        |
|        |        |                                       | alizumab; |
+--------+--------+---------------------------------------+-----------+
| 11756  | Q2143g | 28 y o female developed injection     | dis       |
|        |        | site edema, throat and tongue edema 2 | continued |
|        |        | hours after her fourth Omalizumab     | Om        |
|        |        | dose                                  | alizumab; |
+--------+--------+---------------------------------------+-----------+

y o = year old

The following are brief narratives for the two subjects who discontinued
the studies because of anaphylaxis following SC administration of
Omalizumab:

-Subject 11756 in Study Q2143g: Two hours following the fourth
Omalizumab dose, the subject noted that the injection site had
\"swollen\" to \"soft ball size.\" She also noticed mild throat and
tongue swelling but experienced no dyspnea. She self-medicated herself
that evening with oral steroids and antihistamines and the event
resolved over the next four days. She presented for follow-up with the
site investigator two days following the fourth Omalizumab injection at
which time the anaphylaxis event was recorded.

-Subject 12411 in Study Q2143g: Ninety minutes after the first
Omalizumab dose (while away from the clinical site), the subject noted
hives, itching and dyspnea. She returned to the clinic and received SC
epinephrine and IV steroids. The hives improved and she was sent home
but her symptoms worsened over the next few hours and she was seen in an
emergency room where another SC epinephrine injection was administered
and the subject discharged on prednisone. The symptoms all resolved over
the following week.

One control subject experienced an anaphylactoid reaction/anaphylaxis
after the accidental ingestion of peanuts. The subject, who had a
history of peanut allergy, continued in the study.

*Comment: The database shows that two subjects discontinued Omalizumab
following the development of anaphylaxis in association with SC
Omalizumab dosing. Both events resolved with therapy. The subject who
experienced anaphylaxis following Levaquin ingestion continued in the
study and received subsequent Omalizumab injections without recurrent
anaphylaxis. No additional cases of anaphylaxis have been reported among
the on-going studies. Overall, the data suggest that Omalizumab
administration rarely may be associated with anaphylactic reactions.*

**2. Skin rash (including urticaria):**

Table 45 summarizes the incidence of any rash within all controlled
studies and all placebo controlled studies. The \"any rash\" AE
designation includes those AE identified by any one of the following
terms: \"skin rash,\" \"urticaria,\" \"dermatitis,\" or \"pruritis.\"

Table 45. Rash AE in all controlled studies and all placebo controlled
studies

+-------------+-------------+-------------+-------------+-------------+
| *           | **All       |             | **All       |             |
| *Severity** | controlled  |             | placebo     |             |
|             | studies, n  |             | controlled  |             |
|             | (%)**       |             | studies, n  |             |
|             |             |             | (%)**       |             |
+-------------+-------------+-------------+-------------+-------------+
|             | Omalizumab, | Control,    | Omalizumab, | Control,    |
|             |             |             |             |             |
|             | n = 3224    | n = 2019    | n = 1801    | n = 1310    |
+-------------+-------------+-------------+-------------+-------------+
| Any event   | 211 (6.5)   | 98 (4.9)    | 111 (6.2)   | 86 (6.6)    |
+-------------+-------------+-------------+-------------+-------------+
| Mild        | 127 (3.9)   | 62 (3.1)    | 70 (3.9)    | 56 (4.3)    |
+-------------+-------------+-------------+-------------+-------------+
| Moderate    | 74 (2.3)    | 34 (1.7)    | 38 (2.1)    | 28 (2.1)    |
+-------------+-------------+-------------+-------------+-------------+
| Severe      | 10 (0.3)    | 2 (0.1)     | 3 (0.2)     | 2 (0.2)     |
+-------------+-------------+-------------+-------------+-------------+

*Comment: Among subjects in all controlled studies, the incidence of
rash was higher within the Omalizumab group (as previously noted for
both the group of all controlled studies and AA controlled studies in
the summary of AE by body system-\"skin\"). As shown in Table 45, the
higher rate within the Omalizumab group mainly derives from the
non-placebo controlled studies.*

Within all controlled studies, urticaria was assessed as drug related in
18 subjects, 17 Omalizumab-exposed subjects and 1 placebo subject. All
but eight of the Omalizumab urticaria cases occurred in the placebo
controlled studies. Four subjects (all Omalizumab-exposed) discontinued
study drug because of urticaria.

*Comment: The proportions of subjects experiencing the AE of urticaria
was similar between Omalizumab and control subjects (data not shown).
Overall, the data suggest that Omalizumab administration may be
associated with a higher incidence of rash that is not characterized as
urticarial.*

**3. Urticaria concomitant with bronchospasm:**

Within all controlled studies, urticaria and bronchospam occurred
concomitantly in nine subjects (6 Omalizumab subjects and 3 control).
Table 46 summarizes the features of the six Omalizumab subjects.

Table 46. Urticaria concomitant with bronchospams following Omalizumab
exposure

  ------------- ----------- ----------------------------------- ------------------
  **Subject**   **Study**   **Features**                        **Outcome**

  2251          006         44 y o female developed localized   Continued in
                            urticaria, dyspnea, coughing,       study; assessed as
                            wheezing and headache within 30     related
                            minutes after first dose; events    
                            resolved in 1 day;                  

  10228         Q2143g      37 y o female developed localized   Discontinued
                            urticaria, dyspnea and skin         Omalizumab;
                            flushing one day following third    assessed as
                            Omalizumab dose; events resolved    related
                            over several months                 

  11397         Q2143g      44 y o female experienced multiple  Continued in
                            episodes of chest tightness (over 2 study; assessed as
                            days) and rash for 14 weeks after   related
                            first Omalizumab dose;              

  12246         Q2143g      31 y o female experienced rash and  Continued in
                            pruritis (over 9 days) after first  study; assessed as
                            Omalizumab dose, followed by rash   unrelated
                            and dyspnea (lasting over 4 weeks)  

  10594         Q2143g      10 y o female experienced wheezing  Continued in
                            and rash at week 10 (lasting        study; assessed as
                            approximately 14 weeks\--throughout unrelated
                            the remainder of study)             

  12826         Q2143g      41 y o male experienced rash and    Continued in
                            asthma exacerbation 16 days after   study; assessed as
                            first Omalizumab dose (episode      unrelated
                            lasted approximately 1 week);       
  ------------- ----------- ----------------------------------- ------------------

The three control subjects with urticaria and bronchospams all received
placebo in Study 009. The subjects experienced rash or urticaria and
asthma exacerbation approximately 2 months, 5 months and 4 days
post-treatment and all episodes were assessed as unrelated to study drug
by the site investigators and all events resolved within approximately
one week.

*Comment: The comparison of the cluster of urticaria concomitant with
bronchospam AE shows that these events were uncommon but occurred in
twice as many Omalizumab-exposed subjects as control subjects. All but
one of the Omalizumab-exposed subjects continued receiving Omalizumab in
the clinical studies. The AE generally lasted longer in
Omalizumab-exposed subjects than similar events in the controls.
Overall, the data suggest that Omalizumab administration may uncommonly
be associated with urticaria and concomitant bronchospasm that, in some
cases, may take weeks before resolving. In general, these events did not
progress to worse allergic reactions despite the continuation of
Omalizumab.*

**4. Serum sickness and AE cluster compatible with serum sickness-like
syndrome**

No AE were reported as serum-sickness. In order to examine the incidence
of certain AE that, together, might be indicative of serum sickness
(ie., serum sickness-like syndrome), the following analysis was
submitted: the database was examined for the cluster of AE that
consisted of any type of rash lasting for \> 3 days (primary identifier)
then at least one of the following AE occurring concomitantly (onset
within 2 weeks of rash onset):

-fever,

-arthralgia,

-influenza-like symptoms,

-malaise,

-lymphadenopathy,

-proteinuria

-urine abnormality heading for the AE

Using this definition of serum sickness-like syndrome, three Omalizumab
subjects were identified along with one control subject. The Omalizumab
subjects are summarized in Table 47.

Table 47. Subjects with serum sickness-like syndrome following
Omalizumab exposure

  ------------- ----------- ----------------------------------- -------------------
  **Subject**   **Study**   **Features**                        **Outcome**

  4621          008         fever (lasted 1 day) with rash      Continued in study;
                            (lasted 12 days) that were          assessed as
                            suspected to be related to chicken  unrelated
                            pox                                 

  10048         Q2143g      rash (lasted 4 weeks) associated    Continued in study;
                            with arthralgia, myalgia, pruritus  assessed as
                            and headache (lasting 6 - 11 days)  unrelated

  11397         Q2143g      influenza-like symptoms (lasting 3  Continued in study;
                            days) followed by a rash that       rash assessed as
                            lasted 4 days                       related
  ------------- ----------- ----------------------------------- -------------------

The one control subject with a serum sickness-like syndrome was subject
4260 who developed shoulder pain associated with urticaria following
placebo injection.

*Comment: The resolution of the \"syndromes\" in three subjects despite
the continuation of Omalizumab administration suggests the cluster of
\"serum sickness-like syndrome\" events may have little clinical
meaningfulness.*

**E. Other immune-type AE:**

One Omalizumab subject experienced a Sjogren\'s-like syndrome which led
to discontinuation of the study drug. No other case of a similar event
occurred within the studies.

*Comment: The female subject with Sjogren\'s-like syndrome experienced
dry mouth and fatigue following several weeks of Omalizumab exposure.
Biopsy of a minor salivary gland showed a lymphocytic infiltration. The
subject\'s symptoms persisted despite the discontinuation of Omalizumab.
No similar event was detected among subjects in the safety database.*

*Overall, Omalizumab administration appears to be associated with rare
hypersensitivity events: anaphylaxis and skin rashes. The skin rashes
were not uniformly urticarial and may or may not have been part of a
related adverse event cluster. Several of the rash events were of severe
grade in their manifestations.*

**F. Bleeding-related AE and hemoglobin data:**

Bleeding related AE are highlighted for review because of the
preclinical finding of thrombocytopenia within monkeys and certain
hemoglobin findings from the clinical review of laboratory data.
Overall, the incidence of any bleeding-related AE was numerically higher
among Omalizumab subjects than control subjects, as summarized in Table
48.

**Table 48. Bleeding-related AE (events that occurred in ** 0.1%
subjects in any group)

+------------------+------------+------------+------------+------------+
| **Term**         | **All      |            | **AA       |            |
|                  | controlled |            | controlled |            |
|                  | studies, n |            | studies\*, |            |
|                  | (%)**      |            | n (%)**    |            |
+------------------+------------+------------+------------+------------+
|                  | O          | Control,   | O          | Control,   |
|                  | malizumab, |            | malizumab, |            |
|                  |            | n = 2019   |            | n = 1383   |
|                  | n = 3224   |            | n = 2076   |            |
+------------------+------------+------------+------------+------------+
| Any event        | 81 (2.5)   | 33 (1.6)   | 60 (2.8)   | 24 (1.7)   |
+------------------+------------+------------+------------+------------+
| Epi              | 45 (1.4)   | 22 (1.0)   | 26 (1.2)   | 14 (1.0)   |
| staxis/nosebleed |            |            |            |            |
+------------------+------------+------------+------------+------------+
| Menorrhagia      | 8 (0.2)    | 0          | 8 (0.4)    | 0          |
+------------------+------------+------------+------------+------------+
| Hematoma         | 6 (0.2)    | 2 (0.1)    | 5 (0.2)    | 2 (0.2)    |
+------------------+------------+------------+------------+------------+
| Blood in stool   | 4 (0.1)    | 2 (0.1)    | 4 (0.2)    | 2 (0.1)    |
+------------------+------------+------------+------------+------------+
| Hematuria        | 4 (0.1)    | 0          | 4 (0.2)    | 0          |
+------------------+------------+------------+------------+------------+
| Rectal           | 3 (0.1)    | 0          | 3 (0.1)    | 0          |
| hemorrhage       |            |            |            |            |
+------------------+------------+------------+------------+------------+
| Conjunctival     | 2 (0.1)    | 2 (0.1)    | 2 (0.1)    | 1 (0.1)    |
| hemorrhage       |            |            |            |            |
+------------------+------------+------------+------------+------------+
| Purpura          | 2 (0.1)    | 1 (0)      | 2 (0.1)    | 1 (0.1)    |
+------------------+------------+------------+------------+------------+
| Vaginal          | 1 (0.1)    | 2 (0.1)    | 1 (0.1)    | 1 (0.1)    |
| hemorrhage       |            |            |            |            |
+------------------+------------+------------+------------+------------+

\*adolescent/adult female subjects (ages ≥ 12 yrs in Studies 008, 009,
011C, 012, IA04 and Q2143g)

A numerically higher incidence of bleeding AE was also found among
comparisons of Omalizumab to placebo in the placebo controlled studies
(data not shown).

*Comment: Table 48 shows a small excess in the proportion of Omalizumab
subjects experiencing bleeding-related AE compared to control groups. In
general, this excess is largely related to an excess number of the
following bleeding events among Omalizumab subjects: epistaxis,
menorrhagia and hematoma.*

As shown in Table 48, among all controlled studies, 81
Omalizumab-exposed subjects and 33 control subjects experienced
bleeding-related AE. The bleeding-related AE are summarized by severity
in Appendix A. None of the subjects with bleeding AE developed
thrombocytopenia (no post-baseline platelet count \< 150,000/cmm).

*Comment: Over half the bleeding-related AE were graded as mild for both
study groups with a disproportionately larger number of the mild and
moderate grade severity events within the Omalizumab group. Severe grade
bleeding-related AE were not at excess in the Omalizumab group.*

Each of the seven severe grade bleeding-related AE occurred among unique
subjects (3 Omalizumab subjects and 4 control subjects). The severe
grade bleeding-related AE for the three Omalizumab subjects were:
epistaxis (subject 12384 in Study Q2143g), bloody diarrhea (subject
12641 in Study Q2143g) and hemoptysis (subject 3 in Study IA04). The
epistaxis AE occurred at an approximate time when the subject had a 20%
decrease in platelets (from baseline of 323,000/cmm to 252,000/cmm; the
subject with bloody diarrhea and the subject with hemoptysis both had no
decrease in platelets around the time of the bleed.

Table 49 summarizes platelet and hemoglobin changes among subjects with
and without bleeding-related AE in the controlled studies. This table is
limited to subjects with both a baseline and follow-up value for
hemoglobin or platelet count.

Table 49. Hemoglobin and platelet decrease from baseline for subjects
with and without bleeding-related AE

+-------------+------------+------------+--------------+-------------+
| **Max       | **Subjects |            | **Subjects   |             |
| decrease:** | with       |            | without      |             |
|             | bleeding   |            | bleeding     |             |
| **Plt Ct    | events, n  |            | events, n    |             |
| from        | (%)**      |            | (%)**        |             |
| Bsln\***    |            |            |              |             |
+-------------+------------+------------+--------------+-------------+
|             | Omalizumab | Control    | Omalizumab   | Control     |
|             |            |            |              |             |
|             | n = 80     | n = 32     | n = 3065     | n = 1916    |
+-------------+------------+------------+--------------+-------------+
| ≤ 0         | 24 (30.0)  | 14 (43.8)  | 928 (30.3)   | 713 (37.2)  |
+-------------+------------+------------+--------------+-------------+
| \> 0 - \<   | 45 (56.3)  | 16 (50.0)  | 1688 (55.1)  | 975 (50.9)  |
| 50          |            |            |              |             |
+-------------+------------+------------+--------------+-------------+
| 50 - \< 100 | 8 (10.0)   | 1 (3.1)    | 358 (11.7)   | 193 (10.1)  |
+-------------+------------+------------+--------------+-------------+
| 100 - \<    | 3 (3.8)    | 1 (3.1)    | 68 (2.2)     | 27 (1.4)    |
| 150         |            |            |              |             |
+-------------+------------+------------+--------------+-------------+
| 150 - \<    | 0          | 0          | 13 (0.4)     | 5 (0.3)     |
| 200         |            |            |              |             |
+-------------+------------+------------+--------------+-------------+
| ≥ 200       | 0          | 0          | 10 (0.3)     | 3 (0.2)     |
+-------------+------------+------------+--------------+-------------+
| **Max %     | Omalizumab | Control    | Omalizumab   | Control     |
| decrease:   |            |            |              |             |
| Hgb from    | n = 80     | n = 32     | n = 3045     | n = 1914    |
| Bsln**      |            |            |              |             |
+-------------+------------+------------+--------------+-------------+
| ≤ 0         | 20 (25.0)  | 6 (18.8)   | 819 (26.9)   | 609 (31.8)  |
+-------------+------------+------------+--------------+-------------+
| \> 0 - \<   | 56 (70.0)  | 24 (75.0)  | 2022 (66.4)  | 1193 (62.3) |
| 10          |            |            |              |             |
+-------------+------------+------------+--------------+-------------+
| 10 - \< 15  | 3 (3.8)    | 2 (6.3)    | 168 (5.5)    | 90 (4.7)    |
+-------------+------------+------------+--------------+-------------+
| 15 - \< 20  | 0          | 0          | 28 (0.9)     | 11 (0.6)    |
+-------------+------------+------------+--------------+-------------+
| 20 - \< 25  | 1 (1.3)    | 0          | 28 (0.9)     | 11 (0.6)    |
+-------------+------------+------------+--------------+-------------+
| ≥ 25        | 0          | 0          | 4 (0.1)      | 6 (0.3)     |
+-------------+------------+------------+--------------+-------------+

\*units of 10^-9^/L

Max = maximum, Plt Ct = platelet count, Bsln = baseline, Hgb =
hemoglobin

*Comment: Table 49 shows that a greater percentage of Omalizumab
subjects than control subjects had some decrease in platelet counts
during the studies, a finding present in subjects with or without
bleeding-related AE. The magnitude of the platelet count decrease was
greater for the Omalizumab subjects\--although the decreases resulted in
counts that still qualified as \"normal\" in all subjects. These
observations suggest that the Omalizumab group\'s platelet count
changes, alone, did not account for the group\'s slight excess in
bleeding-related AE.*

*The lower portion of Table 49 shows that the decrease in hemoglobin was
generally mild for all but one of the subjects with bleeding-related AE,
with the Omalizumab and control groups having similar changes in
hemoglobin values. Table 49 also shows that, for subjects without
bleeding events, more Omalizaumb subjects had a decrease in hemoglobin
than control subjects.*

In order to examine hemoglobin alterations more comprehensively, Table
50 summarizes shift analyses of hemoglobin from all subjects with
baseline and some follow-up hemoglobin data (including data from
subjects with abnormal baseline values). In this table \"notably\" low
refers to a change of \< 0.8 X LLN (for example, if LLN is 10 g/dL, then
a clinically notable value would be less than 8 g/dL).

Table 50. Shift analyses of hemoglobin

+--------------------+----------+----------+-----------+-------------+
| **Category**       | **All    |          | **AA      |             |
|                    | co       |          | c         |             |
|                    | ntrolled |          | ontrolled |             |
|                    | studies, |          | s         |             |
|                    | n (%)**  |          | tudies,\* |             |
|                    |          |          | n (%)**   |             |
+--------------------+----------+----------+-----------+-------------+
|                    | Oma      | Control, | Om        | Control,    |
|                    | lizumab, |          | alizumab, |             |
|                    |          | n = 1946 |           | n = 1328    |
|                    | n = 3125 |          | n = 2004  |             |
+--------------------+----------+----------+-----------+-------------+
| **Normal or high   | 2883     | 1820     | 1857      | 1236        |
| at baseline**      |          |          |           |             |
+--------------------+----------+----------+-----------+-------------+
| Shift to low       | 290      | 151      | 221       | 109 (8.8)   |
|                    | (10.1)   | (8.3)    | (11.9)    |             |
+--------------------+----------+----------+-----------+-------------+
| Shift to notably   | 2 (0.1)  | 1 (0.1)  | 1 (0.1)   | 1 (0.1)     |
| low                |          |          |           |             |
+--------------------+----------+----------+-----------+-------------+
| **Low at           | 242      | 126      | 147       | 92          |
| baseline**         |          |          |           |             |
+--------------------+----------+----------+-----------+-------------+
| Shift to even      | 131      | 51       | 95 (64.6) | 42 (45.7)   |
| lower              | (54.1)   | (40.5)   |           |             |
+--------------------+----------+----------+-----------+-------------+
| **Low at baseline, | 227      | 123      | 135       | 89          |
| but not notably    |          |          |           |             |
| low**              |          |          |           |             |
+--------------------+----------+----------+-----------+-------------+
| Shift to notably   | 7 (3.1)  | 4 (3.3)  | 5 (3.7)   | 4 (4.5)     |
| low                |          |          |           |             |
+--------------------+----------+----------+-----------+-------------+

\*adolescent/adult female subjects (ages ≥ 12 yrs in Studies 008, 009,
011C, 012, IA04 and Q2143g)

*Comment: Table 50 shows that more Omalizumab subjects had decreases in
hemoglobin than control subjects, an observation that was most profound
among subjects with low baseline hemoglobin values.*

Table 51 summarizes the magnitude of hemoglobin decreases from baseline
for all subjects with baseline and follow-up hemoglobin data.

Table 51. Decrease from baseline in hemoglobin

+--------------+-----------+-------------+-------------+-------------+
| **Max %      | **All     |             | **All AA    |             |
| decrease**   | c         |             | controlled  |             |
|              | ontrolled |             | studies,\*  |             |
|              | studies,  |             | n (%)**     |             |
|              | n (%)**   |             |             |             |
+--------------+-----------+-------------+-------------+-------------+
|              | Om        | Control, n  | Omalizumab, | Control, n  |
|              | alizumab, | = 1946      |             | = 1328      |
|              |           |             | n = 2004    |             |
|              | n = 3125  |             |             |             |
+--------------+-----------+-------------+-------------+-------------+
| ≤ 0          | 839       | 615 (31.6)  | 407 (20.3)  | 346 (26.1)  |
|              | (26.8)    |             |             |             |
+--------------+-----------+-------------+-------------+-------------+
| \> 0 - \< 10 | 2078      | 1217 (62.5) | 1439 (71.8) | 890 (67.0)  |
|              | (66.5)    |             |             |             |
+--------------+-----------+-------------+-------------+-------------+
| 10 - \< 15   | 171 (5.5) | 92 (4.7)    | 129 (6.4)   | 73 (5.5)    |
+--------------+-----------+-------------+-------------+-------------+
| 15 - \< 20   | 28 (0.9)  | 11 (0.6)    | 21 (1.0)    | 10 (0.8)    |
+--------------+-----------+-------------+-------------+-------------+
| 20 - \< 25   | 5 (0.2)   | 5 (0.3)     | 5 (0.2)     | 5 (0.4)     |
+--------------+-----------+-------------+-------------+-------------+
| ≥ 25         | 4 (0.1)   | 6 (0.3)     | 3 (0.1)     | 4 (0.3)     |
+--------------+-----------+-------------+-------------+-------------+

\*adolescent/adult female subjects (ages ≥ 12 yrs in Studies 008, 009,
011C, 012, IA04 and Q2143g)

*Comment: Table 51 shows that the decrease in hemoglobin was generally
mild for both study groups although more Omalizumab-exposed subjects
than controls experienced the mild decreases. Decreases in hemoglobin
from baseline \> 10% were noted in 7% Omalizumab subjects and 6% control
subjects.*

Within all controlled studies, a decrease in hemoglobin of ≥ 20%,
compared to baseline was detected in 20 subjects\--9 Omalizumab subjects
(0.3%) and 11 control subjects (0.6%). Women accounted for all nine
Omalizumab subjects and 7/11 control subjects. Bleeding AE occurred in
three of the 20 subjects (two Omalizumab subjects experienced
menorrhagia and one control subject was recorded as having a nonspecific
\"anemia.\")

*Comment: Overall, the hemoglobin data suggest that approximately 5%
more Omalizumab subjects than control subjects had at least one
follow-up time point showing a decrease in hemoglobin from baseline
(Table 51) but the magnitude of this decrease was small (\< 10%) for the
vast majority of subjects.*

Combining the bleeding-related AE data with the hemoglobin data, the
studies suggest two major observations:

*1) Slightly more Omalizumab subjects had bleeding-related AE than
control subjects, a difference that was:*

*-largely due to an excess number of subjects with non-severe grade
epistaxis and*

> *menorrhagia*

*-not clearly related to changes in platelet counts, and*

*2) Slightly more Omalizumab subjects had decreases in hemoglobin from
baseline, a difference that was:*

*-not clearly related to bleeding AE*

*-associated with mild decreases in hemoglobin.*

*The basis for the small excess in numbers of Omalizumab-exposed
subjects with decreases in hemoglobin is not evident from the data. No
evidence of an excess in severe or serious hemorrhage was observed.*

**G. Injection site reaction AE:**

Injection site reactions were assessed in two manners:

1\) In most placebo controlled studies (8 of 10 studies), the protocol
required investigators to assess the injection site following each study
drug injection (Studies 008, 009, 010, 011, 006, 007, 013 and D01).
These CRF required each study drug injection to be designated as one
with no reaction or some form of reaction (with detailed questions
regarding the specific types of reaction). Injection site reactions
could also be recorded as AE within these studies.

2\) In the standard therapy controlled studies, the two placebo
controlled Studies 012 and 014 and the uncontrolled studies, injection
site reactions were assessed only as AE. In these studies, the reporting
of the reactions was contingent upon the occurrence of signs and/or
symptoms sufficient to draw attention to the AE reaction.

*Comment: The differences in ascertainment processes among the studies
may account for inter-study differences in injection site reaction
rates\--with higher rates from studies requiring assessment of every
site injection and lower rates from the other studies. In general, the
most comprehensive study injection site reaction information comes from
the eight placebo controlled studies that required vigilant assessment
of injection sites. However, the ascertainment process in these studies
may have resulted in the reporting of mild injection site reactions that
(outside of the study setting) might not have been regarded as
clinically eventful. Table 52 provides the most meaningful summary of
the Omalizumab injection site reaction rate and a summary of the nature
of the reactions. Within this table, a subject with multiple site
reactions is reported once within the category and classified according
to the maximum severity of any reaction.*

**Table 52. Injection site reactions in major placebo controlled
studies\*,**

by severity

  ---------------------- ------------ ------------ ----------- ------------
  **Omalizumab, n =                                            
  1635**                                                       

  **Severity**           **Mild**     **Mod.**     **Sev.**    **All**

  Any reaction event, n  283 (17.3)   261 (16.0)   194 (11.9)  738 (45.1)
  (%)                                                          

  **Placebo, n = 1142**                                        

  Any reaction event, n  208 (18.2)   191 (16.7)   97 (8.5)    496 (43.4)
  (%)                                                          
  ---------------------- ------------ ------------ ----------- ------------

\*Studies 008, 009, 010, 011, 006, 007, D01 and 013

\*\*includes bruising, redness, warmth, burning, stinging, itching and
hive formation

Mod = moderate, Sev = severe

*Comment: Table 52 shows that \"some\" form of injection site reaction
was very common among both Omalizumab and control groups, with the rate
45% for Omalizumab and 43% for control\--the difference due exclusively
to a higher rate of severe grade injection site reactions among
Omalizumab subjects. \"Severe\" injection site reactions were reported
for 12% Omalizumab subjects and 9% control subjects.*

Information regarding the time to onset of local injection site
reactions and the duration of the reactions was collected in some of the
placebo controlled studies. In general, the time to onset for the
reactions was the same between Omalizumab and placebo injection (onset
was ≤ 1 hour for the majority of reactions). More Omalizumab (16%) than
placebo subjects (14%) had site reactions lasting more than seven days.
No injection site reactions were SAE.

The extent of injection site reaction information collected within most
of the placebo controlled studies provides an estimate of the rate of
reaction after the first treatment course (month) and all subsequent
courses. The data are summarized in Appendix A. In general, the
incidence of injection site reactions increased for both placebo and
Omalizumab injections after the first treatment course with the increase
in rates similar for the two groups.

Study 006E provides another way to examine the incidence of injection
site reactions following prior exposure to Omalizumab. Within this
uncontrolled, seasonal allergic rhinitis study, subjects received
Omalizumab during a second pollen season having been off Omalizumab
therapy for many months. No injection site AE were recorded during the
study\'s second season of Omalizumab administration.

*Comment: Overall, the incidence of injection site reactions increased
for study agent injections after the first treatment course, with the
increase in rates similar for both Omalizumab and placebo subjects.
Notably, no injection site AE were reported in Study 006E, an
uncontrolled, seasonal rhinitis study in which subjects received
Omalizumab during a second pollen season. In this study, subjects were
off Omalizumab for many months prior to resuming the injections.*

*Overall, the data suggest that approximately 45% Omalizumab-exposed
subjects experience some form of injection site reaction and
approximately 12% of Omalizumab-exposed subjects experience severe grade
injection site reactions (Table 52). These rates are generally two to
three absolute percentage points greater than the rates for control
subjects. The reactions are various combinations of local signs and
symptoms (such as redness, burning, warmth and occasionally localized
hive formation). The reactions generally develop within hours of the
injection and most resolve within a seven day period. However, 16% of
Omalizumab-exposed subjects had injection site reactions that took more
than seven days for resolution. No injection site reactions were
reported as SAE.*

**11. Laboratory results:**

The review of laboratory data focuses upon the controlled studies.
However, notable findings from the uncontrolled studies are also
identified.

**A. Hematology:**

**1. Hemoglobin and leukocytes:**

Appendix F contains tables summarizing the shifts in hematology tests
from normal at baseline to abnormal at any time post-treatment in
controlled studies.

*Comment: The hematology changes were most notable for a numeric excess
in the number of Omalizumab-exposed subjects with shifts to lower
hemoglobin/hematocrit/RBC and lower leukocytes (including lymphocytes
and neutrophils). The hemoglobin findings were discussed in the review
of bleeding-related AE.*

*Approximately 0.3% (absolute percentage point) more Omalizumab subjects
than control subjects experienced a decrease in leukocyte count at some
point in follow-up. The difference is so small it may be related to
chance alone (for example, randomization alone resulted in a 0.5%
difference at baseline in the proportion of subjects with low leukocyte
counts). The observed leukocyte decreases were mild and clinically
inconsequential. In general, these events were associated with
viral-type illnesses or were isolated time point findings. No subject
developed persistent neutropenia and no subject experienced a decrease
in WBC count below 2,300/cmm.*

**2. Platelets:**

**a. Summary findings:**

The incidence of shifts to lower platelet count values were generally
similar between the Omalizumab group and control groups in all
controlled studies. However, preclinical studies suggested Omalizumab
was associated with thrombocytopenia in some primates. Consequently,
multiple platelet count analyses are presented below.

Table 53 summarizes platelet shift data from the controlled studies. A
clinically notable value (\"notably low\") refers to a platelet count ≤
75 x 10^9^/L. The numbers represent subjects with baseline and follow-up
data.

**Table 53.** Shift analyses of platelets

+--------------------+----------+----------+-----------+-------------+
| **Category**       | **All    |          | **AA      |             |
|                    | co       |          | c         |             |
|                    | ntrolled |          | ontrolled |             |
|                    | studies, |          | s         |             |
|                    | n (%)**  |          | tudies,\* |             |
|                    |          |          | n (%)**   |             |
+--------------------+----------+----------+-----------+-------------+
|                    | Oma      | Control, | Om        | Control,    |
|                    | lizumab, |          | alizumab, |             |
|                    |          | n = 1948 |           | n = 1330    |
|                    | n = 3145 |          | n = 2024  |             |
+--------------------+----------+----------+-----------+-------------+
| **Normal or high   | 3080     | 1906     | 1993      | 1305        |
| at baseline**      |          |          |           |             |
+--------------------+----------+----------+-----------+-------------+
| Shift to low       | 44 (1.4) | 24 (1.3) | 21 (1.1)  | 18 (1.4)    |
+--------------------+----------+----------+-----------+-------------+
| Shift to notably   | 4 (0.1)  | 1 (0.1)  | 1 (0.1)   | 0           |
| low                |          |          |           |             |
+--------------------+----------+----------+-----------+-------------+
| **Low at           | 65       | 42       | 31        | 25          |
| baseline**         |          |          |           |             |
+--------------------+----------+----------+-----------+-------------+
| Shift to even      | 21       | 11       | 8 (25.8)  | 8 (32.0)    |
| lower              | (32.3)   | (26.2)   |           |             |
+--------------------+----------+----------+-----------+-------------+
| **Low at baseline, | 63       | 41       | 29        | 25          |
| but not notably    |          |          |           |             |
| low**              |          |          |           |             |
+--------------------+----------+----------+-----------+-------------+
| Shift to notably   | 0        | 1 (2.4)  | 0         | 1 (4.0)     |
| low                |          |          |           |             |
+--------------------+----------+----------+-----------+-------------+

\*adolescent/adult female subjects (ages ≥ 12 yrs in Studies 008, 009,
011C, 012, IA04 and Q2143g)

*Comment: Table 53 suggests no remarkable difference between the study
groups in the proportions of subjects with shifts from a normal or high
baseline platelet count to some decrease at a follow-up time point.
Among the subjects with a baseline low platelet count (2.1% Omalizumab
subjects and 2.2% control subjects), a shift to an even lower value was
detected in proportionally more Omalizumab subjects than control
subjects\--however no Omalizumab subjects within this subgroup had a
decrease in platelet count to a value ≤ 75 x 10^9^/L. Given the small
number of subjects within the low baseline platelet count subgroup, the
relatively small changes during follow-up and the variability within
platelet count measurements, the subgroup differences appear
unremarkable.*

*Overall, no subject with normal or elevated baseline platelet counts
developed thrombocytopenia during a controlled study..*

Table 54 compares the magnitude of absolute platelet decreases between
the groups in the controlled studies. This table identifies the maximum
decrease in platelet value recorded at any time in follow-up, not the
end-of-study value.

Table 54. Decrease from baseline in platelet counts, n (%)

+---------------+------------+------------+-------------+-------------+
| **Maximum     | **All      |            | **AA        |             |
| absolute      | controlled |            | controlled  |             |
| decrease      | studies**  |            | studies\*** |             |
| \*\***        |            |            |             |             |
+---------------+------------+------------+-------------+-------------+
|               | O          | Control,   | Omalizumab, | Control,    |
|               | malizumab, |            |             |             |
|               |            | n = 1948   | n = 2024    | n = 1330    |
|               | n = 3145   |            |             |             |
+---------------+------------+------------+-------------+-------------+
| ≤ 0           | 952 (30.3) | 727 (37.3) | 483 (23.9)  | 450 (33.8)  |
+---------------+------------+------------+-------------+-------------+
| \> 0 - \< 50  | 1733       | 991 (50.9) | 1198 (59.2) | 715 (53.8)  |
|               | (55.1)     |            |             |             |
+---------------+------------+------------+-------------+-------------+
| 50 - \< 100   | 366 (11.6) | 194 (10.0) | 277 (13.7)  | 139 (10.5)  |
+---------------+------------+------------+-------------+-------------+
| 100 - \< 150  | 71 (2.3)   | 28 (1.4)   | 53 (2.6)    | 20 (1.5)    |
+---------------+------------+------------+-------------+-------------+
| 150 - \< 200  | 13 (0.4)   | 5 (0.3)    | 10 (0.5)    | 4 (0.3)     |
+---------------+------------+------------+-------------+-------------+
| ≥ 200         | 10 (0.3)   | 3 (0.2)    | 3 (0.1)     | 2 (0.2)     |
+---------------+------------+------------+-------------+-------------+

\*adolescent/adult female subjects (ages ≥ 12 yrs in Studies 008, 009,
011C, 012, IA04 and Q2143g)

\*\*in units of x 10^9^/L

All subjects with a decrease in platelet count of ≥ 100 x 10^9^/L had
baseline counts that were normal or high and their nadir decreased
platelet count value was either normal or a single time point value that
was normal upon retesting.

*Comment: Table 54 shows that more Omalizumab than control subjects had
at least one follow-up platelet count with some decrease from
baseline\--a difference between the groups of approximately 7% (absolute
percentage points) in the group of all controlled studies. Most (82%) of
the excessive numbers of Omalizumab subjects with a decrease in platelet
count had a decrease of \< 100 x 10^9^/L.*

Within the controlled studies, four subjects (3 Omalizumab and 1
control) had baseline platelet counts ≤ 75 x 10^9^/L. These counts were
consistent with laboratory error in two subjects (all retest values were
normal) while the other two subjects (both Omalizumab) had increases in
their platelet counts following Omalizumab exposure. Shifts to
clinically notable low platelet counts occurred in four Omalizumab
subjects and two control subjects. Bleeding-related AE were detected in
none of these six subjects.

Three subjects in the controlled studies had platelet count changes
reported as SAE (Study Q2143g, two Omalizumab subjects and one control
subject). All three of the events were isolated time point findings
(follow-up while receiving Omalizumab showed normal platelet counts).

The only AE related to a platelet change in the controlled studies was
an increase to a high value for an Omalizumab of 404 x 10^9^/L to 505 x
10^9^/L at week two of the study. All subsequent values were normal.

Within the uncontrolled studies, no subject developed thrombocytopenia.
The platelet changes from the on-going studies are remarkable for one
Omalizumab-exposed subject (Appendix G) who had a low baseline platelet
count and was subsequently diagnosed with idiopathic thrombocytopenia
purpura. Three subjects with SAE of thrombocytopenia were recorded in
on-going studies, but in all three subjects the thrombocytopenia
diagnosis was found to have been made based upon a laboratory error
(retesting shortly following the abnormality had showed normal platelet
counts).

As noted in the review of bleeding-related AE, 81 Omalizumab subjects
experienced bleeding related AE. None of these 81 subjects had
abnormally low platelet counts during the studies.

*Comment: Together, these data do not suggest Omalizumab administration
was associated with the development of thrombocytopenia but do suggest
that Omalizumab administration may have decreased platelet counts in
approximately 7% of exposed subjects. The decrease in platelet counts
was largely by a magnitude of \< 100 x 10^9^/L and resulted in counts
that were still within normal limits. The magnitude of the platelet
count decrease is such that, based on the numeric change in platelet
numbers alone, one would not generally anticipate bleeding unless the
function of the platelets was also altered. The sponsor has performed
several studies of Omalizumab effects upon platelet function and none
have shown an altered function.*

**b. Platelet changes by serum Omalizumab concentration comparisons:**

Animal studies showed high blood concentrations of Omalizumab were
associated with thrombocytopenia. Although the Omalizumab dosages
associated with the preclinical thrombocytopenia were higher than those
proposed for marketing, it is useful to examine the clinical study data
regarding serum Omalizumab concentrations and platelet counts. Terminal
trough (prior to last dose) serum Omalizumab concentrations were
determined in most of the major AA controlled studies (Studies 008, 009,
011, 012 and Q2143g). Table 55 summarizes the distribution of terminal
serum Omalizumab concentration (by quartile) for adult/adolescent
subjects within these studies. Within the table, quartiles were defined
by using values of the last available trough Omalizumab concentration.

Table 55. Quartiles of terminal serum Omalizumab concentration

+-----------+-------------------------+----------------+--------------+
| **Q       | **Serum Omalizumab      | **n,           | **n,**       |
| uartile** | concentration**         | adul           |              |
|           |                         | t/adolescent** | **ages 12 -  |
|           |                         |                | 17**         |
+-----------+-------------------------+----------------+--------------+
| 1         | 0 - 21.4 mcg/mL         | 426            | 14           |
+-----------+-------------------------+----------------+--------------+
| 2         | \> 21.4 - 36.6 mcg/mL   | 419            | 18           |
+-----------+-------------------------+----------------+--------------+
| 3         | \> 36.6 - 64.9 mcg/mL   | 423            | 30           |
+-----------+-------------------------+----------------+--------------+
| 4         | \> 64.9 - 305.1 mcg/mL  | 422            | 58           |
+-----------+-------------------------+----------------+--------------+
| All       | All                     | 1690           | 120          |
+-----------+-------------------------+----------------+--------------+

The maximum trough Omalizumab concentration for any subject within the
studies was 305 mcg/mL, a value lower than the threshold value
associated with notable platelet decreases in adult monkeys (\~ 800
mcg/mLin adult monkeys and \~400 mcg/mL in juvenile monkeys). The
subject with the 305 mcg/mL value represented an extreme, isolated
value. No other subjects had terminal trough Omalizumab serum
concentrations \> 250 mcg/mL and only nine of the 1690 subjects with
terminal trough serum Omalizumab concentrations had values greater than
200 mcg/mL.

*Comment: The sponsor performed several animal studies that culminated
in the observation that the development of thrombocytopenia was closely
related to serum steady state Omalizumab concentrations. The use of
clinical subjects\' terminal trough Omalizumab serum concentration
allows a comparison of platelet changes to serum drug concentrations
that should approximate steady state concentrations. Table 55 shows
that, of the 1690 AA adult/adolescent subjects with available terminal
Omalizumab serum concentrations, 120 (7%) are adolescents. Notably,
approximately half the adolescents are in the fourth (high) quartile.*

The change in platelet concentrations by study time point and terminal
serum Omalizumab trough concentration are tabulated in Appendix F.
Overall, no clinically remarkable pattern of alterations in platelet
counts at the follow-up time points were found among the serum
Omalizumab quartiles or among the quartiles and control group. Among
adult/adolescents, the median absolute change from baseline in the
Omalizumab quartiles ranged between a decrease of 7 X 10^9^/L from
baseline to an increase of 15 X 10^9^/L.

During clinical development, Study Q0694 examined doses of Omalizumab
that were greater than those proposed for marketing. This study involved
repetitive IV administration (every two weeks) of Omalizumab over a
period of 20 weeks. Of the 106 subjects randomized to the highest dose
group within the study, seven subjects had peak serum Omalizumab
concentrations that exceeded 900 mcg/mL at multiple time points during
the clinical study. Five of these subjects had peak serum Omalizumab
concentrations greater than 1,100 mcg/mL at end-of-study. The trough
serum concentrations for these subjects generally ranged from 250 - 350
mcg/mL. Platelet counts were normal for these seven subjects throughout
the clinical study with no remarkable changes from baseline.

*Comment: In general, no notable alteration or trend for decrease in
platelet count was noted when analyzed according to terminal trough
Omalizumab serum concentration quartiles for the group of AA
adult/adolescent subjects. The data from adolescents (alone) are more
limited, but consistent with the data for adults. Six months or more of
follow-up terminal trough serum Omalizumab concentration data were
available for only 66 adolescent subjects. However, the sponsor does
have clinical data from children exposed to Omalizumab at dosages
proposed for marketing and, as summarized below, these data show no
alterations in platelet counts. These data derive from Study 010 and its
follow-up series of studies (Omalizumab exposure of one year for the
completed studies and \> 1 year in the on-going, extension study). The
platelet count data from a study of Omalizumab doses higher than those
proposed for marketing also show no significant platelet changes.
Together, the clinical study data suggest no correlatin of serum
Omalizumab concentrations with alterations in platelet counts.*

**c. Platelet changes in pediatric subjects:**

Within the overall safety database, Omalizumab exposure occurred in 318
pediatric subjects between the ages of ≥ 12 to 16 years. No remarkable
alterations of platelet counts occurred within this group. Notably, the
sponsor conducted an AA study among subjects \< 12 years of age. Study
010 enrolled approximately 300 AA subjects aged 6 to 12 years,
randomizing the subjects 2:1 to Omalizumab or placebo. The study
consisted of a seven month double blind treatment period followed by a
five month open label extension period. Consequently, the Omalizumab
subjects had either a 12 or five month exposure time. No subject
developed thrombocytopenia in the study. Three subjects within this
study had decreases in platelet counts to ≤ 75 x 10^9^/L and in all
three subjects the abnormalities were isolated changes suggestive of
laboratory errors (follow-up values while receiving Omalizumab were
normal). A summary of the maximum changes from baseline in platelet
counts is shown in Table 56.

**Table 56. Maximum change from baseline in platelet counts in Study
010,**

n (%) of subjects

+---------------------+------------------------+-----------------------+
| **Maximum absolute  | **Omalizumab,**        | **Omalizumab,**       |
| decrease\***        |                        |                       |
|                     | **12 month exposure**  | **5 month exposure**  |
|                     |                        |                       |
|                     | **n = 210**            | **n = 99**            |
+---------------------+------------------------+-----------------------+
| ≤ 0                 | 47 (22.4)              | 28 (28.3)             |
+---------------------+------------------------+-----------------------+
| \> 0 - \< 50        | 113 (53.8)             | 55 (55.6)             |
+---------------------+------------------------+-----------------------+
| 50 - \< 100         | 42 (20.0)              | 13 (13.1)             |
+---------------------+------------------------+-----------------------+
| 100 - \< 150        | 5 (2.4)                | 3 (3.0)               |
+---------------------+------------------------+-----------------------+
| ≥ 200               | 3 (1.4)                | 0                     |
+---------------------+------------------------+-----------------------+

> \*change from baseline is shown in units of x 10^9^/L

*Comment: No remarkable platelet count alterations were detected in the
study of approximately 300 children receiving Omalizumab. Serum
Omalizumab concentrations are not available for these subjects.
Nevertheless, the subjects received Omalizumab dosages consistent with
those proposed for marketing and the absence of any clinically
significant alterations in platelet counts is also consistent with the
studies in adolescent/adult subjects.*

**d. Platelet responses very early in treatment:**

Animals developing thrombocytopenia frequently developed the decrease
very shortly following Omalizumab exposure. Clinical Studies Q2143g and
Q2195g had platelet counts measured at both week one and two following
initiation of Omalizumab. Comparisons of these two time points showed no
change in platelet count values.

*Comment: The clinical findings of no acute change in platelet counts is
not surprising given the suggestion from animal data that high serum
Omalizumab concentrations correlate most closely with platelet
decreases. The doses used in the clinical studies were considerably less
than those associated with thrombocytopenia in animals.*

*Overall, platelet analyses showed a small (\~ 7%) excess proportion of
Omalizumab subjects had decreases in platelet concentrations compared to
control subjects. Approximately 80% of the Omalizumab subjects with
decreases in platelet concentrations had no more than a decrease of 50 x
10^9^/L. The decreases from baseline in the platelet concentrations
resulted in values that were still within normal limits with the only
exceptions being isolated events that appeared to represent laboratory
errors based upon retesting.*

**B. Blood chemistry:**

Serum chemistry was measured in most, but not all, the major clinical
studies. The following table summarize the findings from the studies
with available data.

**1. Liver tests:**

Summaries of shifts in liver tests from baseline to follow-up are
tabulated in Appendix F. These analyses generally showed no remarkable
differences between the two study groups. Shifts to a clinically notably
high SGOT value (\> 3X ULN) were seen in nine control subjects and two
Omalizumab subjects. No AE were reported in either of the two Omalizumab
subjects and the elevations were not accompanied by remarkable
elevations in other liver tests. The two subjects were:

-Subject 1902 in Study D01 had a baseline SGOT of 11 U/L. At month two,
the SGOT

> had increased to 62 U/L. By month four the SGOT was normal at 12 U/L.

-Subject 5076 in Study 009 had a baseline SGOT of 52 (abnormally high);
during the

> year-long Omalizumab exposure the SGOT was unchanged until month seven
> when at value of 224 U/L was recorded. The end-of-study value was 106
> U/L.

*Comment: Overall, no remarkable alterations of liver tests during
Omalizumab exposure were noted. The SGOT elevations noted in two
Omalizumab subjects were small elevations unaccompanied by any other
evidence of liver injury.*

**2. Renal tests:**

Shift analyses of changes in serum creatinine and urinalyses from
baseline are tabulated in Appendix F. In 140 (7%) Omalizumab subjects
and 58 (4%) control subjects \> 20% increases from baseline in serum
creatinine were reported on ≥ 2 visits or at the final visit. Of these
198 subjects, 9 (1%) Omalizumab subjects and 11 (1%) control subjects
also had urinary protein detected in urinalyses. Overall, the increases
in serum creatinine generally resulted in values still within normal
limits and the subjects with any evidence of proteinuria had resolution
of the proteinuria on repetition of urinalysis or the values returned to
baseline levels. The uncontrolled studies showed no remarkable
alterations of renal tests.

No remarkable renal test findings were detected in the uncontrolled
studies.

*Comment: Serum creatinine changes were clinically insignificant for
both control and Omalizumab groups in the clinical studies. The
urinalyses are notable for a slight excess in the proportion of
Omalizumab subjects with positive RBC and WBC post-treatment. The
differences are minor and, in the context of the overall laboratory
findings, unremarkable.*

*Overall, clinical laboratory data are most remarkable for the changes
in hemoglobin and the lack of changes in platelet counts.*

**12. Antibody formation:**

Antibody formation to Omalizumab was evaluated in all but three of the
major clinical studies (Studies Q2143g, Q2195g and IA04). No samples are
reported as having detectable antibodies to Omalizumab. One of the
concerns related to the antibody assay was the sponsor\'s observation
that the presence of study drug within the sample lessens the
sensitivity of the assay. FDA is awaiting additional information in
order to verify the antibody formation data.

Notably, all 282 of available baseline blood samples from Study 006E are
reported as having no detectable antibodies to Omalizumab. In this SAR
study, the subjects had completed one treatment course of Omalizumab (in
Study 006) approximately nine months prior to enrollment into Study
006E. Consequently, these subjects would not have been expected to have
Omalizumab within their baseline blood samples.

*Comment: The occurrence of at least two cases of anaphylaxis in
association with Omalizumab but no report of any antibody formation
appears surprising. Additional data regarding the assay performance
characteristics are to be submitted for FDA to review. Consequently, FDA
is currently unable to verify the reports of no antibody formation to
Omalizumab.*

**13. Retreatment data:**

Study 006E was a repeat treatment SAR study that enrolled subjects who
had completed Study 006 (the core study, see Appendix C). Study 006 was
designed to assess Omalizumab effects upon the control of SAR symptoms
during a season of allergy exposure. Subjects completing this 12 week
study were, following nine months off study drug, eligible for a second
allergen\'s season of Omalizumab administration. It is important to note
that the Omalizumab dosages used in Studies 006 and 006E were generally
less than those proposed for marketing. In Study 006, Omalizumab dose
response (50, 150, or 300 mg every 3 or 4 weeks) was evaluated and the
300 mg dose was chosen for retreatment testing. In Study 006E, all 287
subjects receiving Omalizumab were treated with a dose of 300 mg every
three or four weeks (depending on baseline IgE).

The incidence of AE was 47% in both the core and retreatment study. AE
reported by at least 3% of subjects in either the core or retreatment
study, respectively, included the following:

-headache, 12% and 11%

-upper respiratory tract infection, 6% and 9%

-viral infection, 5% and 6%

-sinusitis, 2% and 4%

Suspected drug-related AE were less frequent in the retreatment study
than in the core study (2% versus 6%). The most frequently reported drug
related AE in the retreatment study was fatigue (2 subjects, 1%).

Notable findings in the retreatment study included:

-no cases of anaphylaxis

-no bleeding-related AE

-six subjects (2%) had AE of rash reported, with only one of these a
report of urticaria

-one SAE was reported (appendicitis)

-no notable laboratory alterations (including no alteration in
platelets)

*Comment: Study 006E findings suggest that retreatment with relatively
low Omalizumab doses (following several months off treatment) is
associated with no excess in AE or abnormal laboratory findings compared
to the initial treatment course. However, the sample size within the
retreatment database is relatively small (approximately 300 subjects)
and the subjects were selected for enrollment because of SAR symptoms
(not AA) and few co-morbid diseases. Consequently, the findings are
notable but of limited utility in estimating the potential consequences
of Omalizumab retreatment courses in AA.*

**14. Pregnancy:**

In all completed studies, 27 subjects were diagnosed as pregnant during
the study. In all studies, subjects diagnosed with an on-going pregnancy
had Omalizumab discontinued. The outcomes for the 27 subjects from the
completed studies are summarized in Table 57.

Table 57. Pregnancies in completed studies

+-------------------------------+---------------+----------+---------+
| **Event**                     | **Group**     |          |         |
+-------------------------------+---------------+----------+---------+
|                               | Omalizumab    | Control  | Total   |
|                               |               |          |         |
|                               | n = 17        | n = 10   | n = 27  |
+-------------------------------+---------------+----------+---------+
| Normal delivery               | 11            | 6        | 17      |
+-------------------------------+---------------+----------+---------+
| Delivery outcome unknown      | 0             | 2        | 2       |
+-------------------------------+---------------+----------+---------+
| Spontaneous abortion          | 3             | 2        | 5       |
+-------------------------------+---------------+----------+---------+
| Elective abortion             | 3             | 0        | 3       |
+-------------------------------+---------------+----------+---------+

In the on-going studies, 12 subjects have had pregnancies recorded (one
detected prior to enrollment). One of the 12 subjects experienced a
spontaneous abortion. All other subjects had normal deliveries or were
awaiting delivery at the time of data cut-off. Three male subjects
within the on-going studies had partners diagnosed with pregnancy and
each pregnancy outcome was as follows: one resulted in a spontaneous
abortion, one resulted in a normal pregnancy and delivery and one
outcome was unrecorded because the subject discontinued the study.

*Comment: The overall pattern of AE related to pregnancy do not signal
substantial concerns. However, the clinical studies were not designed to
evaluate Omalizumab effects in pregnancy in any manner other than as
adverse events. No clinical data assess the use of Omalizumab during
pregnancy. Reproduction studies in monkeys showed no maternal toxicity,
embryotoxicity or teratogenicity when Omalizumab was administered
throughout organogenesis. In these studies, Omalizumab was administered
at doses up to 12-fold greater than those proposed for marketing*

**15. Drug-level effects on AE:**

As previously noted, terminal serum Omalizumab concentrations were
determined in several major studies. In Appendix A, AE are tabulated by
body system cluster and terminal trough serum Omalizumab concentration
for adult/adolescent subjects in the controlled AA studies. Five system
clusters had with inter-quartile rates showing increased rates of AE
with increasing serum drug concentrations: digestive,
infections/infestations, musculoskeletal, nervous and skin/appendages.
The common preferred term rates that also appear to suggest a
correlation with study drug concentration (for the five cited system
clusters) are summarized in Table 58. The preferred term events within
this table are those with rates that increase in sequential quartiles
and occur at a rate \> 1% within any quartile.

*Comment: The comparisons of AE by terminal serum Omalizumab trough
concentrations and body system clusters include data from both blinded
studies and the open label Study Q2143g. The overall (non-quartile)
rates may be somewhat biased by knowledge of the treatment assignment.
However, knowledge of treatment assignment should not impact the pattern
of rates within the study drug concentration quartiles and this pattern
may be as important (if not more important) than comparing the overall
rates between the active and control study groups.*

**Table 58.** Common AE in AA adult/adolescent controlled studies,\* by
preferred term and quartile of terminal serum Omalizumab concentration
(all rates \> 1% within any Omalizumab quartile and increasing within
sequential quartiles )

+-----------------+---------+---------+----------+---------+---------+
| **System/term** | **Oma   |         |          |         | **Con   |
|                 | lizumab |         |          |         | trol,** |
|                 | Qu      |         |          |         |         |
|                 | artile, |         |          |         | **n     |
|                 | n (%)** |         |          |         | (%)**   |
|                 |         |         |          |         |         |
|                 |         |         |          |         | n =     |
|                 |         |         |          |         | 1216    |
+-----------------+---------+---------+----------+---------+---------+
|                 | 1 (low) | 2       | 3        | 4       |         |
|                 |         |         |          | (high)  |         |
|                 | n = 426 | n = 419 | n = 423  |         |         |
|                 |         |         |          | n = 422 |         |
+-----------------+---------+---------+----------+---------+---------+
| Digestive       |         |         |          |         |         |
+-----------------+---------+---------+----------+---------+---------+
| Dyspepsia       | 8 (1.9) | 13      | 13 (3.1) | 14      | 59      |
|                 |         | (3.1)   |          | (3.3)   | (4.9)   |
+-----------------+---------+---------+----------+---------+---------+
| Vomiting        | 4 (0.9) | 7 (1.7) | 8 (1.9)  | 12      | 19      |
|                 |         |         |          | (2.8)   | (1.6)   |
+-----------------+---------+---------+----------+---------+---------+
| Infectio        |         |         |          |         |         |
| ns/infestations |         |         |          |         |         |
+-----------------+---------+---------+----------+---------+---------+
| Viral infection | 68      | 95      | 98       | 134     | 385     |
|                 | (16.0)  | (22.7)  | (23.3)   | (31.8)  | (31.7)  |
+-----------------+---------+---------+----------+---------+---------+
| Musculoskeletal |         |         |          |         |         |
+-----------------+---------+---------+----------+---------+---------+
| Back pain       | 28      | 29      | 37 (8.7) | 37      | 92      |
|                 | (6.6)   | (6.9)   |          | (8.8)   | (7.6)   |
+-----------------+---------+---------+----------+---------+---------+
| Arthralgia      | 17      | 23      | 24 (5.7) | 25      | 49      |
|                 | (4.0)   | (5.5)   |          | (5.9)   | (4.0)   |
+-----------------+---------+---------+----------+---------+---------+
| Sprains/strains | 9 (2.1) | 16      | 20 (4.7) | 21      | 92      |
|                 |         | (3.8)   |          | (5.0)   | (7.6)   |
+-----------------+---------+---------+----------+---------+---------+
| Leg pain        | 4 (0.9) | 9 (2.1) | 9 (2.1)  | 10      | 15      |
|                 |         |         |          | (2.4)   | (1.2)   |
+-----------------+---------+---------+----------+---------+---------+
| Nervous         |         |         |          |         |         |
+-----------------+---------+---------+----------+---------+---------+
| Headache        | 53      | 61      | 67       | 88      | 201     |
|                 | (12.4)  | (14.6)  | (15.8)   | (20.9)  | (16.5)  |
+-----------------+---------+---------+----------+---------+---------+
| Skin/appendages |         |         |          |         |         |
+-----------------+---------+---------+----------+---------+---------+
| Rash            | 10      | 13      | 13 (3.1) | 22      | 25      |
|                 | (2.3)   | (3.1)   |          | (5.2)   | (2.1)   |
+-----------------+---------+---------+----------+---------+---------+
| Bruising        | 6 (1.4) | 7 (1.7) | 7 (1.7)  | 9 (2.1) | 14      |
|                 |         |         |          |         | (1.2)   |
+-----------------+---------+---------+----------+---------+---------+

\*Studies 008, 009, 011, 012 and Q2143g

*Comment: Table 58 shows drug-concentration correlations with AE for
several preferred term events although most of these events occurred at
rates that were, overall, lower than control. Consequently, the
meaningfulness of the serum concentration-relatedness is unclear. The
difference between the highest quartile rate and the control rate is
especially remarkable for \"rash\"\--an event (especially for severe
grade rash) signaled as a safety concern from prior analyses. These
data, combined with severity grade analyses of \"rash\" AE, provide
strong evidence of an Omalizumab-related increase in AE incidence
related to rash.*

**16. AE by drug exposure duration:**

Tabulations of AE rates by various Omalizumab study exposure periods are
shown in Appendix A. Overall, no remarkable pattern of AE rate
differences are found between the control and Omalizuamb groups when
analyzed according to exposure period.

*Comment: Comparative analyses of AE by study drug exposure are confined
to the AA studies. The other studies (mainly rhinitis) were generally of
four months or less durations and sometimes used Omalizumab dosages
lower than those proposed for marketing. Although the main AA safety and
efficacy studies were of one year duration, approximately one half of
the subjects contributing to the safety database had exposures of less
than one year\--generally six to seven months. Consequently, the most
extensive safety information comes from six to seven months of
Omalizumab exposure.*

*In general, no striking findings are evident when body system clusters
are analyzed according to Omalizumab exposure period. Within the group
of AA controlled studies, the systems with an excessive proportion of
affected Omalizumab subjects in the final period also had the excess
evident in the earliest period except for
\"Infections/infestations\"\--a system that showed similar proportions
between the two study groups within the placebo controlled studies in
the last exposure period. The \"body as a whole\" and \"skin/appendage\"
systems had especially notable differences in proportions in the
earliest exposure period\--differences that lessened in subsequent
periods but did not disappear. The preferred terms accounting for most
of the excess proportion of \"body as a whole\" events were: injection
site reactions and fatigue. The preferred terms accounting for most of
the excess proportion of \"skin/appendages\" events were: rash, pruritis
and bruising.*

**17. Analyses of AE by demographic subsets and in-study
characteristics:**

Analyses were performed comparing the study groups for the following
subsets of subjects: ages 6 - 11, 12 - 17, 18 - 64 and ≥ 65 years;
gender; race; asthma severity and certain concomitant asthma medications
and antibiotics. In general, differences in the proportion of AE by
system and preferred term were similar between the study groups within
these subsets in a pattern consistent with the differences evident in
the overall analyses. Remarkable findings were confined to analyses of
age subsets and within those, only the geriatric subset raised concerns.
Table 59 shows the AE by body system cluster analysis for the geriatric
population. Other age subset tabulations are shown in Appendix A.

**Table 59. AE by body system rates for ages ≥ 65 years**

in adolescent/adult controlled studies

+---------------+-----------+------------+------------+-------------+
| **System**    | **All     |            | **AA       |             |
|               | c         |            | controlled |             |
|               | ontrolled |            | studies\*, |             |
|               | studies,  |            | n (%)**    |             |
|               | n (%)**   |            |            |             |
+---------------+-----------+------------+------------+-------------+
|               | Om        | Control,   | O          | Control,    |
|               | alizumab, |            | malizumab, |             |
|               |           | n = 71     |            | n = 65      |
|               | n = 142   |            | n = 134    |             |
+---------------+-----------+------------+------------+-------------+
| Any event     | 102       | 54 (76.1)  | 99 (73.9)  | 51 (78.5)   |
|               | (71.8)    |            |            |             |
+---------------+-----------+------------+------------+-------------+
| **Body as     | 28 (19.7) | 6 (8.5)    | 28 (20.9)  | 5 (7.7)     |
| whole**       |           |            |            |             |
+---------------+-----------+------------+------------+-------------+
| **Car         | 14 (9.9)  | 3 (4.2)    | 14 (10.4)  | 3 (4.6)     |
| diovascular** |           |            |            |             |
+---------------+-----------+------------+------------+-------------+
| **Digestive** | 20 (14.1) | 7 (9.9)    | 20 (14.9)  | 7 (10.9)    |
+---------------+-----------+------------+------------+-------------+
| He            | 2 (1.4)   | 1 (1.4)    | 2 (1.5)    | 1 (1.5)     |
| mic/lymphatic |           |            |            |             |
+---------------+-----------+------------+------------+-------------+
| Infections    | 26 (18.3) | 16 (22.5)  | 26 (19.4)  | 15 (23.1)   |
| /infestations |           |            |            |             |
+---------------+-----------+------------+------------+-------------+
| Lab           | 4 (2.8)   | 2 (2.8)    | 4 (3.0)    | 2 (3.1)     |
| abnormality   |           |            |            |             |
+---------------+-----------+------------+------------+-------------+
| **Musc        | 11 (7.7)  | 3 (4.2)    | 29 (21.6)  | 13 (20.0)   |
| uloskeletal** |           |            |            |             |
+---------------+-----------+------------+------------+-------------+
| **Nervous**   | 23 (16.2) | 6 (8.5)    | 23 (17.2)  | 6 (9.2)     |
+---------------+-----------+------------+------------+-------------+
| Respiratory   | 67 (47.2) | 35 (49.3)  | 66 (49.3)  | 34 (52.3)   |
+---------------+-----------+------------+------------+-------------+
| Sk            | 17 (12.0) | 10 (14.1)  | 17 (12.7)  | 9 (13.8)    |
| in/appendages |           |            |            |             |
+---------------+-----------+------------+------------+-------------+
| Special       | 10 (7.0)  | 6 (8.5)    | 9 (6.7)    | 6 (9.2)     |
| senses        |           |            |            |             |
+---------------+-----------+------------+------------+-------------+
| **GU/r        | 9 (6.3)   | 2 (2.8)    | 9 (6.7)    | 2 (3.1)     |
| eproductive** |           |            |            |             |
+---------------+-----------+------------+------------+-------------+

\*Studies 008, 009, 011, 012, IA04 and Q2143g

*Comment: In general, the findings in the ≥ 65 year group stand out for
fairly strikingly higher rates among the Omalizumab group for several
body system clusters, as follows: body as a whole; cardiovascular;
digestive; musculoskeletal, nervous and GU/reproductive. The changes are
especially notable within the AA subgroups.*

Table 60 summarizes the most common (\> 2% in Omalizumab group for all
controlled studies) AE by preferred term for the six body system
clusters with higher rates for Omalizumab subjects than control among
subjects ≥ 65 years of age in the AA studies.

*Comment: Table 60 identifies the most common AE in the elderly group by
preferred term. Each of the cited events occurred in a small number of
subjects, a reflection of the very small overall sample size. However,
an excess of Omalizumab-exposed subjects experienced the following AE:
injury, peripheral edema, injection site reaction, chest pain,
dyspepsia, diverticulitis, abdominal pain, back pain, arthralgia,
arthrosis, sprains/strains, headache, hypoesthesia, anxiety, dizziness,
paresthesia and renal calculus. Of special note, the excess proportion
of Omalizumab subjects experiencing cardiovascular system AE was related
to no more than 2 subjects experiencing a broad range of events.
Overall, the very small sample size of geriatric subjects largely
precludes the ability to make definitive conclusions regarding the AE
rates within the geriatric population but the data raise substantial
concern about the safety of Omalizumab in older patients.*

**Table 60. Common (\> 2% in Omalizumab group, controlled studies) AE by
preferred term for subjects ** 65 years of age in selected body
systems, AA studies

+-----------------+----------+-----------+-----------+----------------+
| **System/term** | **AA     |           | **AA      |                |
|                 | studies, |           | placebo   |                |
|                 | n (%)**  |           | c         |                |
|                 |          |           | ontrolled |                |
|                 |          |           | studies,  |                |
|                 |          |           | n (%)**   |                |
+-----------------+----------+-----------+-----------+----------------+
|                 | Oma      | Control,  | Om        | Control,       |
|                 | lizumab, |           | alizumab, |                |
|                 | n = 134  | n = 65    |           | n = 26         |
|                 |          |           | n = 40    |                |
+-----------------+----------+-----------+-----------+----------------+
| Body as whole   |          |           |           |                |
+-----------------+----------+-----------+-----------+----------------+
| Injury          | 6 (4.5)  | 0         | 3 (7.5)   | 0              |
+-----------------+----------+-----------+-----------+----------------+
| Peripheral      | 4 (3.0)  | 0         | 2 (5.0)   | 0              |
| edema           |          |           |           |                |
+-----------------+----------+-----------+-----------+----------------+
| Fever           | 4 (3.0)  | 2 (3.1)   | 4 (10.0)  | 1 (3.8)        |
+-----------------+----------+-----------+-----------+----------------+
| Injection site  | 4 (3.0)  | 0         | 0         | 0              |
| reaction        |          |           |           |                |
+-----------------+----------+-----------+-----------+----------------+
| Chest pain      | 3 (2.2)  | 0         | 2 (5.0)   | 0              |
+-----------------+----------+-----------+-----------+----------------+
| Cardiovascular  |          |           |           |                |
+-----------------+----------+-----------+-----------+----------------+
| Hypertension    | 3 (2.2)  | 2 (3.1)   | 2 (5.0)   | 2 (7.7)        |
+-----------------+----------+-----------+-----------+----------------+
| Digestive       |          |           |           |                |
+-----------------+----------+-----------+-----------+----------------+
| Diarrhea        | 7 (5.2)  | 4 (6.2)   | 5 (12.5)  | 2 (7.7)        |
+-----------------+----------+-----------+-----------+----------------+
| Dyspepsia       | 4 (3.0)  | 0         | 2 (5.0)   | 0              |
+-----------------+----------+-----------+-----------+----------------+
| Nausea          | 4 (3.0)  | 2 (3.1)   | 3 (7.5)   | 2 (7.7)        |
+-----------------+----------+-----------+-----------+----------------+
| Diverticulitis  | 3 (2.2)  | 0         | 1 (2.5)   | 0              |
+-----------------+----------+-----------+-----------+----------------+
| Abdominal pain  | 3 (2.2)  | 1 (1.5)   | 2 (5.0)   | 1 (3.8)        |
+-----------------+----------+-----------+-----------+----------------+
| Musculoskeletal |          |           |           |                |
+-----------------+----------+-----------+-----------+----------------+
| Back pain       | 10 (7.5) | 3 (4.6)   | 5 (12.5)  | 1 (3.8)        |
+-----------------+----------+-----------+-----------+----------------+
| Arthralgia      | 6 (4.5)  | 1 (1.5)   | 3 (7.5)   | 1 (3.8)        |
+-----------------+----------+-----------+-----------+----------------+
| Arthrosis       | 3 (2.2)  | 1 (1.5)   | 1 (2.5)   | 0              |
+-----------------+----------+-----------+-----------+----------------+
| Sprains/strains | 3 (2.2)  | 0         | 1 (2.5)   | 0              |
+-----------------+----------+-----------+-----------+----------------+
| Nervous         |          |           |           |                |
+-----------------+----------+-----------+-----------+----------------+
| Headache        | 12 (9.0) | 3 (4.6)   | 13 (32.5) | 4 (15.4)       |
+-----------------+----------+-----------+-----------+----------------+
| Hypoesthesia    | 4 (3.0)  | 0         | 1 (2.5)   | 0              |
+-----------------+----------+-----------+-----------+----------------+
| Anxiety         | 3 (2.2)  | 1 (1.5)   | 3 (7.5)   | 1 (3.8)        |
+-----------------+----------+-----------+-----------+----------------+
| Dizziness       | 3 (2.2)  | 0         | 0         | 0              |
+-----------------+----------+-----------+-----------+----------------+
| Paresthesia     | 3 (2.2)  | 0         | 0         | 0              |
+-----------------+----------+-----------+-----------+----------------+
| GU/reproductive |          |           |           |                |
+-----------------+----------+-----------+-----------+----------------+
| Renal calculus  | 2 (1.5)  | 0         | 1 (2.5)   | 0              |
+-----------------+----------+-----------+-----------+----------------+

\*Studies 008, 009, 011, 012, IA04 and Q2143g

**18. Summary:**

**A. Overview:**

The sponsor seeks an indication for the maintenance use of Omalizumab in
the treatment of AA in adults and adolescents (≥ 12 years of age) with
moderate to severe allergic asthma that is inadequately controlled
despite the use of inhaled corticosteroids. Three clinical studies
examined the safety and efficacy of Omalizumab in this subject
population (Studies 008, 009 and 011). Subjects exposed to Omalizumab in
these three studies account for approximately 20% of all subjects
exposed to Omalizumab in the major clinical studies. Other clinical
studies examined the safety and bioactivity of Omalizumab among subjects
with allergic asthma or its usage among subjects with SAR, PAR or AD.

Overall, the safety database consists of 3,507 subjects exposed to
Omalizumab in the major clinical studies. Approximately 70% of these
subjects were enrolled in AA studies. The vast majority of subjects in
the safety database are Caucasians between the ages of 18 and 64 years.
Adolescents (aged 12 to 17 years) and geriatric subjects (age ≥ 65
years) account for only nine and four percent of the safety database,
respectively. Omalizumab exposure in the clinical studies was limited to
one year or less.

Most of the safety data is derived from controlled clinical studies of
Omalizumab use in AA. However, several of the clinical studies for
non-AA indications were also controlled. Consequently, the group of
\"all controlled studies\" contains both AA and non-AA studies. The
group of \"AA controlled studies\" is limited to the AA studies. The
three studies designed to assess safety and efficacy in AA (Studies 008,
009 and 011) were placebo controlled while most of the studies designed
to focus solely upon safety in AA used \"standard therapy\" controls.
Findings from these controlled clinical studies provide the most
meaningful safety observations.

In general, most of the safety findings relate to uncommon events or
events that occurred at only a modestly higher rate among
Omalizumab-exposed subjects than control subjects. The basis for citing
several of these events relate to the biological plausibility that
anti-IgE therapy might alter immunity (especially altered mucosal
immunity and immunity to cancer) and the possibility that events
appearing infrequently in the premarketing experience may signal very
important safety concerns once large numbers of patients are exposed to
Omalizumab following marketing.

**B. Serious adverse events:**

Deaths were rare in the clinical studies. Only three subjects died
during the major studies: two Omalizumab-exposed subjects and one
placebo subject. Both Omalizumab subject deaths were from events that
appeared unrelated to Omalizumab exposure. One additional death has been
reported for an Omalizumab-exposed subject during an on-going study.
This subject died of rapidly progressive meningococcal sepsis. The
subject had received approximately one year of Omalizumab exposure prior
to his death. The assocation of the Omalizuamb exposure with the death
is unclear.

Nonfatal SAE occurred at a slightly higher rate among Omalizumab-exposed
subjects than controls in the group of all controlled studies (4.2%
versus 3.8%) as well as the group of AA controlled studies (5.6% versus
4.6%). Two major SAE findings were observed:

-   Malignancy:

> Comparisons of malignancy rates suggest (but do not establish) an
> increased rate for Omalizumab-exposed subjects. Malignancies occurred
> at a rate of 6.3 events/1000 patient years exposure for the Omalizumab
> group and 3.3 events/1000 patient years exposure for the control
> group. Excluding non-melanoma skin cancer, the difference between the
> two study groups is greater (5.1 events/1000 patient years versus 1.3
> events/1000 patient years). The malignancies were largely solid
> organ/epithelial type cancers. Comparisons of the clinical study data
> to a large epidemiological database suggested Omalizumab-exposed
> subjects experienced more malignancies than expected while the control
> group experienced fewer malignancies.

-   Anaphylaxis:

> Anaphylaxis or anaphylactoid reactions were experienced by four
> subjects exposed to Omalizumab and one subject in a control group. One
> reaction followed IV Omalizumab administration and the other three
> Omalizumab cases involved SC administration. One Omalizumab-exposed
> subject\'s reaction appeared related to Levofloxacin allergy and not
> the Omalizumab. Two other Omalizumab-exposed subjects\' reactions
> could only be related to the Omalizumab exposure. All anaphylaxis
> reactions were treated with multiple medications (antihistamines,
> epinephrine, steroids) and no subjects experienced respiratory
> failure. The one anaphylaxis reaction among a control subject involved
> peanut ingestion by a subject known to be allergic to peanuts.

**C. Other adverse events:**

Within the controlled studies, adverse events occurred among
approximately 75% of both the control and Omalizumab-exposed subjects.
Because of the possibility anti-IgE therapy might impact mucosal
immunity, digestive, respiratory and GU events were examined in detail.
The following are the most notable observations:

-   Rash AE:

> Rash AE occurred among 6.5% of Omalizumab-exposed subjects and 4.9% of
> control subjects in the group of all controlled studies. The excess
> among the Omalizumab group was observed for all grades of rash AE
> severity. The incidence of rash correlated with end-of-study trough
> serum Omalizumab concentrations. In general, the rash AE were
> non-urticarial reactions that resolved despite the continuation of
> Omalizumab adminstration.

-   Digestive system AE:

> A small excess of digestive system AE were observed among more
> Omalizumab-exposed subjects than controls (19% versus 18% in all
> controlled studies). The excess was related to AE of nausea, vomiting,
> diarrhea and abdominal pain. The events were of mild to moderate
> severity. Although uncommon, appendicitis occurred among more
> Omalizumab-exposed subjects than control subjects (six versus three
> subjects). The incidence of digestive system AE correlated with
> end-of-study trough Omalizumab concentrations.

-   Bleeding-related AE:

> More Omalizumab-exposed subjects experienced bleeding-related AE than
> control subjects (2.5% versus 1.6% in all controlled studies). The
> excess was attributable to mild to moderate severity grades of the
> following AE: epistaxis, menorrhagia and hematoma. The events did not
> appear to be related to alterations in blood platelet concentrations.

-   Female GU AE:

> Although very uncommon, female GU AE appeared at a higher rate among
> Omalizumab-exposed subjects than controls (11.3% versus 10.4% in all
> controlled studies). The events accounting for the excess included a
> higher rate of severe grade dysmenorrhea AE and urinary tract
> infection AE.

-   AE among the geriatric population:

> Only 142 geriatric subjects were exposed to Omalizumab in the
> controlled studies. Analyses of AE by body system cluster showed the
> Omalizumab-exposed subjects experienced substantially more system
> cluster events than control subjects. The systems included the
> following: body as a whole, cardiovascular, digestive,
> musculoskeletal, nervous and GU/reproductive. The numbers of subjects
> experiencing any specific type of AE within a system cluster were too
> small to attribute the overall system cluster excess to any specific
> AE or small group of AE.

**D. Other findings:**

-   Hemoglobin and platelets:

> A decrease in hemoglobin at some point during follow-up was common in
> the controlled clinical studies. More Omalizumab-exposued subjects
> than controls experienced a decrease (73% versus 68%). The decrease
> for both groups was mild in magnitude and did not appear related to
> bleeding events or alterations in platelets.
>
> A decrease in platelet count at some point during follow-up was also
> common in the controlled studies. More Omalizumab-exposed subjects
> than controls experienced a decrease (70% versus 63%). The decrease
> for both groups was mild in magnitude. No Omalizumab-exposed subject
> with normal baseline or high platelet counts developed abnormally low
> platelet counts.

-   Antibody formation:

> No antibody formation to Omalizumab was reported. However, FDA review
> of these data are pending the submission of additional information.

**Appendix A. Adverse event tables cited in text**

Table 61. AE occurring at a rate \> 1% among Omalizumab group and at a
higher rate than control, all controlled studies & AA controlled
studies\*

+-------------------------+-----------+--------+-----------+---------+
| **System/term**         | **All     |        | **AA      |         |
|                         | c         |        | c         |         |
|                         | ontrolled |        | ontrolled |         |
|                         | studies** |        | st        |         |
|                         |           |        | udies\*** |         |
+-------------------------+-----------+--------+-----------+---------+
|                         | Om        | Co     | Om        | C       |
|                         | alizumab, | ntrol, | alizumab, | ontrol, |
|                         |           |        |           |         |
|                         | n = 3224  | n =    | n = 2076  | n =     |
|                         |           | 2019   |           | 1383    |
+-------------------------+-----------+--------+-----------+---------+
| Body as a whole         |           |        |           |         |
+-------------------------+-----------+--------+-----------+---------+
| Injury                  | 90 (2.8)  | 47     | 65 (3.1)  | 39      |
|                         |           | (2.3)  |           | (2.8)   |
+-------------------------+-----------+--------+-----------+---------+
| Injection site reaction | 85 (2.6)  | 4      | 69 (3.3)  | 1 (0.1) |
|                         |           | (0.2)  |           |         |
+-------------------------+-----------+--------+-----------+---------+
| Chest pain              | 60 (1.9)  | 32     | 53 (2.6)  | 17      |
|                         |           | (1.6)  |           | (1.2)   |
+-------------------------+-----------+--------+-----------+---------+
| Fatigue                 | 59 (1.8)  | 21     | 54 (2.6)  | 17      |
|                         |           | (1.0)  |           | (1.2)   |
+-------------------------+-----------+--------+-----------+---------+
| Trauma                  | 58 (1.8)  | 30     | 36 (1.7)  | 23      |
|                         |           | (1.5)  |           | (1.7)   |
+-------------------------+-----------+--------+-----------+---------+
| Digestive               |           |        |           |         |
+-------------------------+-----------+--------+-----------+---------+
| Nausea                  | 118 (3.7) | 64     | 88 (4.2)  | 47      |
|                         |           | (3.2)  |           | (3.4)   |
+-------------------------+-----------+--------+-----------+---------+
| Diarrhea                | 113 (3.5) | 64     | 90 (4.3)  | 49      |
|                         |           | (3.2)  |           | (3.5)   |
+-------------------------+-----------+--------+-----------+---------+
| Abdominal pain          | 108 (3.4) | 63     | 58 (2.8)  | 40      |
|                         |           | (3.1)  |           | (2.9)   |
+-------------------------+-----------+--------+-----------+---------+
| Vomiting                | 65 (2.0)  | 37     | 39 (1.9)  | 19      |
|                         |           | (1.8)  |           | (1.4)   |
+-------------------------+-----------+--------+-----------+---------+
| GE reflux               | 25 (0.8)  | 13     | 25 (1.2)  | 10      |
|                         |           | (0.6)  |           | (0.7)   |
+-------------------------+-----------+--------+-----------+---------+
| Infections/infestations |           |        |           |         |
+-------------------------+-----------+--------+-----------+---------+
| Abscess                 | 31 (1.0)  | 13     | 29 (1.4)  | 16      |
|                         |           | (0.6)  |           | (1.2)   |
+-------------------------+-----------+--------+-----------+---------+
| Musculoskeletal         |           |        |           |         |
+-------------------------+-----------+--------+-----------+---------+
| Arthralgia              | 122 (3.8) | 63     | 98 (4.7)  | 50      |
|                         |           | (3.1)  |           | (3.6)   |
+-------------------------+-----------+--------+-----------+---------+
| Fracture                | 47 (1.5)  | 25     | 35 (1.7)  | 17      |
|                         |           | (1.2)  |           | (1.2)   |
+-------------------------+-----------+--------+-----------+---------+
| Leg pain                | 39 (1.2)  | 21     | 33 (1.6)  | 15      |
|                         |           | (1.0)  |           | (1.1)   |
+-------------------------+-----------+--------+-----------+---------+
| Nervous                 |           |        |           |         |
+-------------------------+-----------+--------+-----------+---------+
| Dizziness               | 62 (1.9)  | 25     | 52 (2.5)  | 15      |
|                         |           | (1.2)  |           | (1.1)   |
+-------------------------+-----------+--------+-----------+---------+
| Anxiety                 | 34 (1.1)  | 14     | 32 (1.5)  | 11      |
|                         |           | (0.7)  |           | (0.8)   |
+-------------------------+-----------+--------+-----------+---------+
| Respiratory             |           |        |           |         |
+-------------------------+-----------+--------+-----------+---------+
| Pharyngitis             | 331       | 187    | 221       | 143     |
|                         | (10.3)    | (9.3)  | (10.7)    | (10.3)  |
+-------------------------+-----------+--------+-----------+---------+
| Dyspnea                 | 52 (1.6)  | 25     | 37 (1.8)  | 19      |
|                         |           | (1.2)  |           | (1.4)   |
+-------------------------+-----------+--------+-----------+---------+
| Epistaxis               | 43 (1.3)  | 18     | 26 (1.3)  | 14      |
|                         |           | (0.9)  |           | (1.0)   |
+-------------------------+-----------+--------+-----------+---------+
| Bronchospasm            | 37 (1.2)  | 22     | 28 (1.4)  | 16      |
|                         |           | (1.1)  |           | (1.2)   |
+-------------------------+-----------+--------+-----------+---------+
| Laryngitis              | 24 (0.7)  | 12     | 23 (1.1)  | 11      |
|                         |           | (0.6)  |           | (0.8)   |
+-------------------------+-----------+--------+-----------+---------+
| Pneumonia               | 29 (0.9)  | 18     | 23 (1.1)  | 12      |
|                         |           | (0.9)  |           | (0.8)   |
+-------------------------+-----------+--------+-----------+---------+
| Skin and appendages     |           |        |           |         |
+-------------------------+-----------+--------+-----------+---------+
| Rash                    | 86 (2.7)  | 39     | 69 (3.3)  | 28      |
|                         |           | (1.9)  |           | (2.0)   |
+-------------------------+-----------+--------+-----------+---------+
| Pruritis                | 55 (1.7)  | 13     | 47 (2.3)  | 8 (0.6) |
|                         |           | (0.6)  |           |         |
+-------------------------+-----------+--------+-----------+---------+
| Contact dermatitis      | 39 (1.2)  | 19     | 25 (1.2)  | 18      |
|                         |           | (0.9)  |           | (1.3)   |
+-------------------------+-----------+--------+-----------+---------+
| Bruising                | 34 (1.1)  | 17     | 32 (1.5)  | 14      |
|                         |           | (0.8)  |           | (1.0)   |
+-------------------------+-----------+--------+-----------+---------+
| Dermatitis              | 34 (1.1)  | 16     | 29 (1.4)  | 13      |
|                         |           | (0.8)  |           | (0.9)   |
+-------------------------+-----------+--------+-----------+---------+
| Eczema                  | 27 (0.8)  | 19     | 23 (1.1)  | 11      |
|                         |           | (0.9)  |           | (0.8)   |
+-------------------------+-----------+--------+-----------+---------+
| Special senses          |           |        |           |         |
+-------------------------+-----------+--------+-----------+---------+
| Otitis media            | 59 (1.8)  | 32     | 32 (1.5)  | 21      |
|                         |           | (1.6)  |           | (1.5)   |
+-------------------------+-----------+--------+-----------+---------+
| Ear ache                | 50 (1.6)  | 23     | 25 (1.2)  | 9 (0.7) |
|                         |           | (1.1)  |           |         |
+-------------------------+-----------+--------+-----------+---------+

GE = gastroesophageal

> \*adolescent/adult subjects, (ages ≥ 12 yrs in Studies 008, 009, 011C,
> 012, IA04 and Q2143g)
>
> **Table 62.** AE occurring at a rate \> 1% among Omalizumab group and
> at a higher rate than control, all placebo controlled studies & AA
> placebo controlled studies\*

+---------------------+-----------+-----------+-----------+------------+
| System/term         | All       |           | AA        |            |
|                     | placebo   |           | placebo   |            |
|                     | c         |           | c         |            |
|                     | ontrolled |           | ontrolled |            |
|                     | studies   |           | studies\* |            |
+---------------------+-----------+-----------+-----------+------------+
|                     | Om        | Placebo,  | Om        | Placebo,   |
|                     | alizumab, |           | alizumab, |            |
|                     |           | n = 1310  |           | n = 717    |
|                     | n = 1801  |           | n = 738   |            |
+---------------------+-----------+-----------+-----------+------------+
| Body as a whole     |           |           |           |            |
+---------------------+-----------+-----------+-----------+------------+
| Pain                | 69 (3.8)  | 53 (4.1)  | 48 (6.5)  | 39 (5.4)   |
+---------------------+-----------+-----------+-----------+------------+
| Injury              | 52 (2.9)  | 34 (2.6)  | 28 (3.8)  | 26 (3.6)   |
+---------------------+-----------+-----------+-----------+------------+
| Fatigue             | 28 (1.6)  | 18 (1.4)  | 23 (3.1)  | 14 (2.0)   |
+---------------------+-----------+-----------+-----------+------------+
| Chest pain          | 23 (1.3)  | 21 (1.6)  | 18 (2.4)  | 15 (2.1)   |
+---------------------+-----------+-----------+-----------+------------+
| Fever               | 95 (5.1)  | 68 (5.2)  | 38 (5.2)  | 36 (5.0)   |
+---------------------+-----------+-----------+-----------+------------+
| Influenza like      | 23 (1.3)  | 13 (1.0)  | 13 (1.8)  | 9 (1.3)    |
| symptoms            |           |           |           |            |
+---------------------+-----------+-----------+-----------+------------+
| Trauma              | 36 (2.0)  | 25 (1.9)  | 14 (1.9)  | 18 (2.5)   |
+---------------------+-----------+-----------+-----------+------------+
| Digestive           |           |           |           |            |
+---------------------+-----------+-----------+-----------+------------+
| Diarrhea            | 69 (3.8)  | 59 (4.5)  | 48 (6.5)  | 44 (6.1)   |
+---------------------+-----------+-----------+-----------+------------+
| Nausea              | 70 (3.9)  | 55 (4.2)  | 42 (5.7)  | 39 (5.4)   |
+---------------------+-----------+-----------+-----------+------------+
| Gastroenteritis     | 56 (3.1)  | 44 (3.4)  | 40 (5.4)  | 32 (4.5)   |
+---------------------+-----------+-----------+-----------+------------+
| Toothache           | 46 (2.6)  | 33 (2.5)  | 34 (4.6)  | 27 (3.8)   |
+---------------------+-----------+-----------+-----------+------------+
| Vomiting            | 44 (2.4)  | 33 (2.5)  | 22 (3.0)  | 17 (2.4)   |
+---------------------+-----------+-----------+-----------+------------+
| Infe                |           |           |           |            |
| ctions/infestations |           |           |           |            |
+---------------------+-----------+-----------+-----------+------------+
| Moniliasis          | 29 (1.6)  | 27 (2.1)  | 29 (3.9)  | 26 (3.6)   |
+---------------------+-----------+-----------+-----------+------------+
| Abscess             | 20 (1.1)  | 13 (1.0)  | 18 (2.4)  | 12 (1.7)   |
+---------------------+-----------+-----------+-----------+------------+
| Musculoskeletal     |           |           |           |            |
+---------------------+-----------+-----------+-----------+------------+
| Back pain           | 122 (6.8) | 106 (8.1) | 92 (12.5) | 86 (12.0)  |
+---------------------+-----------+-----------+-----------+------------+
| Arthralgia          | 81 (4.5)  | 59 (4.5)  | 57 (7.7)  | 46 (6.4)   |
+---------------------+-----------+-----------+-----------+------------+
| Sprains/strains     | 63 (3.5)  | 47 (3.6)  | 42 (5.7)  | 34 (4.7)   |
+---------------------+-----------+-----------+-----------+------------+
| Myalgia             | 65 (3.6)  | 51 (3.9)  | 47 (6.4)  | 43 (6.0)   |
+---------------------+-----------+-----------+-----------+------------+
| Fracture            | 28 (1.6)  | 17 (1.3)  | 18 (2.4)  | 10 (1.4)   |
+---------------------+-----------+-----------+-----------+------------+
| Leg pain            | 32 (1.8)  | 19 (1.5)  | 26 (3.5)  | 13 (1.8)   |
+---------------------+-----------+-----------+-----------+------------+
| Arm pain            | 21 (1.2)  | 9 (0.7)   | 14 (1.9)  | 6 (0.8)    |
+---------------------+-----------+-----------+-----------+------------+
| Nervous             |           |           |           |            |
+---------------------+-----------+-----------+-----------+------------+
| Headache            | 408       | 319       | 196       | 190 (26.5) |
|                     | (22.7)    | (24.4)    | (26.6)    |            |
+---------------------+-----------+-----------+-----------+------------+
| Dizziness           | 28 (1.6)  | 21 (1.6)  | 20 (2.7)  | 11 (1.5)   |
+---------------------+-----------+-----------+-----------+------------+
| Anxiety             | 18 (1.0)  | 12 (0.9)  | 16 (2.2)  | 9 (1.3)    |
+---------------------+-----------+-----------+-----------+------------+
| Depression          | 19 (1.1)  | 12 (0.9)  | 17 (2.3)  | 10 (1.4)   |
+---------------------+-----------+-----------+-----------+------------+
| Respiratory         |           |           |           |            |
+---------------------+-----------+-----------+-----------+------------+
| Pharyngitis         | 225       | 161       | 126       | 120 (16.7) |
|                     | (12.5)    | (12.3)    | (17.1)    |            |
+---------------------+-----------+-----------+-----------+------------+
| Rhinitis            | 145 (8.1) | 134       | 107       | 101 (14.1) |
|                     |           | (10.2)    | (14.5)    |            |
+---------------------+-----------+-----------+-----------+------------+
| Epistaxis           | 29 (1.6)  | 13 (1.0)  | 15 (2.0)  | 9 (1.3)    |
+---------------------+-----------+-----------+-----------+------------+
| Pneumonia           | 12 (0.7)  | 8 (0.6)   | 8 (1.1)   | 3 (0.4)    |
+---------------------+-----------+-----------+-----------+------------+
| Skin and appendages |           |           |           |            |
+---------------------+-----------+-----------+-----------+------------+
| Rash                | 45 (2.5)  | 34 (2.6)  | 29 (3.9)  | 23 (3.2)   |
+---------------------+-----------+-----------+-----------+------------+
| Pruritis            | 23 (1.3)  | 12 (0.9)  | 16 (2.2)  | 7 (1.0)    |
+---------------------+-----------+-----------+-----------+------------+
| Contact dermatitis  | 25 (1.4)  | 17 (1.3)  | 14 (1.9)  | 16 (2.2)   |
+---------------------+-----------+-----------+-----------+------------+
| Dermatitis          | 20 (1.1)  | 12 (0.9)  | 18 (2.4)  | 9 (1.3)    |
+---------------------+-----------+-----------+-----------+------------+
| Special senses      |           |           |           |            |
+---------------------+-----------+-----------+-----------+------------+
| Ear infection, nos  | 30 (1.7)  | 23 (1.8)  | 16 (2.2)  | 15 (2.1)   |
+---------------------+-----------+-----------+-----------+------------+
| Otitis media        | 42 (2.3)  | 26 (2.0)  | 18 (2.4)  | 16 (2.2)   |
+---------------------+-----------+-----------+-----------+------------+
| Ear ache            | 40 (2.2)  | 21 (1.6)  | 15 (2.0)  | 7 (1.0)    |
+---------------------+-----------+-----------+-----------+------------+

nos = not otherwise specified

\*adolescent/adult subjects (ages ≥ 12 yrs in Studies 008, 009, 011C,
012, IA04 and Q2143g)

**Table 63. Common respiratory system AE (≥ 1% any group) by severity**

in all controlled studies

  ------------- --------------- --------- --------- ------------ --------- ---------
  **Preferred   **Omalizumab, n                     **Control, n           
  term**        = 3224, n (%)**                     = 2019, n              
                                                    (%)**                  

                Mild            Mod.      Sev.      Mild         Mod.      Sev.

  URI           214 (6.6)       344       29 (0.9)  114 (5.6)    246       18 (0.9)
                                (10.7)                           (12.2)    

  Pharyngitis   176 (5.5)       141 (4.4) 14 (0.4)  87 (4.3)     94 (4.7)  6 (0.3)

  Sinusitis     109 (3.4)       281 (8.7) 21 (0.7)  53 (2.6)     225       26 (1.3)
                                                                 (11.1)    

  Rhinitis      133 (4.1)       89 (2.8)  9 (0.3)   90 (4.5)     77 (3.8)  15 (0.7)

  Coughing      117 (3.6)       94 (2.9)  5 (0.2)   90 (4.5)     65 (3.2)  6 (0.3)

  Bronchitis    48 (1.5)        141 (4.4) 11 (0.3)  32 (1.6)     107 (5.3) 10 (0.5)

  Epistaxis     35 (1.1)        7 (0.2)   1 (0)     13 (0.6)     3 (0.1)   2 (0.1)

  Chest         7 (0.2)         32 (1.0)  8 (0.2)   6 (0.3)      27 (1.3)  4 (0.2)
  infection                                                                
  ------------- --------------- --------- --------- ------------ --------- ---------

URI = upper respiratory tract infection

**Table 64. Common respiratory system AE (≥ 1% any group) by severity**

in AA controlled studies\*

  ------------- --------------- --------- --------- ------------ --------- ---------
  **Preferred   **Omalizumab, n                     **Control, n           
  term**        = 2076, n (%)**                     = 1383, n              
                                                    (%)**                  

                Mild            Mod.      Sev.      Mild         Mod.      Sev.

  URI           157 (7.6)       239       19 (0.9)  89 (6.4)     182       13 (0.9)
                                (11.5)                           (13.2)    

  Pharyngitis   126 (6.1)       86 (4.1)  9 (0.4)   64 (4.6)     73 (5.3)  6 (0.4)

  Sinusitis     91 (4.4)        231       19 (0.9)  39 (2.8)     182       23 (1.7)
                                (11.1)                           (13.2)    

  Rhinitis      107 (5.2)       72 (3.5)  9 (0.4)   65 (4.7)     68 (4.9)  14 (1.0)

  Coughing      76 (3.7)        56 (2.7)  3 (0.1)   54 (3.9)     43 (3.1)  4 (0.3)

  Bronchitis    42 (2.0)        131 (6.3) 9 (0.4)   30 (2.2)     102 (7.4) 10 (0.7)

  Epistaxis     21 (1.0)        4 (0.2)   1 (0)     10 (0.7)     3 (0.2)   1 (0.1)

  Chest         7 (0.3)         32 (1.5)  8 (0.4)   6 (0.4)      27 (2.0)  4 (0.3)
  infection                                                                
  ------------- --------------- --------- --------- ------------ --------- ---------

\*adolescent/adult subjects (ages ≥ 12 yrs in Studies 008, 009, 011C,
012, IA04 and Q2143g)

URI = upper respiratory tract infection

Table 65. Asthma exacerbation AE from AA controlled studies\*, by
severity

+--------------------+------------------------+------------------------+
| **Grade**          | **Omalizumab,**        | **Control,**           |
|                    |                        |                        |
|                    | **n = 2076, n (%)**    | **n = 1383, n (%)**    |
+--------------------+------------------------+------------------------+
| Mild               | 46 (2.2)               | 30 (2.2)               |
+--------------------+------------------------+------------------------+
| Moderate           | 100 (4.8)              | 68 (4.9)               |
+--------------------+------------------------+------------------------+
| Severe             | 40 (1.9)               | 25 (1.8)               |
+--------------------+------------------------+------------------------+

\*adolescent/adult subjects (ages ≥ 12 yrs in Studies 008, 009, 011C,
012, IA04 and Q2143g)

**Table 66. Asthma-related hospitalizations**

in AA adolescent/adult and pediatric controlled studies

  -------------------- ---------------- ------------------ -------- ------------- ------------------ --------
  **Study category**   **Omalizumab**                               **Control**                      

                       Total n          Asthma                      Total n       Asthma             
                                        Hospitalizations                          Hospitalizations   

                                        n (%) of subjects  No. of                 n (%) of subjects  No. of
                                                           events                                    events

  **Adolescent/adult                                                                                 
  studies**                                                                                          

  Placebo controlled   718              3 (0.4)            5        694           10 (1.4)           13
  (008, 009, 011C,                                                                                   
  012)                                                                                               

  STC controlled       1467             42 (2.9)           61       744           27 (3.6)           38
  (Q2143g, IA04)                                                                                     

  **Pediatric study                                                                                  
  (study 010)**                                                                                      

  Placebo controlled   225              0                  0        109           5 (4.6)            6
  core                                                                                               

  Open label extension 309              0                  0        0             0                  0

  **Total**            2509\*           45 (1.8)           66       1547          42 (2.7)           57
  -------------------- ---------------- ------------------ -------- ------------- ------------------ --------

\*subjects exposed to Omalizumab during both the core and extension
periods are counted only once

STC = standard therapy controlled

Table 67. AE in controlled studies, by severity

+-------------+-------------+-------------+-------------+-------------+
| **Maximum   | **All       |             | **AA        |             |
| severity**  | controlled  |             | controlled  |             |
|             | studies, n  |             | studies,\*  |             |
|             | (%)**       |             | n (%)**     |             |
+-------------+-------------+-------------+-------------+-------------+
|             | Omalizumab  | Control     | Omalizumab  | Control     |
|             |             |             |             |             |
|             | n = 3224    | n = 2019    | n = 2076    | n = 1383    |
+-------------+-------------+-------------+-------------+-------------+
| Mild        | 643 (19.9)  | 373 (18.5)  | 416 (20.0)  | 227 (16.4)  |
+-------------+-------------+-------------+-------------+-------------+
| Moderate    | 1396 (43.3) | 883 (43.7)  | 962 (46.3)  | 638 (46.1)  |
+-------------+-------------+-------------+-------------+-------------+
| Severe      | 372 (11.5)  | 274 (13.6)  | 294 (14.2)  | 215 (15.5)  |
+-------------+-------------+-------------+-------------+-------------+

\*adolescent/adult subjects (ages ≥ 12 yrs in Studies 008, 009, 011C,
012, IA04 and Q2143g)

**Table 68. AE in placebo controlled studies, by severity**

+-------------+-------------+-------------+-------------+-------------+
| **Maximum   | **All       |             | **AA        |             |
| severity**  | placebo     |             | placebo     |             |
|             | controlled  |             | controlled  |             |
|             | studies, n  |             | studies, n  |             |
|             | (%)**       |             | (%)**       |             |
+-------------+-------------+-------------+-------------+-------------+
|             | Omalizumab  | Control     | Omalizumab  | Control     |
|             |             |             |             |             |
|             | n = 1801    | n = 1310    | n = 738     | n = 717     |
+-------------+-------------+-------------+-------------+-------------+
| Mild        | 319 (17.7)  | 246 (18.8)  | 115 (15.6)  | 110 (15.3)  |
+-------------+-------------+-------------+-------------+-------------+
| Moderate    | 797 (44.3)  | 616 (47.0)  | 397 (53.8)  | 385 (53.7)  |
+-------------+-------------+-------------+-------------+-------------+
| Severe      | 202 (11.2)  | 194 (14.8)  | 130 (17.6)  | 137 (19.1)  |
+-------------+-------------+-------------+-------------+-------------+

Table 69. Bleeding-related AE, by severity

+----------------+---------------+-----------+-------------+----------+
| **O            | **All         |           | **AA        |          |
| utcome/grade** | controlled    |           | controlled  |          |
|                | studies**     |           | studies\*** |          |
+----------------+---------------+-----------+-------------+----------+
|                | Omalizumab    | Control   | Omalizumab  | Control  |
|                |               |           |             |          |
|                | n = 3224      | n = 2019  | n = 2076    | n = 1383 |
+----------------+---------------+-----------+-------------+----------+
| Any event      | 81 (2.5)      | 33 (1.6)  | 60 (2.8)    | 24 (1.7) |
+----------------+---------------+-----------+-------------+----------+
| Mild           | 55 (1.7)      | 20 (1.0)  | 38 (1.8)    | 14 (1.0) |
+----------------+---------------+-----------+-------------+----------+
| Moderate       | 23 (0.7)      | 9 (0.4)   | 19 (0.9)    | 7 (0.5)  |
+----------------+---------------+-----------+-------------+----------+
| Severe         | 3 (0.1)       | 4 (0.2)   | 3 (0.1)     | 3 (0.2)  |
+----------------+---------------+-----------+-------------+----------+

\*adolescent/adult female subjects (ages ≥ 12 yrs in Studies 008, 009,
011C, 012, IA04 and Q2143g)

**Table 70. Number of subjects with injection site reactions after
treatment course 1 and after all subsequent treatment courses in placebo
controlled studies\***

  --------------------- ------------ ------------ ------------ ------------
  Number of injection   1            2            3            4
  sites                                                        

  **Treatment course                                           
  1**                                                          

  Omalizumab, n         209          644          70           389

  n (%) with reactions  29 (13.9)    134 (20.8)   22 (31.4)    134 (34.4)

  Placebo, n            173          493          43           132

  n (%) with reactions  28 (16.2)    97 (19.7)    7 (16.3)     46 (34.8)

  **All subsequent                                             
  treatment courses**                                          

  Omalizumab, n         209          644          70           389

  n (%) with reactions  46 (22.0)    211 (32.8)   39 (55.7)    129 (33.2)

  Placebo, n            173          493          43           132

  n (%) with reactions  49 (28.3)    138 (28.0)   19 (44.2)    48 (36,4)
  --------------------- ------------ ------------ ------------ ------------

\*Studies 008, 009, 010C, 011, 006, 007

**Table 71. Common AE in AA adult/adolescent controlled studies,\* by
body system and quartile of terminal serum Omalizumab concentration**

all rates \> 1% any Omalizumab quartile)

+--------------+----------+----------+----------+----------+----------+
| **System**   | **Om     |          |          |          | **       |
|              | alizumab |          |          |          | Control, |
|              | Q        |          |          |          | n (%)**  |
|              | uartile, |          |          |          |          |
|              | n (%)**  |          |          |          |          |
+--------------+----------+----------+----------+----------+----------+
|              | 1 (low)  | 2        | 3        | 4 (high) | n = 1216 |
|              |          |          |          |          |          |
|              | n = 426  | n = 419  | n = 423  | n = 422  |          |
+--------------+----------+----------+----------+----------+----------+
| Any system   | 344      | 340      | 339      | 366      | 957      |
|              | (80.8)   | (81.1)   | (80.1)   | (86.7)   | (78.7)   |
+--------------+----------+----------+----------+----------+----------+
| Body as a    | 86       | 102      | 113      | 108      | 256      |
| whole        | (20.2)   | (24.3)   | (26.7)   | (25.6)   | (21.1)   |
+--------------+----------+----------+----------+----------+----------+
| Ca           | 21 (4.9) | 15 (3.6) | 10 (2.4) | 19 (4.5) | 51 (4.2) |
| rdiovascular |          |          |          |          |          |
+--------------+----------+----------+----------+----------+----------+
| Digestive    | 77       | 92       | 101      | 102      | 236      |
|              | (18.1)   | (21.7)   | (23.9)   | (24.2)   | (19.4)   |
+--------------+----------+----------+----------+----------+----------+
| Hemic and    | 6 (1.4)  | 9 (2.1)  | 4 (0.9)  | 6 (1.4)  | 15 (1.2) |
| lymphatic    |          |          |          |          |          |
+--------------+----------+----------+----------+----------+----------+
| Infections/  | 92       | 113      | 116      | 152      | 385      |
| infestations | (21.6)   | (27.0)   | (27.4)   | (36.0)   | (31.7)   |
+--------------+----------+----------+----------+----------+----------+
| Lab          | 9 (2.1)  | 3 (0.7)  | 3 (0.7)  | 7 (1.7)  | 17 (1.4) |
| abnormality  |          |          |          |          |          |
+--------------+----------+----------+----------+----------+----------+
| Metabolic    | 5 (1.2)  | 0        | 3 (0.7)  | 4 (0.9)  | 7 (0.6)  |
+--------------+----------+----------+----------+----------+----------+
| Mus          | 81       | 101      | 106      | 117      | 270      |
| culoskeletal | (19.0)   | (24.1)   | (25.1)   | (27.7)   | (22.2)   |
+--------------+----------+----------+----------+----------+----------+
| Nervous      | 85       | 101      | 102      | 124      | 277      |
|              | (20.0)   | (24.1)   | (24.1)   | (29.4)   | (22.8)   |
+--------------+----------+----------+----------+----------+----------+
| Respiratory  | 217      | 234      | 225      | 244      | 686      |
|              | (50.9)   | (55.8)   | (53.2)   | (57.8)   | (56.4)   |
+--------------+----------+----------+----------+----------+----------+
| Ski          | 57       | 58       | 64       | 74       | 128      |
| n/appendages | (13.4)   | (13.8)   | (15.1)   | (17.5)   | (10.5)   |
+--------------+----------+----------+----------+----------+----------+
| Special      | 41 (9.6) | 41 (9.8) | 38 (9.0) | 50       | 117      |
| senses       |          |          |          | (11.8)   | (9.6)    |
+--------------+----------+----------+----------+----------+----------+
| Med/Surg     | 6 (1.4)  | 7 (1.7)  | 3 (0.7)  | 0        | 7 (0.6)  |
| procedures   |          |          |          |          |          |
+--------------+----------+----------+----------+----------+----------+
| GU and       | 35 (8.2) | 51       | 30 (7.1) | 38 (9.0) | 100      |
| reproductive |          | (12.2)   |          |          | (8.2)    |
+--------------+----------+----------+----------+----------+----------+

Med/Surg = medical or surgical procedures; GU = genitourinary; lab =
laboratory

\*Studies 008, 009, 011, 012 and Q2143g

Table 72. Overall frequency of AE during sequential exposure periods in
AA adolescent/adult AA controlled studies\*

  -------------------- ------------ ------------ ------------ --------------
  **Exposure period**  **All                     **Placebo    
                       controlled                controlled   
                       studies, n                studies, n   
                       (%)**                     (%)**        

                       Omalizumab   Control      Omalizumab   Control

  ≤ 12 weeks                                                  

  Total n              2076         1383         738          717

  Subjects with AE, n  1306 (62.9)  789 (57.0)   483 (65.4)   473 (66.0)
  (%)                                                         

  \> 12 - 28 weeks                                            

  Total n              1985         1333         722          692

  Subjects with AE, n  1178 (59.3)  761 (57.1)   531 (73.5)   497 (71.8)
  (%)                                                         

  \> 28 weeks                                                 

  Total n              882          733          685          634

  Subject with AE, n   549 (62.2)   455 (62.1)   426 (62.2)   399 (62.9)
  (%)                                                         
  -------------------- ------------ ------------ ------------ --------------

\*Studies 008, 009, 011, 012, IA04 and Q2143g

**Table 73. AE rates by exposure period ≤ 12 weeks**

in AA adolescent/adultcontrolled studies\*

+---------------+-----------+------------+------------+--------------+
| **System**    | **AA      |            | **AA       |              |
|               | c         |            | Placebo    |              |
|               | ontrolled |            | controlled |              |
|               | studies,  |            | studies, n |              |
|               | n (%)**   |            | (%)**      |              |
+---------------+-----------+------------+------------+--------------+
|               | Om        | Control,   | O          | Control,     |
|               | alizumab, |            | malizumab, |              |
|               |           | n = 1383   |            | n = 717      |
|               | n = 2076  |            | n = 738    |              |
+---------------+-----------+------------+------------+--------------+
| Any event     | 1306      | 789 (57.0) | 483 (65.4) | 472 (65.8)   |
|               | (62.9)    |            |            |              |
+---------------+-----------+------------+------------+--------------+
| Body as whole | 269       | 110 (8.0)  | 90 (12.2)  | 80 (11.2)    |
|               | (13.0)    |            |            |              |
+---------------+-----------+------------+------------+--------------+
| C             | 43 (2.1)  | 25 (1.8)   | 14 (1.9)   | 18 (2.5)     |
| ardiovascular |           |            |            |              |
+---------------+-----------+------------+------------+--------------+
| Digestive     | 265       | 116 (8.4)  | 114 (15.4) | 90 (12.6)    |
|               | (12.8)    |            |            |              |
+---------------+-----------+------------+------------+--------------+
| He            | 17 (0.8)  | 6 (0.4)    | 11 (1.5)   | 4 (0.6)      |
| mic/lymphatic |           |            |            |              |
+---------------+-----------+------------+------------+--------------+
| Infections    | 261       | 218 (15.8) | 129 (17.5) | 159 (22.2)   |
| /infestations | (12.6)    |            |            |              |
+---------------+-----------+------------+------------+--------------+
| Mu            | 234       | 129 (9.3)  | 108 (14.6) | 94 (13.1)    |
| sculoskeletal | (11.3)    |            |            |              |
+---------------+-----------+------------+------------+--------------+
| Nervous       | 310       | 169 (12.2) | 147 (19.9) | 136 (19.0)   |
|               | (14.9)    |            |            |              |
+---------------+-----------+------------+------------+--------------+
| Respiratory   | 633       | 428 (30.9) | 218 (29.5) | 232 (32.4)   |
|               | (30.5)    |            |            |              |
+---------------+-----------+------------+------------+--------------+
| Sk            | 164 (7.9) | 58 (4.2)   | 59 (8.0)   | 48 (6.7)     |
| in/appendages |           |            |            |              |
+---------------+-----------+------------+------------+--------------+
| Special       | 88 (4.2)  | 55 (4.0)   | 36 (4.9)   | 36 (5.0)     |
| senses        |           |            |            |              |
+---------------+-----------+------------+------------+--------------+
| GU            | 90 (4.3)  | 44 (3.2)   | 38 (5.1)   | 36 (5.0)     |
| /reproductive |           |            |            |              |
+---------------+-----------+------------+------------+--------------+

\*Studies 008, 009, 011, 012, IA04 and Q2143g

**Table 74. AE rates by exposure period \> 12 to 28 weeks**

in AA adolescent/adult controlled studies\*

+---------------+-----------+------------+------------+--------------+
| **System**    | **AA      |            | **AA       |              |
|               | c         |            | Placebo    |              |
|               | ontrolled |            | controlled |              |
|               | studies,  |            | studies, n |              |
|               | n (%)**   |            | (%)**      |              |
+---------------+-----------+------------+------------+--------------+
|               | Om        | Control,   | O          | Control,     |
|               | alizumab, |            | malizumab, |              |
|               |           | n = 1333   |            | n = 692      |
|               | n = 1985  |            | n = 722    |              |
+---------------+-----------+------------+------------+--------------+
| Any event     | 1178      | 761 (57.1) | 531 (73.5) | 497 (71.8)   |
|               | (59.3)    |            |            |              |
+---------------+-----------+------------+------------+--------------+
| Body as whole | 205       | 112 (8.4)  | 92 (12.7)  | 88 (12.7)    |
|               | (10.3)    |            |            |              |
+---------------+-----------+------------+------------+--------------+
| C             | 39 (2.0)  | 26 (2.0)   | 16 (2.2)   | 17 (2.5)     |
| ardiovascular |           |            |            |              |
+---------------+-----------+------------+------------+--------------+
| Digestive     | 176 (8.9) | 119 (8.9)  | 102 (14.1) | 99 (14.3)    |
+---------------+-----------+------------+------------+--------------+
| He            | 9 (0.5)   | 6 (0.5)    | 2 (0.3)    | 1 (0.1)      |
| mic/lymphatic |           |            |            |              |
+---------------+-----------+------------+------------+--------------+
| Infections    | 301       | 208 (15.6) | 192 (26.6) | 160 (23.1)   |
| /infestations | (15.2)    |            |            |              |
+---------------+-----------+------------+------------+--------------+
| Mu            | 213       | 130 (9.8)  | 126 (17.5) | 100 (14.5)   |
| sculoskeletal | (10.7)    |            |            |              |
+---------------+-----------+------------+------------+--------------+
| Nervous       | 238       | 170 (12.8) | 155 (21.5) | 151 (21.8)   |
|               | (12.0)    |            |            |              |
+---------------+-----------+------------+------------+--------------+
| Respiratory   | 621       | 441 (33.1) | 283 (39.2) | 302 (43.6)   |
|               | (31.3)    |            |            |              |
+---------------+-----------+------------+------------+--------------+
| Sk            | 120 (6.0) | 66 (5.0)   | 54 (7.5)   | 55 (7.9)     |
| in/appendages |           |            |            |              |
+---------------+-----------+------------+------------+--------------+
| Special       | 97 (4.8)  | 61 (4.6)   | 50 (6.9)   | 44 (6.4)     |
| senses        |           |            |            |              |
+---------------+-----------+------------+------------+--------------+
| GU            | 83 (4.2)  | 52 (3.9)   | 44 (6.1)   | 43 (6.2)     |
| /reproductive |           |            |            |              |
+---------------+-----------+------------+------------+--------------+

\*Studies 008, 009, 011, 012, IA04 and Q2143g

**Table 75. AE rates by exposure period \> 28 weeks**

in AA adolescent/adult controlled studies\*

+---------------+-----------+------------+------------+--------------+
| **System**    | **AA      |            | **AA       |              |
|               | c         |            | Placebo    |              |
|               | ontrolled |            | controlled |              |
|               | studies,  |            | studies, n |              |
|               | n (%)**   |            | (%)**      |              |
+---------------+-----------+------------+------------+--------------+
|               | Om        | Control,   | O          | Control,     |
|               | alizumab, |            | malizumab, |              |
|               |           | n = 733    |            | n = 399      |
|               | n = 882   |            | n = 685    |              |
+---------------+-----------+------------+------------+--------------+
| Any event     | 549       | 455 (62.1) | 426 (62.2) | 399 (62.9)   |
|               | (62.2)    |            |            |              |
+---------------+-----------+------------+------------+--------------+
| Body as whole | 125       | 95 (13.0)  | 100 (14.6) | 90 (14.2)    |
|               | (14.2)    |            |            |              |
+---------------+-----------+------------+------------+--------------+
| C             | 15 (1.7)  | 13 (1.8)   | 9 (1.3)    | 11 (1.7)     |
| ardiovascular |           |            |            |              |
+---------------+-----------+------------+------------+--------------+
| Digestive     | 114       | 81 (11.1)  | 92 (13.4)  | 75 (11.8)    |
|               | (12.9)    |            |            |              |
+---------------+-----------+------------+------------+--------------+
| He            | 7 (0.8)   | 6 (0.8)    | 5 (0.7)    | 4 (0.6)      |
| mic/lymphatic |           |            |            |              |
+---------------+-----------+------------+------------+--------------+
| Infections    | 171       | 136 (18.6) | 121 (17.7) | 113 (17.8)   |
| /infestations | (19.4)    |            |            |              |
+---------------+-----------+------------+------------+--------------+
| Mu            | 117       | 105 (14.3) | 103 (15.0) | 99 (15.6)    |
| sculoskeletal | (13.3)    |            |            |              |
+---------------+-----------+------------+------------+--------------+
| Nervous       | 125       | 103 (14.1) | 107 (15.6) | 99 (15.6)    |
|               | (14.2)    |            |            |              |
+---------------+-----------+------------+------------+--------------+
| Respiratory   | 312       | 279 (38.1) | 235 (34.3  | 240 (37.9)   |
|               | (35.4)    |            |            |              |
+---------------+-----------+------------+------------+--------------+
| Sk            | 73 (8.3)  | 41 (5.6)   | 58 (8.5)   | 40 (6.3)     |
| in/appendages |           |            |            |              |
+---------------+-----------+------------+------------+--------------+
| Special       | 47 (5.3)  | 36 (4.9)   | 36 (5.3)   | 32 (5.0)     |
| senses        |           |            |            |              |
+---------------+-----------+------------+------------+--------------+
| GU            | 52 (5.9)  | 44 (6.0)   | 42 (6.1)   | 38 (6.0)     |
| /reproductive |           |            |            |              |
+---------------+-----------+------------+------------+--------------+

\*Studies 008, 009, 011, 012, IA04 and Q2143g

**Table 76. AE by body system rates for ages 12 - 17 years**

in adolescent/adult controlled studies

+---------------+-----------+------------+------------+-------------+
| **System**    | **All     |            | **AA       |             |
|               | c         |            | controlled |             |
|               | ontrolled |            | studies\*, |             |
|               | studies,  |            | n (%)**    |             |
|               | n (%)**   |            |            |             |
+---------------+-----------+------------+------------+-------------+
|               | Om        | Control,   | O          | Control, n  |
|               | alizumab, |            | malizumab, | = 97        |
|               |           | n = 190    |            |             |
|               | n = 296   |            | n = 151    |             |
+---------------+-----------+------------+------------+-------------+
| Any event     | 223       | 150 (78.9) | 117 (77.5) | 81 (83.5)   |
|               | (75.3)    |            |            |             |
+---------------+-----------+------------+------------+-------------+
| Body as whole | 64 (21.6) | 41 (21.6)  | 32 (21.2)  | 20 (20.6)   |
+---------------+-----------+------------+------------+-------------+
| C             | 8 (2.7)   | 3 (1.6)    | 5 (3.3)    | 1 (1.0)     |
| ardiovascular |           |            |            |             |
+---------------+-----------+------------+------------+-------------+
| Digestive     | 41 (13.8) | 32 (16.8)  | 22 (14.6)  | 14 (14.4)   |
+---------------+-----------+------------+------------+-------------+
| He            | 3 (1.0)   | 0          | 2 (1.3)    | 0           |
| mic/lymphatic |           |            |            |             |
+---------------+-----------+------------+------------+-------------+
| Infections    | 62 (20.9) | 51 (26.8)  | 39 (25.8)  | 32 (33.0)   |
| /infestations |           |            |            |             |
+---------------+-----------+------------+------------+-------------+
| Mu            | 38 (12.8) | 25 (13.2)  | 21 (13.9)  | 15 (15.5)   |
| sculoskeletal |           |            |            |             |
+---------------+-----------+------------+------------+-------------+
| Nervous       | 70 (23.6) | 47 (24.7)  | 31 (20.5)  | 22 (22.7)   |
+---------------+-----------+------------+------------+-------------+
| Respiratory   | 143       | 105 (55.3) | 82 (54.3)  | 67 (69.1)   |
|               | (48.3)    |            |            |             |
+---------------+-----------+------------+------------+-------------+
| Sk            | 30 (10.1) | 23 (12.1)  | 20 (13.2)  | 9 (9.3)     |
| in/appendages |           |            |            |             |
+---------------+-----------+------------+------------+-------------+
| Special       | 27 (9.1)  | 23 (12.1)  | 12 (7.9)   | 15 (15.5)   |
| senses        |           |            |            |             |
+---------------+-----------+------------+------------+-------------+
| GU            | 7 (2.4)   | 3 (1.6)    | 2 (1.3)    | 3 (3.1)     |
| /reproductive |           |            |            |             |
+---------------+-----------+------------+------------+-------------+

\*Studies 008, 009, 011, 012, IA04 and Q2143g

**Table 77. AE by body system rates for ages 18 - 64 years**

in adolescent/adult controlled studies

+---------------+-----------+------------+------------+-------------+
| **System**    | **All     |            | **AA       |             |
|               | c         |            | controlled |             |
|               | ontrolled |            | studies\*, |             |
|               | studies,  |            | n (%)**    |             |
|               | n (%)**   |            |            |             |
+---------------+-----------+------------+------------+-------------+
|               | Om        | Control,   | O          | Control,    |
|               | alizumab, |            | malizumab, |             |
|               |           | n = 1561   |            | n = 1221    |
|               | n = 2441  |            | n = 1791   |             |
+---------------+-----------+------------+------------+-------------+
| Any event     | 1801      | 1167       | 1456       | 948 (77.6)  |
|               | (73.8)    | (74.8)     | (81.3)     |             |
+---------------+-----------+------------+------------+-------------+
| Body as whole | 487       | 282 (18.1) | 433 (24.2) | 247 (20.2)  |
|               | (20.0)    |            |            |             |
+---------------+-----------+------------+------------+-------------+
| C             | 80 (3.3)  | 59 (3.8)   | 71 (4.0)   | 51 (4.2)    |
| ardiovascular |           |            |            |             |
+---------------+-----------+------------+------------+-------------+
| Digestive     | 462       | 278 (17.8) | 402 (22.4) | 239 (19.6)  |
|               | (18.9)    |            |            |             |
+---------------+-----------+------------+------------+-------------+
| He            | 31 (1.3)  | 18 (1.2)   | 28 (1.6)   | 17 (1.4)    |
| mic/lymphatic |           |            |            |             |
+---------------+-----------+------------+------------+-------------+
| Infections    | 594       | 443 (28.4) | 512 (28.6) | 392 (32.1)  |
| /infestations | (24.3)    |            |            |             |
+---------------+-----------+------------+------------+-------------+
| Lab           | 29 (1.2)  | 19 (1.2)   | 29 (1.6)   | 18 (1.5)    |
| abnormality   |           |            |            |             |
+---------------+-----------+------------+------------+-------------+
| Mu            | 459       | 297 (19.0) | 398 (22.2) | 258 (21.1)  |
| sculoskeletal | (18.8)    |            |            |             |
+---------------+-----------+------------+------------+-------------+
| Nervous       | 545       | 359 (23.0) | 438 (24.5) | 275 (22.5)  |
|               | (22.3)    |            |            |             |
+---------------+-----------+------------+------------+-------------+
| Respiratory   | 1064      | 758 (48.6) | 938 (52.4) | 666 (54.5)  |
|               | (43.6)    |            |            |             |
+---------------+-----------+------------+------------+-------------+
| Sk            | 300       | 135 (8.6)  | 266 (14.9) | 118 (9.7)   |
| in/appendages | (12.3)    |            |            |             |
+---------------+-----------+------------+------------+-------------+
| Special       | 204 (8.4) | 133 (8.5)  | 181 (10.1) | 111 (9.1)   |
| senses        |           |            |            |             |
+---------------+-----------+------------+------------+-------------+
| GU            | 198 (8.1) | 116 (7.4)  | 174 (9.7)  | 105 (8.6)   |
| /reproductive |           |            |            |             |
+---------------+-----------+------------+------------+-------------+

\*Studies 008, 009, 011, 012, IA04 and Q2143g

**Appendix B. Anaphylaxis and Anaphylactoid Reaction Narratives:**

**Subjects receiving Omalizumab:**

1\. Subject 11756 was a 28 y o female diagnosed with anaphylaxis (SAE)
following her fourth Omalizumab injection in Study Q2143g. The
subject\'s past history was remarkable for several allergies, especially
a peanut and chocolate allergy. The subject experienced localized
redness and edema around the second and third injection sites. Two hours
following her fourth Omalizumab injection, the subject noted that the
site had \"swollen\" to \"soft ball size.\" She also noticed mild throat
and tongue swelling but experienced no dyspnea. She self-medicated
herself that evening with oral steroids and antihistamines and the event
resolved over the next four days. She presented for follow-up two days
following the fourth Omalizumab injection when the anaphylaxis event was
recorded. The event was assessed as related to the study drug and
Omalizumab was discontinued.

2\. Subject 12411 was a 19 y o female who developed a severe
anaphylactic reaction (SAE) following her first Omalizumab dose in Study
Q2143g. Ninety minutes after the dose (while away from the site clinic),
the subject noted hives, itching and dyspnea. She returned to the clinic
and received SC epinephrine and IV steroids. The hives improved and she
was sent home but her symptoms worsened over the next few hours and she
was seen in an emergency room where another SC epinephrine injection was
administered and the subject was discharged on prednisone. The symptoms
all resolved over the following week. The reaction was assessed as
related to Omalizumab and the study drug was discontinued.

3\. Subject 4621 was a 39 year old woman who, approximately three months
after beginning Study 008, had an anaphylaxis reaction (SAE, assessed as
unrelated to Omalizumab). The patient had a history of allergy to Septra
and penicillin and also experienced migraine headaches. The last
Omalizumab dose was received 21 days prior to the anaphylaxis. Thirty
minutes prior to the anaphylaxis reaction the patient had taken one dose
of Levaquin 500 mg to treat a sinus infection. The patient subsequently
developed facial edema, hives and edema of the extremities, along with
difficulty breathing. The patient was at work at an urgent care facility
at the time of the reaction and she was treated with SC epinephrine, IV
bendadryl and Celestone. Her condition improved and she was discharged
two hours later. She had completely recovered within two days. The
investigator reported that Ocuflox (another quinolone) had been used
within 10 days prior to the event and may have contributed. The
anaphylaxis reaction was not assessed as related to Omalizumab. The
patient received subsequent Omalizumab doses without events.

4\. Subject 2712 was a 30 year old man who had an anaphylactoid reaction
1.5 hours after the initial IV Omalizumab dose in Study Q0694 (a phase 2
asthma study in which Omalizumab was administered intravenously). Few
details of the reaction are available. The reaction required the
administration of SC epinephrine and nebulized albuterol followed by
prednisone. No other medications, beside Omalizumab could be causally
implicated in the reaction. The event was assessed as related to
Omalizumab and the study agent discontinued.

**Control subjects:**

5\. Subject 10879 in Study Q2143g experienced wheezing after ingestion
of peanuts. The subject had a history of peanut allergy. The subject
continued in the study.

**Appendix C. Summaries of clinical studies**

**1. Allergic rhinitis studies:**

Five of the major studies examined Omalizumab use in allergic rhinitis
(AR).

Four of the major studies examined Omalizumab use in seasonal allergic
rhinitis (SAR, Studies 006, 006E, 004 and D01). One of these studies
(Study 006E) was an uncontrolled study enrolling subjects who had
received Omalizumab in an earlier study in order to assess the effects
of \"retreatment\" during a second allergen season. The three other SAR
studies were controlled studies that generally used the same design:
randomized, double blinded, placebo controlled studies assessing
treatment effects upon a primary endpoint of an allergy symptom score.
Three studies (Studies 006, 006E and 007) examined effects over a three
month treatment period and one study (Study D01) examined effects over a
six month treatment period.

One major study (Study 014) examined Omalizumab use in perennial
allergic rhinitis (PAR). This four month study used a randomized, double
blinded, placebo controlled design with a primary endpoint assessing a
nasal symptom score.

The following pages summarize the major features of the studies\'
design. Information regarding efficacy results are not included within
this summary. Information regarding the safety findings are included
within the Integrated summary of safety.

**A. Study 006:**

**Title:** A phase IIb, randomized, double-blind, placebo-controlled,
multiple-dose, (subcutaneous administrations of 50 mg, 150 mg or 300
mg), multicenter, dose-ranging trial to assess the efficacy, safety,
tolerability, pharmacokinetics and biological effect of Omalizumab
versus placebo for symptom prevention in patients with ragweed-induced
seasonal allergic rhinitis.

**Summary:** This randomized, double blind, placebo controlled study was
a \"phase IIb\" study designed to assess the safety and efficacy of
Omalizumab in SAR associated with ragweed pollen. The study compared the
effect of three doses of Omalizumab (50 mg, 150 mg or 300 mg) to placebo
(1:1:1:1 randomization). The study agent was administered SC every three
weeks to patients who had a baseline serum IgE concentration ≥ 301 IU/mL
or SC every four weeks to patients who had a baseline serum IgE
concentration ≤ 300 IU/mL. All subjects were to receive four SC
injections at the time of each dose administration. All subjects had
access to \"rescue medication\" (Chlorpheniramine, 4 mg) which was to be
taken for severe SAR symptoms. The study consisted of a 12 week
treatment period and a 12 week (off treatment) follow-up period. The
collection of AE data was truncated at the end of the treatment period
(week 12)\--it did not extend to week 24. The week 24 visit was limited
to collection of anti-Omalizumab and ragweed-specific antibody levels.
The study was a parallel design with the study treatment period
beginning at the start of the annual ragweed SAR season.

Subjects eligible for the trial had to meet the following criteria:

-ages between 12 -75, inclusive

-skin test sensitivity to ragweed

-history of two or more years of moderate to severe SAR

-baseline IgE ≥ 30 IU/mL and ≤ 700 IU/mL

-weight ≤ 100 kg

-no ragweed immunotherapy within the prior 2 years

-no regular beta adrenergic antagonist, antihistamine, tricyclic
anti-depressant or

> monoamine-oxidase therapy.

Subjects were examined at baseline and weeks 3, 6, 9, 12 and 24.
Clinical laboratory evaluations were to be performed at screening,
baseline, end of treatment phase and at the six month follow-up time
point.

The primary endpoint was a comparison of the daily nasal severity score.
Subject disposition is summarized below.

Table 78. Study 006 subject disposition

  ----------------- ------------ ------------ ------------ ---------- ----------
  Number of         Omalizumab   Omalizumab   Omalizumab   Placebo    Total
  subjects          300 mg       150 mg       50 mg                   

  Randomized        129          134          137          136        536

  Received ≥ 1      126          132          137          134        529
  injection                                                           

  Completed study   121          124          129          125        499

  Discontinued                                                        

  for AE            0            2            1            0          3

  for futility      1            0            1            3          5

  for other reasons 7            8            6            8          29
  ----------------- ------------ ------------ ------------ ---------- ----------

*Comment: The Omalizumab dosages used in this study were not weight
adjusted and were generally lower than those proposed for marketing for
the treatment of AA.*

**B. Study 006E:**

**Title:** An open-label extension trial to assess the safety of
Omalizumab in patients with seasonal allergic rhinitis previously
treated in the core trial Protocol 006

**Summary:** This was an open label, uncontrolled phase 2 study that
allowed patients who had received active treatment in Study 006 to again
receive Omalizumab during a second ragweed allergen season. The study\'s
primary objective was assessment of safety and tolerability\--efficacy
was not assessed. The treatment period was very similar to Study 006\--a
12 week active treatment phase during which patients who had baseline
serum IgE concentrations ≤ 150 IU/mL received 300 mg Omalizumab every
three weeks and patients who had baseline serum IgE concentrations ≥ 151
IU/mL received 300 mg Omalizumab every four weeks. The product was
administered as two SC injections at the time of each dose
administration. During the active treatment period, subjects in the
subgroup of higher baseline IgE concentration returned for visits on
weeks 4, 8 and 12\--with examinations and recording of adverse events.
The same evaluations for patients with the lower baseline IgE
concentration were performed on weeks 3, 6, 9 and 12. Clinical
laboratory data were collected at baseline and week 12. Following the
active treatment period patients returned at week 24 for follow-up free
and total IgE concentrations and anti-Omalizumab blood concentrations.

As in Study 006, collection of adverse event data was truncated to only
the active treatment period and was not collected out to week 24.

The study did not have any efficacy endpoints proposed for analysis. The
study\'s main endpoints were summaries of safety and pharmacokinetic
data.

Eligibility criteria required that subjects:

-had to complete active treatment in Study 006 successfully, including
completion

> of all study visits

-had the potential to benefit, in the investigator\'s opinion, from the
study agent

Subject disposition is summarized below.

Table 79. Study 006E subject disposition

  ----------------- ----------------- ----------------- -----------------
  Number of         Baseline IgE ≤    Baseline IgE ≥    Total
  subjects          150 IU/mL         151 IU/mL         

  Enrolled          182 (63%)         105 (37%)         287

  Stopped for AE    4                 1                 5

  Stopped for other 1                 0                 1

  Completed study   177               104               281
  ----------------- ----------------- ----------------- -----------------

*Comment: This study provided useful safety information regarding the
potential effect of Omalizumab readministration to subjects who had been
\"off\" study drug for many months. The Omalizumab dosages used in this
study were not weight adjusted and were generally lower than those
proposed for marketing for the treatment of AA.*

**C. Study 007:**

**Title:** A phase 3, randomized, double-blind, parallel-group, multiple
dose, multi-center trial to assess the efficacy, safety and tolerability
of subcutaneously administered Omalizumab versus placebo for symptom
prevention in patients with birch-induced seasonal allergic rhinitis

**Summary:** This phase 3 study examined the effect of Omalizumab among
adult patients who had SAR related to birch pollen. The study was
conducted in northern Europe (Sweden, Finland and Norway), an area with
a high prevalence of birch pollen SAR. The study was a randomized,
double blind, placebo-controlled study that consisted of two study arms:
the study compared the effect of Omalizumab to placebo (1:1). The dose
of Omalizumab was 300 mg every three weeks for patients with baseline
serum IgE ≥ 30 IU/mL to ≤ 150 IU/mL, and 300 mg every four weeks for
patients with baseline serum IgE \> 150 IU/mL to ≤ 700 IU/mL. The study
agent was administered as two SC doses. Hence, the high IgE group was to
receive three active study drug injections (baseline, week 3 and week 6)
and the low IgE group was to receive two active study drug injections
(baseline, week 4).

The study consisted of an eight week treatment period and a 12 week
follow-up (no study agent administration) period. The study treatment
period began at the start of the annual birch pollen season.

Subjects eligible for the trial had to meet the following (most notable)
criteria:

-ages between 18 -75, inclusive and weight ≤ 100 kg

-skin test sensitivity to birch pollen

-history of two or more years of moderate to severe seasonal birch
allergic rhinits

-baseline IgE ≥ 30 IU/mL and ≤ 700 IU/mL

-no use in the prior six weeks of inhaled steroids for the treatment of
asthma

> such that the dose exceeds 1000 mcg beclomethasone or budesonide or
> 500 mcg fluticasone or equivalent

-no birch pollen immunotherapy within the prior 2 years

-no regular beta adrenergic antagonist, antihistamine, tricyclic
anti-depressant or

> monoamine-oxidase therapy.

-no use of Zafirlukast (Accolate) or other leukotriene receptor
inhibitors and

> Zileuton (Zyflor) or other 5-lipoxygenase inhibitors within past 72
> hours

-no known parasitic infections

Subjects were examined at baseline (visit 2) and weeks 3, 6, and 8
(visit 5) for the high IgE subgroup and at baseline (visit 2) and weeks
4, 6 and 8 (visit 5) for the low IgE subgroup. All subjects returned for
blood collection (antibody, serum free and total IgE) at 12 weeks after
the last dose (week 20). Adverse experience collection was truncated at
the end of the treatment period (i.e., at week 8). Clinical laboratory
evaluations were performed at screening, baseline, and the eight week
time-point (the end of the treatment phase).

The primary endpoint was a comparison of the daily nasal severity score.
Subject disposition is shown below.

Table 80. Study 007 subject disposition

  --------------------------------------------- --------------- -------------
  Number of subjects                            Omalizumab300   Placebo
                                                mg              

  Randomized                                    165             86

  Received study drug                           164             86

  Completed                                     162 (98%)       78 (91%)

  Discontinued for AE                           0               0

  Discontinued for \"other\" protocol           2 (1.2%)        2 (2%)
  violations                                                    

  Discontinued due to unsatisfactory            1 (0.6%)        6 (7%)
  therapeutic response                                          
  --------------------------------------------- --------------- -------------

**D. Study D01:**

**Title:** A phase 3b, randomized, double-blind, placebo-controlled,
parallel-group, multiple-dose, multicenter study to assess the efficacy,
safety and tolerability of subcutaneously administered Omalizumab vs
specific immunotherapy (SIT) vs a combined SIT and Omalizumab therapy
for symptom prevention in children with birch pollen and grass pollen
induced seasonal allergic rhinitis (SAR)

**Summary:** This phase 3 study was conducted among children at multiple
sites in Germany. The study examined the safety and efficacy of
Omalizumab use concomitant with specific immunotherapy (SIT) to birch
pollen and grass pollen. These allergenic seasons overlap. The study was
a randomized, double blind, parallel group design in which approximately
200 subjects were to be randomized (1:1:1:1) to one of four study
groups: SIT for grass pollen + Omalizumab, SIT for grass pollen +
placebo, SIT for birch pollen + Omalizumab, SIT for birch pollen +
placebo. The study consisted of two double blind phases\--the first a 12
week phase in which subjects received only the specific immunotherapy
(\"monotherapy\") and the second a six month treatment phase in which
SIT and Omalizumab/placebo (\"combination therapy\") were administered.
The SIT was administered weekly during the monotherapy phase and monthly
during the combination therapy phase. The Omalizumab was administered
subcutaneously in dosages comparable to those proposed for marketing for
use in AA (based on body weight and baseline serum IgE).

Subjects eligible for the trial had to meet the following (most notable)
criteria:

-no prior SIT within past five years

-aged 6 to \< 18 years, with ≥ 2 years history of birch and grass
allergic rhinitis and

> positive IgE reactivity (CAP ≥ 2) for birch and grass pollen within
> prior 3 months

-asymptomatic or minimally symptomatic during prior month

-FEV1 ≥ 70% predicted

-no PAR

-no chronic heart or lung disease or other significant systemic disease

Subjects were examined at baseline and had SIT administered weekly
during the monotherapy phase. The combination phase was designed to
begin 2 to 4 weeks prior to the start of the pollen season. Physical
exams during the combination phase were performed at baseline and
end-of-study. Throughout the combination phase period, diary cards were
issued and collected and AE information collected. Other evaluations
included spirometry, clinical laboratory, serum IgE and IgE specific for
allergens and anti-IgE. The final study evaluation occurred two weeks
following the last Omalizumab/placebo dose.

The study\'s primary endpoint was a co-primary of investigators\' global
tolerability assessment (a safety variable) and symptom load score (the
\"main efficacy variable\")\--all during the combination therapy phase.
Multiple other outcomes were assessed, including analyses of symptom
severity scores and rescue medication usage. Subject disposition is
summarized below.

Table 81. Study D01 subject disposition

  -------------------- ------------ ------------ ------------ ------------ ---------
  Number of subjects   SITgrass +   SITgrass +   SITbrich +   SITbirch +   Total
                       Omalizumab   placebo      Omalizumab   placebo      

  Randomized           60           54           56           55           225

  Received study drug  59           53           55           55           222 (99%)

  Completed            59 (98%)     52 (96%)     54 (96%)     54 (98%)     219 (97%)

  Discontinued for AE  0            0            1 (2%)       0            1 (\<1%)

  Discontinued, other  0            2 (4%)       1 (2%)       1 (2%)       5 (2%)
  reason                                                                   
  -------------------- ------------ ------------ ------------ ------------ ---------

**E. Study 014:**

**Title**: A phase 3b, multi-center, multiple-dose, 4-month, randomized,
parallel group, double-blind, placebo-controlled study to assess the
efficacy, safety and tolerability of Omalizumab for the treatment of
symptomatic patients 12 - 75 years old with perennial allergic rhinitis

**Summary:** This phase 3 study was designed to assess the safety and
efficacy of Omalizumab use in the treatment of perennial allergic
rhinitis (PAR) among adolescents/adults with moderate to severe PAR
symptoms. The study was randomized, double-blinded, placebo controlled
and was to randomized approximately 300 subjects to Omalizumab or
placebo (1:1). The study consisted of a four month treatment phase
followed by a three month (off study drug) follow-up phase. The study
was conducted among multiple sites in the USA. The Omalizumab dose was
administered subcutaneously in a manner consistent with that proposed
for AA marketing (based on weight and baseline serum IgE).

Subjects eligible for the trial had to meet the following (most notable)
criteria:

-ages 12 - 75 years with + skin test to one of certain allergens

-history of ≥ 2 years moderate to severe PAR symptoms and specific
symptom scores

-nasal examinations consistent with PAR

-no history of SAR

-no history of asthma and no concomitant use of inhaled or oral
steroids, leukotriene

> modifiers or theophylline

-no other significant systemic disease

Subjects were evaluated extensively during the four month treatment
phase with limited physical exams, symptom card questionnaires and
recording of concomitant medication usage. At 12 weeks after the last
dose of study drug, subjects had the recording of concomitant
medications, AE and blood IgE/anti-IgE.

The study\'s primary endpoint was a comparison between the groups in the
average daily nasal severity score. Multiple other endpoints were
assessed, including proportion of days with rescue and/or concomitant
medication use, tablet counts on rescue medication use and global
evaluations of treatment efficacy. Subject disposition is summarized
below.

Table 82. Study 014 subject disposition

  ------------------------------ --------------------- -------------------
  Number of subjects:            Omalizumab            Placebo

  Randomized                     144                   145

  Completed                      132 (92%)             136 (94%)

  Discontinued for AE            2 (1%)                2 (1%)

  Discontinued, other reason     10 (7%)               7 (5%)
  ------------------------------ --------------------- -------------------

**2. Atopic dermatitis:**

One of the major studies explored the use of Omalizumab in the treatment
of atopic dermatitis. This study (Study 013) terminated enrollment early
because of recruiting difficulty. The study is summarized below.

**Study 013:**

**Title:** A 6-month, parallel-group, randomized, investigator blind,
placebo-controlled, multicenter, proof of concept trial comparing the
efficacy of Omalizumab to that of placebo in the treatment of moderate
to severe atopic dermatitis in subjects 6 - 16 years of age

**Summary:** This study examined the effect of 6 months of
administration of Omalizumab or placebo to subjects who were dependent
upon the topical use of triamcinolone for the treatment of atopic
dermatitis. The study used a randomized (2:1, Omalizumab:placebo),
placebo-controlled, parallel group design in which subjects and
evaluators were blinded but study drug was shipped unblinded to each
clinical site. The study consisted of two phases, the blinded treatment
phase of six months and a four month (no study drug) follow-up phase.
During the treatment phase, placebo or Omalizumab was administered SC
(the Omalizumab dose same as that proposed for AA marketing) and, at
certain time points, attempts were made to discontinue the topical
steroid therapy. The study had planned to enroll 60 subjects but
ultimately only 25 subjects were enrolled.

Subjects eligible for the trial had to meet the following (most notable)
criteria:

-aged 6 to 16 years with moderate to severe AD and whose disease can be
managed

> with triamcinolone actenoide ointment 0.1%

-no photherapy or systemic therapy known to impact AD within prior month

-no topical steroids since the subject was screened

-no concurrent skin disease

Subjects had visits every two weeks during the treatment phase for
collection of AE and outcome data. At the end of the six month treatment
phase, subjects were to return at eight and 16 weeks for collection of
AE data, blood IgE and anti-IgE.

The study\'s primary efficacy endpoint was a co-primary endpoint of:
total weight of corticosteroids used and the overall assessment of
corticosteroid use. Multiple other outcomes were analyzed, including:
skin scores, subjects\' assessments of pruritus and overall efficacy,
rate of 50% and 100% reduction in steroid use and incidence of rescue
medication use. Subject disposition is summarized below:

Table 83. Study 013 subject disposition

  --------------------------------------- ---------------- ---------------
  Number of subjects:                     Omalizumab       Placebo

  Randomized                              16               9

  Completed                               13 (81%)         9 (100%)

  Discontinued for AE                     0                0

  Discontinued for other reasons          3 (19%)          0
  --------------------------------------- ---------------- ---------------

**3. Allergic asthma:**

Of the 15 major studies, nine examined the use of Omalizumab in AA. All
nine studies used Omalizumab doses consistent with those proposed for
marketing.

Three of the nine AA studies (Studies 008, 009 and 011) were placebo
controlled, double blinded studies designed to assess the safety and
efficacy of Omalizumab use among adult/adolescents with AA. Studies 008
and 009 shared the same study design characteristics. Both studies were
of one year duration and enrolled moderate to severe AA subjects who
were not receiving certain concomitant AA medications. Study 011 was
notably different from Studies 008 and 009 in that it was an eight month
study examining Omalizumab effects upon severe AA subjects

who may have been receiving oral steroids for AA. Overall, these three
studies studied \~1400 subjects.

Two of the nine AA studies were standard therapy controlled, unblinded
studies designed to assess Omalizumab safety (Studies Q2143g and IA04).
Study Q2143g had the largest sample size of any AA study (\~1900
subjects) and examined Omalizumab use over a six month period. Study
IA04 examined Omalizumab use over a one year period in \~ 300 subjects.

One of the nine AA studies was a placebo controlled, double blinded
study assessing safety and efficacy of Omalizumab use in children (Study
010). The study examined Omalizumab administration over a seven month
period in \~ 300 subjects.

Two of the nine AA studies were uncontrolled, extension studies: Study
010E followed Study 010 and Study Q2195g followed Study Q2143g. Study
010E was of five months duration and Study Q2195g of six months
duration.

**A. Study 008 and 009:**

Studies 008 and 009 shared the same basic study design characteristics,
as follows:

**Title:** Study 008: A phase 3, 7-month, randomized, double-blind,
parallel-group, placebo-controlled, multi-center trial with a 5-month
blinded extension period to assess the efficacy, safety, tolerability,
steroid-reduction, pharmacokinetics and pharmacodynamics of subcutaneous
rhuMAb-E25 in adolescents and adults with moderate to severe allergic
asthma requiring daily treatment with inhaled corticosteroids

Study 009: A phase 3, 7-month, randomized, double-blind, parallel-group,
placebo-controlled, multi-center trial with a 5-month blinded extension
period to assess the efficacy, safety, tolerability, steroid-reduction,
pharmacokinetics and pharmacodynamics of subcutaneous rhuMAb-E25 in
adolescents and adults with moderate to severe allergic asthma requiring
daily treatment with inhaled corticosteroids

**Summary:** The studies were randomized, double-blind,
placebo-controlled, multicenter studies in which subjects were
randomized 1:1 to Omalizumab or placebo. The study consisted of several
periods that followed a run-in phase in which subjects were stabilized
on beclomethasone diproopionate (BDP) MDI. Once the run-in phase was
complete subjects were randomized and entered the double blind treatment
period. The most notable treatment periods were the four month
stabilization period, the three month steroid reduction period and the
five month extension period. Notably, eligible subjects had to have
demonstration of a positive skin test reaction to an aeroallergen and
could not be receiving a broad range of concomitant AA medications at
baseline (eg., leukotriene modifying agents, cromolyn, theophylline,
oral or parenteral steroids).

The studies\' primary endpoint consisted of two outcomes:

-number of exacerbations during the steroid reduction period

-number of exacerbations during the stabilization period

These studies\' design and outcomes are described within the efficacy
review documents. Of note, Study 008 was conducted entirely in the USA
and Study 009 was conducted in the USA and several other countries.

**B. Study 011:**

**Title:** A phase 3, 32 week, randomized, double-blind, parallel group,
placebo-controlled, multi-center pilot study to assess corticosteroid
reduction, efficacy, safety, tolerability, steady state, rhuMAb-E25
concentration, and pharmacodynamics of subcutaneous rhuMAb-E25 in
adolescents and adults with severe allergic asthma requiring daily
treatment with high dose inhaled corticosteroids, with or without oral
corticosteroids.

**Summary:** This randomized, double-blind, placebo-controlled study was
conducted at multiple non-USA sites. The primary objective of the study
was to show the reduction of inhaled corticosteroids in subjects with
severe AA. Prior to randomization, subjects completed a run-in phase in
which fluticasone MDI was adjusted for symptom control. The eight month
treatment period consisted of a four month stabilization phase and a
four month steroid reduction phase (when oral or inhaled steroids were
reducted). Following completion of the eight month treatment period,
subjects returned 12 weeks later (off study drug) for a follow-up visit.

Subjects eligible for this study were notably different from those in
Studies 008/009, in that they had to have a diagnosis of severe AA (not
moderate to severe) and had to be using inhaled fluticasone (1 to 2
mg/daily) at randomization. Eligible subjects could also be receiving
oral steroids. All eligible subject had to have either a positive skin
prick test to a specific allergen or a positive RAST test to a specific
allergen. Like Studies 008 and 009, current smokers were excluded from
enrollment as were subjects receiving the following medications:
theophylline, cromolyn, or leukotriene modifying agents and subjects
with non-AA \"clinically significant disease.\" The study\'s design and
outcomes are described within the efficacy review documents.

**C. Study 010 and 010E:**

**Title:** Study 010: A phase 3, 7-month double-blind, randomized,
parallel-group, placebo-controlled, multicenter trial with a 5-month
open label extension period to assess safety and tolerability,
steroid-reduction, pharmacokinetics and pharmacodynamics of subcutaneous
rhuMAb-E25 in children (6 - 12 years) with allergic asthma requiring
daily treatment with inhaled corticosteroids

**Summary:** This study consisted of two main periods, the first being a
randomized, double-blind, placebo controlled period in which subjects
were randomized 2:1 (Omalizumab: placebo) and the second an
uncontrolled, open label extension period. The seven month, double-blind
period is referred to as Study 010 (core) and the five month, open label
portion is referred to as Study 010E (extension). Together, the core and
extension aspects of these studies allowed subjects to receive a total
of either 12 months (prior Omalizumab group) or five months (prior
placebo group). Eligible children could have asthma of any severity as
long as they were \"stable\" and the FEV1 was ≥ 60% predicted and
certain other eligibility criteria were met.

Eligible subjects had to be 6 - 12 years of age and have AA of ≥ 1 year
duration, a positive skin test to a specific allergen, FEV1 ≥ 60%
predicted, and well controlled asthma on beclomethasone MDI ≥ 168 to 420
mcg/day. Subjects could not be taking cromolyn, theophylline, oral
steroids or leukotriene modifiers.

Like Studies 008 and 009, a run-in phase (for stabilization on
beclomethasone dipropionate MDI) preceded the study treatment. The
double blind treatment period consisted of an inhaled steroid
stabilization phase (4 months) and an inhaled steroid reduction phase (3
months). Subjects had a follow-up visit (off study drug) 12 weeks after
completion of the extension period. returned 12 weeks after completion
of the extension period

The primary efficacy endpoint (Study 010) was a comparison of the
percent reduction in dose of beclomethasone dipropionate. Subject
disposition is summarized below.

Table 84. Study 010 subject disposition by periods

+---------------------------+------------+---------------+------------+
| **Total no. patients, n   | **E 25**   | **Placebo**   | **Total**  |
| (%)**                     |            |               |            |
+---------------------------+------------+---------------+------------+
| **Double blind 7 months   |            |               |            |
| core period**             |            |               |            |
+---------------------------+------------+---------------+------------+
| Randomized                | 225        | 109           | 334        |
+---------------------------+------------+---------------+------------+
| Competed stabilization    | 216 (96%)  | 101 (93%)     | 325 (97%)  |
+---------------------------+------------+---------------+------------+
| Completed steroid         | 209 (93%)  | 97 (89%)      | 306 (92%)  |
| reduction                 |            |               |            |
+---------------------------+------------+---------------+------------+
| Discontinued              | 16 (7%)    | 12 (11%)      | 28 (8%)    |
+---------------------------+------------+---------------+------------+
| due to AE                 | 1 (\<1%)   | 1 (\<1%)      | 2 (\<1%)   |
+---------------------------+------------+---------------+------------+
| due to unsatisfactory     | 1 (\<1%)   | 1 (\<1%)      | 2 (\<1%)   |
| therapy                   |            |               |            |
+---------------------------+------------+---------------+------------+
| due to protocol violation | 1 (\<1%)   | 2 (2%)        | 3 (\<1%)   |
+---------------------------+------------+---------------+------------+
| due to consent withdrawal | 7 (3%)     | 5 (5%)        | 12 (4%)    |
+---------------------------+------------+---------------+------------+
| due to administrative     | 3 (1%)     | 3 (3%)        | 6 (2%)     |
| problem                   |            |               |            |
+---------------------------+------------+---------------+------------+
| lost to follow-up         | 3 (1%)     | 0             | 3 (\<1%)   |
+---------------------------+------------+---------------+------------+
| **Open label 5 month      |            |               |            |
| extension period**        |            |               |            |
|                           |            |               |            |
| **(all subjects received  |            |               |            |
| Omalizumab)**             |            |               |            |
+---------------------------+------------+---------------+------------+
| Completed core study but  | 0          |               |            |
| did not enter extension   |            |               |            |
| study                     |            |               |            |
+---------------------------+------------+---------------+------------+
| Entered into extension    | 309 (93%)  |               |            |
+---------------------------+------------+---------------+------------+
| Completed extension       | 298 (89%)  |               |            |
+---------------------------+------------+---------------+------------+
| Discontinued              | 11 (3%)    |               |            |
+---------------------------+------------+---------------+------------+
| due to consent withdrawal | 1 (\<1%)   |               |            |
+---------------------------+------------+---------------+------------+
| due to lost to follow-up  | 1 (\<1%)   |               |            |
+---------------------------+------------+---------------+------------+
| due to administrative     | 9 (3%)     |               |            |
| problems                  |            |               |            |
+---------------------------+------------+---------------+------------+

**D. Study Q2143g (ALTO):**

**Title:** A multicenter, randomized, controlled, open-label study to
evaluate the safety of Xolair in moderate to severe persistent asthma
subjects already treated with other therapies

**Summary:** This study assessed the safety of Omalizumab among a group
of moderate to severe persistent AA subjects who may not have been
eligible for Studies 008/009 because of their use of a broad range of AA
concomitant medications. The study was conducted in the USA and used a
randomized (2:1, Omalizumab:standard therapy control), open label design
to assess safety over a six month treatment period. The primary endpoint
was a comparison of SAE.

Eligible subjects were those with the following criteria:

-moderate to severe persistent asthma (the diagnosis did not have to be
allergic asthma)

-between 6 and 75 years of age and currently receiving:

-moderate doses of any inhaled steroid daily for the past 30 days

and/or

-oral steroids at a stable dose for the past 30 days

and

-currently treated with at least one of the following drugs on a daily
basis at a

> stable dose for at least the past 30 days: salmeterol, leukotriene
> modifiers, xanthines or cromolyn

-no thrombocytopenia or platelet count ≤ 100,000/mcL

-no lung disease other than asthma

-no history of neoplasia

Subjects had visits at baseline, weeks 1, 2, 4, 12 and 24 with
collection of AE information and hematology. However, Omalizumab
subjects also had AE information assessed at every injection visit (a
difference that may have led to an ascertainment bias because control
subjects did not have AE obtained at these time points) At week 24,
serum Omalizumab and anti-Omalizumab was assessed. Spirometry was
assessed at baseline and weeks 4, 12 and 24. Clinical chemistry was not
assessed. In general, evaluations were much less extensive than in the
safety and efficacy studies. Subject disposition is summarized below.

Table 85. Study Q2143g subject disposition

  -------------------------------------- ----------------- ---------------
  **Number of subjects:**                **Omalizumab**    **Control**

  Randomized                             1262              637

  Completed                              1083              566

  Discontinued for AE                    34 (3%)           3 (\<1%)

  Discontinued for other reasons:        145 (11%)         68 (11%)
  -------------------------------------- ----------------- ---------------

*Comment: Study Q2143g is notable in that eligible subjects did not have
to have \"allergic\" asthma, only \"asthma\"\--i.e., no skin test
documentation of atopy or RAST requirement.*

**E. Study Q2195g:**

**Title:** An open-label extension study of Xolair (Omalizumab) in
moderate to severe, persistent asthma subjects who completed Study
Q2143g (ALTO)

**Summary:** This was a six month open label, uncontrolled study that
allowed subjects who completed Study Q2143g to receive Omalizumab. The
study\'s eligibility criteria were notable for not only requiring
successful completion of Study Q2143g but completion of that study such
that the subject could be enrolled in Study Q2195g on or before February
1, 2002. Consequently, not all subjects were eligible for Study Q2195g
because of the time constraint. Other eligibility criteria were the same
as those for Study Q2143g.

Subjects who were newly exposed to Omalizumab had evaluations similar to
those in Study Q2143g, while subjects continuing Omalizumab had less
intensive evaluations. Notable evaluations included (for all subjects):
limited physical exams, spirometry, hematology, anti-Omalizumab and
terminal serum Omalizumab concentrations. Subject disposition is
summarized below:

Table 86. Study Q2195g subject disposition

+---------------------+-------------+----------------+---------------+
| Discontinuation     | New group   | Continued      | Total         |
| variable            |             | group          |               |
|                     | n = 188     |                | n = 613       |
|                     |             | n = 425        |               |
+---------------------+-------------+----------------+---------------+
| Study completion    |             |                |               |
+---------------------+-------------+----------------+---------------+
| No                  | 17 (9%)     | 36 (9%)        | 53 (9%)       |
+---------------------+-------------+----------------+---------------+
| Yes                 | 171 (91%)   | 387 (91%)      | 558 (91%)     |
+---------------------+-------------+----------------+---------------+
| Missing\*           | \-          | 2 (\<1%)       | 2 (\<1%)      |
+---------------------+-------------+----------------+---------------+
| Discontinued for AE | 4 (2%)      | 8 (2%)         | 12 (2%)       |
+---------------------+-------------+----------------+---------------+
| Discontinued for    | 13 (7%)     | 28 (7%)        | 41 (7%)       |
| other reason        |             |                |               |
+---------------------+-------------+----------------+---------------+

**F. Study IA04:**

**Title:** A 52 week randomized, open-label, controlled, multi-center
study to evaluate efficacy and tolerability of subcutaneous
administration of Omalizumab in subjects with poorly controlled moderate
to severe allergic asthma in a naturalistic setting

**Summary:** This safety study was conducted at several sites in Europe.
The study used an open label design in which subjects with moderate to
severe allergic asthma were randomized to Omalizumab or to continued
standard therapy (2:1, Omalizumab:control). The primary objective was to
compare the two study groups for the number of asthma deterioration
related incidents (ADRI).

The study was unique among the group of AA studies in that subjects had
to have had at least one asthma-related hospitalization or ER visit and
at least one additional course of oral steroids due to asthma in the
past year. Other eligibility criteria included:

-ages 12 - 75 with a diagnosis of moderate to severe persistent AA with
a positive skin

> test to at least two clinically relevant allergens

-a history of smoking no greater than ≥ 10 pack years

-no prophylactic treatment with depot steroids or use of an
investigational drug in past 30

> days (no other restrictions on concomitant medications)

-no platelet count below 130,000/mcL

Subjects had requisite visits at baseline and weeks 14, 27, 40 and 52
plus a follow-up visit four weeks after week 52 (off study drug).
Platelet counts were assessed at baseline and weeks 1 and 2 and the
scheduled visits. Other evaluations included spirometry, hematology,
clinical chemistry, quality of life assessments, asthma diary recordings
of symptoms and collection of AE information. Serum Omalizumab and
anti-Omalizumab measurements were not performed. Subject disposition is
summarized below:

Table 87. Study IA04 subject disposition

  -------------------------------- ------------------ -------------------
  **Number of subjects:**          **Omalizumab**     **Control**

  Randomized                       206                106

  Completed                        171 (83%)          73 (69%)

  Discontinued                     35 (17%)           33 (31%)

  Discontinued for AE              15 (7%)            1 (1%)

  Discontinued for other reason    20 (10%)           32 (30%)
  -------------------------------- ------------------ -------------------

**G. Study 012:**

**Title:** A 48-patient, 4-month, randomized, double-blind,
placebo-controlled study to determine the effect of Omalizumab on airway
inflammation in adult patients with mild persistent allergic asthma

**Summary:** This was an exploratory study that focused upon changes in
sputum and bronchoscopic findings associated with Omalizumab
adminstration to adults with mild, persistent allergic asthma. The study
was conducted at 5 sites in the USA and used a randomized, double blind,
placebo controlled design in which subjects were randomized 1:1,
Omalizumab:placebo.

Eligible subjects had to have the following major criteria:

-aged 18 - 50 years with a diagnosis of mild, persistent AA

-positive skin test to a specific allergen

-baseline FEV1 ≥ 70% predicted

-≥ 2% eosinophils in WBC in induced sputum at screening

-no concomitant use of cromolyn, theophylline, steroids (oral,
parenteral, inhaled), long

> acting beta agonists, ipratropium, or leukotriene modifiers

-no significant systemic disease

-no smoking within past year

Evaluations included bronchoscopy and induced sputum at screening and
week 16. Other evaluations throughout the study included: spirometry,
platelet counts, AE collections. Following the 16 week treatment period
subjects returned 12 weeks later for a final evaluations (anti-IgE, AE).
Subject disposition is summarized below.

Table 88. Study 012 Subject disposition

  --------------------------------------- ---------------- ---------------
  Number of subjects:                     Omalizumab       Control

  Randomized                              22               23

  Completed                               22 (100%)        22 (96%)

  Discontinued for AE                     0                0

  Discontinued/lost to follow-up          0                1
  --------------------------------------- ---------------- ---------------

**Appendix D. Narratives for all Subjects with Appendicitis:**

**Subjects receiving Omalizumab:**

1\. Subject 4675 in Study 009 was a 38 y o female who developed
abdominal pain 11 hours after her first Omalizumab injection. An
appendectomy was performed for suppurative appendicitis and the subject
continued in the study.

2\. Subject 4329 in Study 010 was a 12 y o female who developed
abdominal pain six months post initiation of Omalizumab. An appendectomy
was performed and a normal appendix resected. The subject recovered and
continued in the study.

3\. Subject 12643 in Study Q2143g was a 37 y o man who developed
abdominal pain four days after his first Omalizumab dose. An
appendectomy disclosed periappendiceal serosal inflammation. The subject
recovered and continued in the study.

4\. Subject 1279 in Study 006 was a 45 y o female who developed
abdominal pain 17 days post initial Omalizumab dose. Appendectomy
disclosed a normal appendix. The subject recovered and continued in the
study.

5\. Subject 1083 in Study 006 was a 24 y o female who developed
abdominal pain 12 post initial Omalizumab dose. An appendectomy
disclosed a normal appendix but the surgeon noted the mesenteric lymph
nodes were inflamed and the diagnosis was mesenteric adenitis. The
subject recovered and continued in the study.

6\. Subject 10558 in Study Q2143 was a 44 y o male who developed
abdominal pain 31 days post initial Omalizumab injection. An
appendectomy was performed and a normal appendix resected. The subject
was diagnosed with lymphadenitis. The subject recovered and continued in
the study.

7\. Subject 1241 in Study 006E developed abdominal pain five weeks post
completion of the Omalizumab treatment period. An appendectomy disclosed
appendicitis. The subject recovered and continued in the study.

8\. Subject 10882 in Study Q2195g developed abdominal pain on day 94 in
the open label study (nine months after initial Omalizumab exposure in
Study Q2143g). An appendectomy

Disclosed appendicitis. The subject recovered and continued in the
study.

9\. Subject 1798W/4334 in the on-going Study 010ext1 was a 13 y o male
who developed abdominal pain three days after enrollment in the
extension study (following Omalizumab administration for at least five
months in the prior extension study). The pathology was consistent with
acute appendicitis and the event was assessed as unrelated to Omalizumab
by the site investigator.

10\. Subject 1793c/4239 in the on-going Study 010ext1 was a 15 y o
female who developed abdominal pain approximately one month after her
last dose of Omalizumab in the study (having received at least five
months Omalizumab in the prior extension study). The subject underwent
exploratory surgery which revealed a thickened and mildly erythematous
appendix with no gross appendicitis evident. A small right ovarian cyst
was also noted. Ultimately, it was concluded the ovarian cyst had caused
the pain and the event was assessed as unrelated to Omalizumab.

11\. Subject 101/5330 in the on-going Study 011E1 was a 46 y o male who
developed abdominal pain approximately 74 weeks in the study. The
subject underwent an appendectomy and was recovering at the time of
reporting. The event was assessed as unrelated to Omalizumab.

**Control subjects:**

12\. Subject 4784 in Study 008 (control) was a 30 y o female who
developed abdominal pain four months into the study and underwent an
appendectomy. Pathology is unavailable. The subject continued in the
study.

13\. Subject 2264 in Study 006 (control) was a 28 y o male who developed
abdominal pain 16 days after completing 12 weeks of the study.
Appendectomy revealed appendicitis. The subject recovered and continued
in the study.

14\. Subject 2004 in Study 006 (control) was a 25 y o male who developed
abdominal pain 12 days after the first placebo injection. Appendectomy
revealed appendicitis. The subject recovered and continued in the study.

**Blinded subjects:**

15\. Subject 0350/00002 in the on-going Study 2304 developed abdominal
pain six months into the study. The event occurred approximately two
weeks following her most recent study agent injection. An appendectomy
was performed for appendicitis. The subject recovered and continued in
the study, the event assessed as unrelated to the study agent.

**Appendix E: Narratives for subjects with malignancy**

**The following 18 malignancies are listed by the sponsor as occurring
among Omalizumab subjects in all completed phase 1-3 studies.**

1\. Subject 31/2904 (Italy) was a 68 y o male diagnosed with pancreatic
cancer in Study 009 (follow-up period). The subject completed Study 009
(Omalizumab group), receiving his last Omalizumab dose on January 25,
2000. On March 14, 2000, 61 weeks after starting Omalizumab, he
developed jaundice and abdominal pain. He was hospitalized and
pancreatic cancer with multiple liver metastases diagnosed. A biliary
stent was placed and the patient discharged in April, 2000. Follow-up
information in June, 2000 showed the patient\'s condition unchanged with
chemotherapy to be started. The cancer was assessed as unrelated to
Omalizumab.

(Pancreatic cancer)

2\. Subject S00856/11177 was a 40 y o male who experienced recurrence of
a parotid adenocarcinoma as metatstatic disease (SAE), an event recorded
three days after the seventh Omalizumab dose in Study Q2143g. The
subject started Omalizumab on June 29, 2001. Omalizumab was discontinued
after receipt of the eighth dose on October 8, 2001 and the subject
discontinued from the study on November 1, 2001 because of the event.
The subject had a history of recurrent parotid carcinoma. The parotid
carcinoma was originally diagnosed in 1981 and was treated with parotid
excision and local radiation. In 1996, a right rib lesion was shown to
be metastatic disease on biospy. Several ribs were resected at that time
and the subject treated with mitroxantron. In 1998 metastatic lung
disease was diagnosed and in 2000, metastatic disease to the right
clavicle and first rib. The bony lesions were radiated at that time. A
CT in May, 2001 (one month prior to enrollment) showed new T10 and T12
lytic lesions. Nevertheless, the subject was enrolled into the study. A
follow-up chest CT in September, 2001 showed much more metastatic
disease to the vertebrae along with a paraspinal mass. The subject was
discontinued from the study shortly thereafter (having received
Omalizumab over an approximately three month period). A follow-up CT in
October, 2001 showed much more extensive metastatic disease with new
liver lesions, a pelvic bone metastasis and many new and larger
pulmonary nodules. The subject was treated with analgesics and followed.
Follow-up CT scans in February, 2002 showed progressive disease in the
lungs. The metastatic disease was assessed by the investigator as
unrelated to the study drug. Note that following completion of the
study, the site investigator stated that he regarded the neoplasm as
pre-existing such that the event should be recorded as baseline history.

(Recurrent parotid adenocarcinoma)

3\. Subject 10370 was a 45 y o male who experienced an SAE of recurrent
non-Hodgkin\'s lymphoma in Study Q2195g. The subject had completed Study
Q2143g (Omalizumab group). One day following the last (eleventh total
dose, approximately six months exposure) dose of Omalizumab in Study
Q2195g, he noted enlarged lymph nodes (April 10, 2002). The patient\'s
past history was notable for non-Hodgkin\'s lymphoma (grade 3, poorly
differentiated, lymphocytic type) first diagnosed in May, 1989. At that
time he had been treated with an autologous marrow transplant and
chlorambucil, vincristine and prednisolone. The subject was diagnosed
with recurrent non-Hodgkin\'s lymphoma on April 16, 2002 and fludarabine
therapy was initiated on May 9, 2002. Omalizumab was discontinued and
the malignancy assessed as unrelated to Omalizumab.

(Recurrent non-Hodgkin\'s lymphoma)

4\. Subject 10077 was a 50 y o male who experienced an SAE of rectal
adenocarcinoma in Study Q2195g. The subject had completed Study Q2143g
(control arm). On day 139 of Study Q2195g, 13 days after his tenth
Omalizumab dose (approximately four months exposure), he was diagnosed
with adenocarcinoma of the rectum. The subject had no history of cancer
or rectal polyps and no family history of colorectal cancer. A routine
colonoscopy on May 15, 2002 disclosed a rectal polyp\--biopsy revealing
invasive adenocarcinoma, grade 2 with involvement of the submucosa. The
lesion was resected and margins were negative for malignancy\--no
follow-up treatment was recommended. The subject remained in the study
and received his last dose of study agent on June 3, 2002 (because the
cancer was not reported to the site investigator until the dose had been
administered). The subject was to have a six month follow-up
colonoscopy.

(Rectal carcinoma)

5\. Subject 502/4027 was a 40 y o female who experienced the SAE of
melanoma in the follow-up period of Study 014. The subject\'s first
Omalizumab dose was on November 19, 1999 and she received her last dose
on March 10, 2000. The subject had a resection of nevi in 1999 for
benign disease. She had also undergone a parotidectomy in April, 1995
for a benign adenoma. The subject was seen by her physician on April 28,
2000 during the study follow-up period. A skin biopsy on May 10, 2000
disclosed melanoma (Clark level III, superficial spreading type). One
month later a wide local resection was performed along with local node
resections. The lymph nodes were negative for malignancy. The subject is
regarded as recovered. The event was regarded as unrelated to Omalizumab
by the site investigator

(Melanoma)

6\. Subject M2153/5228 was a 66 y o female in Study 009C diagnosed with
a squamous cell carcinoma of the right face. The subject was treated
with Omalizumab from November 10, 1998 to July 27, 1999. The patient had
a past history of skin cancer (1996). Approximately 6 months after her
first Omalizumab dose, she underwent a biopsy of a small lesion on the
right side of her face. This biopsy completely excised a small squamous
carcinoma. The subject continued in the study and the event was assessed
as unrelated to Omalizumab.

(non-melanoma skin cancer)

7\. Subject 2469/5420, a 75 y o female, in Study 009C experienced
multiple skin cancers (2 squamous cell and 2 basal cell). The subject
began Omalizumab on November 13, 1998 and received her last injection on
November 11, 1999. The subject has a history of recurrent skin cancer
prior to study enrollment. The events were:

-Event 1: 12 days after study start, the subject had a squamous cell
carcinoma resected

> from her chest wall

-Event 2: 21 weeks after study start, the subject had a basal cell
carcinoma resected

> rom her left arm

-Event 3: 51 weeks after study start, the subject had a squamous cell
carcinoma of the

> neck removed

-Event 4: 51 weeks after study start (same as event 3) the subject had a
basal cell

> carcinoma resected from her chest. The events were not considered to
> be Omalizumab related.

(non-melanoma skin cancer)

8\. Subject 1418/4212 was a 30 y o female in Study Q0694g who
experienced a skin cancer. The subject began Omalizumab on September 19,
1996. On January 6, 1997, 4 days after her 10th Omalizumab dose, the
subject had excision of a mild skin carcinoma on her chin. The subject
continued in the study and the event was assessed as unrelated to
Omalizumab.

(non-melanoma skin cancer).

9\. Subject 10460 was a 49 y o male who experienced an SAE of basal cell
carcinoma on the right shoulder and later a melanoma in Study Q2195g.
The subject had completed Study Q2143g (Omalizumab group). One day after
his sixteenth Omalizumab dose (day 47 of Study Q2195g), the subject was
diagnosed with the basal cell carcinoma (following approximately 7.5
months Omalizumab exposure, September 28, 2001). The subject was not
receiving concomitant oral steroid therapy. The basal cell carcinoma was
resected and no further therapy recommended. The subject continued in
the study and was subsequently diagnosed with a malignant melanoma (a
diagnosis made on November 30, 2001, 10 days after the subject\'s 20th
Omalizumab dose. The melanoma was diagnosed from a complete resection of
a previously identified skin lesion (a lesion that, on biopsy had shown
a dysplastic nevus). The resected melanoma margins were clear and no
further therapy was recommended. The basal cell carcinoma and melanoma
were assessed as unrelated to Omalizumab and the subject continued in
the study.

(non-melanoma skin cancer)

(melanoma)

10\. Subject 11286 was a 58 y o male who was diagnosed with a basal cell
carcinoma on day 135 of Study Q2195g (nine days after his 22nd dose of
Omalizumab). The subject had completed Study Q2143g (Omalizumab group).
The patient had a history of prior basal cell carcinomas with resections
in 1998, 1999 and 2000. During a routine dermatology follow-up visit, a
biopsy of a suspicious lesion disclosed a basal cell carcinoma. The
lesion was subsequently excised and at the time of the excision another
lesion was excised. This second lesion was found to be a squamous cell
carcinoma (a diagnosis made on study day 177, 26 days after his 24th
Omalizumab dose). The events were assessed as unrelated to Omalizumab
and the subject continued in the study.

(non-melanoma skin cancer)

11\. Subject M2076V/3037 was a 44 y o male who was diagnosed with an
acinic cell parotid cancer in the follow-up period for Study 009. The
subject began Omalizumab on December 19, 1998 and received his last dose
on December 11, 1999. On November 24, 1999, the subject had noted a
painful lump in his right parotid. On February 4, 2000, the subject
underwent a right parotidectomy for an acinic cell carcinoma (a complete
excision). The event was assessed as unrelated to Omalizumab.

(parotid acinic cell carcinoma)

12\. Subject 1286B/1030 in Study 006 was a 47 y o male diagnosed with
bladder cancer. The subject began Omalizumab on July 27, 1997 and
finished the study on October 20, 1997. He had a history of adult onset
diabetes mellitus. Screening urinalysis had shown RBC of 1 - 3 per high
power field. A repeat urinalysis prior to randomization showed no RBC.
On October 20, 1997 the final study visit disclosed a large number of
RBC in the urinalysis. A cystoscopy revealed a 2- 3 cm mass in the dome
of the bladder. The subject then underwent a partial cystectomy for an
adenocarcinoma of the bladder (T3, N0, M0, stageIII). He was a nonsmoker
but his mother had pancreatic cancer. The event was assessed as
unrelated to Omalizumab.

(bladder cancer)

13\. Subject M2466A/3322 in Study 009E was a 74 y o male diagnosed with
prostate cancer. The subject began Omalizumab on November 25, 1998 and
received his final dose on June 23, 1999. Prior to study entry on
December 19, 1997, he had a PSA of 3 (0 - 4 ng/mL). Approximately 7
months after starting Omalizumab a routine check up disclosed a PSA of
4.7 ng/mL. A prostate biopsy on June 15, 1999 disclosed prostate cancer.
He discontinued the study but the event was assessed as unrelated to
Omalizumab. CT and other evaluations disclosed no evidence of metastatic
disease. Definitive therapy was not reported.

(prostate cancer)

14\. Subject DEU/0202/00003 in Study IA04 was a 53 y o male diagnosed
with recurrent prostate cancer. The subject began Omalizumab on August
30, 2000 and finished on July 27, 2001. 131 days after starting
Omalizumab he experienced a relapse of prostate cancer. The subject had
first been diagnosed with prostate cancer in 1998. After resection of
the prostate cancer in 1998 the PSA value was 0.1 ng/mL. On November 6,
2000 routine PSA testing showed a value of 0.5 ng/mL. A bone scan at
that time showed no metasteses. He was hospitalized for a biopsy of the
vesico-urethral anastomosis on January 8, 2001. PSA at that time was 0.7
ng/mL and sonography showed the urethra was surrounded by a
hyperreflexive area. Biopsy showed adenocarcinoma of the prostate. The
subject received radiation therapy from January 26, 2001 to March, 2001
and the subject continued in the study until July, 2001. The event was
assessed as unrelated to Omalizumab.

(Recurrent prostate cancer)

15\. Subject S06698/10307 was a 58 y o female who was diagnosed with
breast cancer (SAE) 14 days after her second Omalizumab dose in Study
Q2143g. The subject had undergone a routine annual mammogram that
disclosed a breast mass. The breast mass was biopsied and found to be a
ductal adenomcarcinoma. The subject subsequently had a lumpectomy with
node dissection. No evidence of metastatic disease was found. The
subject was treated with post-operative radiotherapy and discontinued
the study drug. The cancer was assessed as unrelated to Omalizumab by
the site investigator.

(breast cancer)

16\. Subject S06600/10006 was a 61 y o female diagnosed with breast
cancer on day 83 (10 days after her sixth Omalizumab dose) in Study
Q2195g. The subject had completed Study Q2143g (control). She began
Omalizumab on October 26, 2001. Concomitant medications did not include
oral steroids but did include Premarin. A routine mammogram revealed
suspicious changes during the study and on January 16, 2002 a biopsy
showed infiltrating ductal carcinoma. The subject discontinued the study
and a total mastectomy was performed on April 17, 2002. Her last dose of
Omalizumab was on February 21, 2002. No lymph node metasteses were
detected and no adjuvant therapy recommended. The event was assessed as
unrelated to Omalizumab.

(breast cancer)

17\. Subject S06663/10926 was a 45 y o female diagnosed with breast
cancer on day 94 of Study Q2195g (12 days after her 11th and final
Omalizumab dose). The subject had completed Study Q2143g (Omalizumab
group). Her family history was remarkable for breast cancer in her
mother. Concomitant medications included neither oral steroids or
estrogens. A routine mammogram during the study disclosed suspicious
changes. A needle biopsy on March 4, 2002 disclosed breast cancer and a
right mastectomy was performed on March 26, 2002. The pathology a
colloid carcinoma and multifocal intraductal carcinoma. No lymph node
metasteses were detected and no adjuvant therapy recommended. The
subject discontinued the study because of the event. The event was
assessed as unrelated to Omalizumab by the site investigator.

(breast cancer)

18\. Subject S00852/13071 was a 60 y o female diagnosed with breast
cancer in Study Q2143g. The subject began Omalizumab on January 29,
2002. On June 14, 2002 (day 137, 25 days after her fifth Omalizumab
dose), she was diagnosed with left breast cancer. Concomitant medication
included estradiol. She had a history of two aunts with breast cancer.
The breast cancer was detected as an abnormal area on a routine
mammogram. The subject completed the study receiving her last dose of
Omalizumab on June 18, 2002. The event was assessed as unrelated to
Omalizumab.

(breast cancer)

**The following five malignancies are listed by the sponsor as occurring
among the control group in all phase 1-3 completed studies.**

1\. Subject 61/4546 was a 34 y o male diagnosed with testicular seminoma
in Study 009E. The subject began placebo on August 25, 1998 and stopped
placebo on July 22, 1999 (331 days). On March 31, 1999 (seven months
post randomization), the subject was hospitalized with a mass in the
left testicle. Resection of the lesion showed a seminoma.

(seminoma)

2\. Subject S06648/11194 was a 69 y o male diagnosed with a basal cell
carcinoma in Study Q2143g. The subject began the study on December 28,
2001 and completed the study on June 18, 2002. On day 117 of the study,
the subject was diagnosed with a basal cell carcinoma on his nose. The
lesion was resected.

(non-melanoma skin cancer)

3\. Subject 510/4191 was a 66 y o male diagnosed with a squamous cell
carcinoma in Study 014. The subject completed the study and
approximately nine weeks after the final placebo dose, he had a squamous
cell carcinoma resected from his face. The subject had a prior history
of basal cell carcinoma removals.

(non-melanoma skin cancer)

4\. Subject 11/2035 was a 56 y o male diagnosed with a skin cancer in
Study 009. The subject began the study on December 17, 1998 and stopped
the placebo on June 10, 1999. Six weeks after starting the study, the
subject had a skin cancer removed from her forehead. The lesion was
resected with dry ice.

(non-melanoma skin cancer)

5\. Subject 1436/3777 was a 28 y o female diagnosed with a glioma in
Study Q0694g. The subject began the study on November 13, 1996 and
stopped placebo on March 11, 1997. On March 8, 1997, the subject went to
an emergency room because of headaches. A head CT disclosed a lesion and
the subject subsequently underwent resection of a low-grade astrocytoma
of the right temporal lobe on March 11, 1997.

(gliomoa)

**The following events are classified by the sponsor as \"neoplasms as
medical history.\"**

1\. Subject 21/4005 was a 47 y o female diagnosed with breast cancer in
Study 007. The event was originally reported as an SAE but was later
confirmed by the investigator to be medical history. The subject began
Omalizumab on April 25, 1998. She received her last dose of Omalizumab
on May 25, 1998. Prior to study entry on April 9, 1998, the subject had
noted a solid lump and a brownish secretion from her right breast, but
she did not report this to the investigator until the final visit when
Omalizumab treatment and final assessment had been completed. A
mammogram on June 2, 1998 showed an abnormality and on June 22, 1998, a
4 cm right breast mass was resected (T2, N0, M0). Histology showed a
ductal invasive carcinoma, grade 3. Resection was followed by
chemotherapy. The event was assessed as unrelated to Omalizumab.

(breast cancer)

*Comment: It is impossible to rule out the possibility that Omalizumab
exposure may have enhanced the growth of the breast cancer. Given this
concern, it is probably best to group this malignancy among the other
malignancies detected among subjects receiving Omalizumab in the
completed studies.*

2\. Subject 1230/10045 was a 50 y o female diagnosed initially with
recurrent thyroid cancer on day 87 of Study Q2195g based upon the
findings from a routine follow-up radioiodine scan. Further evaluation
by an oncologist did not confirm the diagnosis of recurrent thyroid
cancer and the subject continued in the study. The subject had completed
Study Q2143g (Omalizumab group, beginning therapy on April 10, 2001).
She began receiving Omalizumab in Study Q2195g on September 24, 2001.
Her past medical history was remarkable for resection of a papillary
thyroid cancer in 1999. A post-op follow-up radioiodine scan disclosed
4% uptake in the thyroid bed and the subject received radioiodine.
Rescanning in September, 2000 showed no evidence of residual uptake.
Notably, the subject\'s mother had also been treated for thyroid cancer.
The suspected thyroid recurrence in Study Q2195g was based upon a
December 12, 2001 radioiodine scan showing bilateral pulmonary hilar
uptake which was suspected to be metastatic disease (the scan was
obtained by the subject\'s endocrinologist). The subject received
empirical I-131 therapy (as directed by the endocrinologist). The
endocrinologist noted an , \"apparent pulmonary recurrence despite the
negative prior scan one year previously and normal serum
thyroglobulin.\" She was given 207 millicuries of I131 based on the
empirical diagnosis of metatstatic disease. The subject received her
last dose of Omalizumab on December 17, 2001. A repeat radioiodine scan
on February 5, 2002 was normal with no trace of uptake in the pulmonary
hilar regions. However, the subject was diagnosed as having a lung mass
based upon a February 8, 2002 CT scan showing a 2.8 x 1.5 cm left upper
lung lesion and a lingular lesion. The subject was then referred to an
oncologist. Subsequently, the subject was extensively evaluated with MRI
and PET scans of the chest through August, 2002 (scans obtained by the
subject\'s oncologist). The reviewing oncologist noted, \"it seems
likely to me that the original thyroid cancer was completely resolved by
surgery and that there was little need for the first course of iodine
radiation therapy and even less for the second course as administered.
The hilar areas are normal on CT scanning and did not reproduce uptake
on the therapeutic radioactive iodine dose raising the possibility that
the initial positive scan in the hilar area done earlier this year was
somehow erroneous. The workup of this has revealed the possible
pulmonary nodule which may reflect the remote possibility of metastatic
thyroid disease although this area did not light up on the scan vs a
second malignancy in the lung as a primary vs a possible scanning from
multiple previous episodes of pneumonia and asthmatic bronchitis. I
believe that likely the patient does not have recurrent or metastatic
thyroid cancer.\" The scans also revealed a rib lesion that was
consistently unchanged. The oncologist concluded that he did not regard
the subject as having evidence of recurrent thyroid cancer\--her chest
scan changes correlating with worsening pulmonary disease that required
prednisone therapy. A follow-up chest CT on August 14, 2002 showed
clearing of all previous lung lesions. The subject discontinued the
study because of the event, but had completed all Omalizumab dosing.

(recurrent thyroid cancer)

*Comment: This subject was given radiation therapy for a suspected
recurrence of thyroid cancer manifest as pulmonary hilar metastases. The
diagnosis was never confirmed by histology and was based upon a routine
radioactive iodine follow-up scan showing pulmonary hilar uptake.
Following the empirical radiation therapy, another radioactive iodine
follow-up scan was normal. This event was followed by the detection of
several pulmonary lesions that resolved with prednisone
therapy\--lesions corresponding with worsening asthma and other
pulmonary symptoms. A consultant physician reviewed the empirical
diagnosis of metatstatic thyroid cancer to the pulmonary hila and
disagreed with the diagnosis. This disagreement was apparently based
upon additional follow-up scans showing unremarkable pulmonary hila and
the therapeutic radioactive iodine scan not showing hilar uptake.
Overall, it is conceivable the empirical diagnosis of metatstatic
thyroid cancer was in error. However, given the empirical administration
of radiation therapy and subsequent scans all negative\--it seems
impossible to rule out the possibility the empirical diagnosis of
metastatic thyroid cancer was the correct diagnosis. Consequently, this
event should probably be added to the list of malignancies occurring
among Omalizumab group subjects.*

**The following are malignancies reported in on-going studies:**

1\. Subject RUS/101/7329 in Study 011E1 (an on-going study) was a 63 y o
female diagnosed with a sigmoid carcinoma. The subject had completed the
core study (Omalizumab) and waited approximately 3.5 month months before
entering the extension study. On January 3, 2001 (one month after her
last dose of Omalizumab in the extension study), the subject experienced
back and abdominal pain. She was hospitalized and a colon carcinoma
diagnosed and a resection performed. The subject continues in the study
and the event was assessed as unrelated to Omalizumab.

(colon cancer)

2\. Subject 101/7333 (Russia) in the on-going Study 011E1 was a 52 y o
female who began the extension study on June 14, 2000. On July 1, 2001 a
routine chest radiograph disclosed a lung tumor. A thoracotomy performed
on August 1, 2001 disclosed a \"Lymphangioma cysticum of anterior
mediastinum (hemangioma).\" The subject was discharged from the hospital
on August 8, 2001 and the event was assessed as unrelated to Omalizumab.

(hemangioma)

3\. Subject GER/202/00004 in the on-going Study IA04E1 was a 72 y o male
diagnosed with prostate carcinoma four months into the extension study.
The subject had a history of known blood PSA elevations dating back four
years prior to enrollment in Study IA04. The subject had begun the core
study on August 14, 2000 and received the last Omalizumab dose within
that study on August 8, 2001. After a gap of 28 weeks, the subject
entered the extension study (on February 20, 2002). In 2000, the PSA was
11.2 (normal \< 6.5), by June, 2001 the PSA was 12 and by April, 2002
the PSA was 19. A prostate biopsy on July 4, 2002 disclosed prostate
cancer. The subject was subsequently treated with \"Androcur.\" The SAE
was assessed as unrelated to the Omalizumab and the subject continues in
the study.

(prostate cancer)

**The following event was classified as a malignancy within the
December, 2002 BLA amendment, but was reclassified as a nonmalignancy in
a March 5, 2003 BLA amendment due to additional follow-up information.**

1\. Subject S06645/10123 was a 32 y o female diagnosed with a recurrent
optic chiasm glioma (SAE) 23 days after her third Omalizumab dose. The
subject had a history of resection of a right sided optic glioma at age
seven. Follow-up scans showed no alterations and the subject was
enrolled in the study in February, 2001. In early April, 2001, a
follow-up MRI scan was interpreted as showing no changes. However, the
subject was hospitalized in late April, 2001 with eye pain and blurring.
A repeat MRI disclosed a 2 mm lesion on the left half of the optic
chiasm. The subject was treated with decadron and the lesion was
followed. Follow-up scans have shown no change in the size of the lesion
and the subject completed the study. The events were assessed as
unrelated to study drug. Subsequent information has disclosed the
following: A follow-up head MRI from August 14, 2001 showed an optic
chiasm that was stable in appearance compared to past scans. In October,
2002, the subject was twice hospitalized for headaches and photophobia
of unknown etiology. An October 9, 2002 head CT showed no evidence of
recurrent tumors. The investigator has subsequently noted, \"at one
point there was a question of recurrence\" of the glioma, but \"it was
not confirmed on follow-up MRI and CT, including the studies of February
5, 2002, October 9, 2002 and October 11, 2002. Based on this review it
appears she did not have recurrent neoplasia.\" The investigator changed
the diagnosis to \"temporary blindness of unknown etiology.\"

*Comment: In general, the sequence of events appears consistent with no
recurrence of the glioma.*

**Appendix F. Laboratory data:**

Table 89. Shift frequency of hematology tests from normal at baseline to
abnormal in all controlled studies

+-------------+-------------+-------------+-------------+-------------+
| **          | **All       |             | **AA        |             |
| Parameter** | controlled  |             | controlled  |             |
|             | studies**   |             | studies\*** |             |
+-------------+-------------+-------------+-------------+-------------+
|             | Omalizumab, | Control,    | Omalizumab, | Control,    |
|             |             |             |             |             |
|             | n (%)       | n (%)       | n (%)       | n (%)       |
+-------------+-------------+-------------+-------------+-------------+
| RBC         | n = 1807    | n = 1291    | 849         | 748         |
+-------------+-------------+-------------+-------------+-------------+
| Low         | 123 (6.8)   | 82 (6.4)    | 57 (6.7)    | 46 (6.2)    |
+-------------+-------------+-------------+-------------+-------------+
| High        | 27 (1.5)    | 34 (2.6)    | 17 (2.0)    | 27 (3.6)    |
+-------------+-------------+-------------+-------------+-------------+
| Hemoglobin  | 2924        | 1858        | 1878        | 1262        |
+-------------+-------------+-------------+-------------+-------------+
| Low         | 289 (9.9)   | 151 (8.1)   | 220 (11.7)  | 109 (8.6)   |
+-------------+-------------+-------------+-------------+-------------+
| High        | 19 (0.7)    | 17 (0.9)    | 16 (0.9)    | 10 (0.8)    |
+-------------+-------------+-------------+-------------+-------------+
| Hematocrit  | 2905        | 1838        | 1862        | 1252        |
+-------------+-------------+-------------+-------------+-------------+
| Low         | 253 (8.7)   | 123 (6.7)   | 175 (9.4)   | 96 (7.7)    |
+-------------+-------------+-------------+-------------+-------------+
| High        | 104 (3.6)   | 96 (5.2)    | 74 (4.0)    | 62 (5.0)    |
+-------------+-------------+-------------+-------------+-------------+
| Basophils   | 1741        | 1174        | 803         | 694         |
+-------------+-------------+-------------+-------------+-------------+
| Low         | 2 (0.1)     | 0           | 2 (0.3)     | 0           |
+-------------+-------------+-------------+-------------+-------------+
| High        | 38 (2.2)    | 32 (2.7)    | 9 (1.1)     | 16 (2.3)    |
+-------------+-------------+-------------+-------------+-------------+
| Eosinophils | 1481        | 997         | 692         | 597         |
+-------------+-------------+-------------+-------------+-------------+
| Low         | 52 (3.5)    | 19 (1.9)    | 36 (5.2)    | 13 (2.2)    |
+-------------+-------------+-------------+-------------+-------------+
| High        | 119 (8.0)   | 144 (14.4)  | 68 (9.8)    | 110 (18.4)  |
+-------------+-------------+-------------+-------------+-------------+
| Leukocytes  | 2996        | 1891        | 1909        | 1287        |
+-------------+-------------+-------------+-------------+-------------+
| Low         | 92 (3.1)    | 53 (2.8)    | 66 (3.5)    | 33 (2.6)    |
+-------------+-------------+-------------+-------------+-------------+
| High        | 195 (6.5)   | 112 (5.9)   | 166 (8.7)   | 91 (7.1)    |
+-------------+-------------+-------------+-------------+-------------+
| Lymphocytes | 1658        | 1118        | 759         | 666         |
+-------------+-------------+-------------+-------------+-------------+
| Low         | 69 (4.2)    | 22 (2.0)    | 33 (4.4)    | 6 (0.9)     |
+-------------+-------------+-------------+-------------+-------------+
| High        | 75 (4.5)    | 55 (4.9)    | 53 (7.0)    | 44 (6.6)    |
+-------------+-------------+-------------+-------------+-------------+
| Monocytes   | 1471        | 985         | 681         | 578         |
+-------------+-------------+-------------+-------------+-------------+
| Low         | 211 (14.3)  | 142 (14.4)  | 127 (18.7)  | 112 (19.4)  |
+-------------+-------------+-------------+-------------+-------------+
| High        | 39 (2.7)    | 34 (3.5)    | 18 (2.6)    | 18 (3.1)    |
+-------------+-------------+-------------+-------------+-------------+
| Neutrophils | 1642        | 1093        | 746         | 651         |
+-------------+-------------+-------------+-------------+-------------+
| Low         | 96 (5.9)    | 50 (4.6)    | 49 (6.6)    | 27 (4.2)    |
+-------------+-------------+-------------+-------------+-------------+
| High        | 53 (3.2)    | 55 (5.0)    | 37 (5.0)    | 40 (6.1)    |
+-------------+-------------+-------------+-------------+-------------+
| Platelets   | 3053        | 1918        | 1949        | 1310        |
+-------------+-------------+-------------+-------------+-------------+
| Low         | 43 (1.4)    | 24 (1.3)    | 21 (1.1)    | 18 (1.4)    |
+-------------+-------------+-------------+-------------+-------------+
| High        | 129 (4.2)   | 43 (2.2)    | 104 (5.3)   | 31 (2.4)    |
+-------------+-------------+-------------+-------------+-------------+

\*adolescent/adult female subjects (ages ≥ 12 yrs in Studies 008, 009,
011C, 012, IA04 and Q2143g)

Table 90. Shift analyses of leukocytes

+--------------------+----------+----------+-----------+-------------+
| **Category**       | **All    |          | **AA      |             |
|                    | co       |          | c         |             |
|                    | ntrolled |          | ontrolled |             |
|                    | studies, |          | s         |             |
|                    | n (%)**  |          | tudies,\* |             |
|                    |          |          | n (%)**   |             |
+--------------------+----------+----------+-----------+-------------+
|                    | Oma      | Control, | Om        | Control,    |
|                    | lizumab, |          | alizumab, |             |
|                    |          | n = 1946 |           | n = 1328    |
|                    | n = 3125 |          | n = 2004  |             |
+--------------------+----------+----------+-----------+-------------+
| Normal or high at  | 3048     | 1908     | 1963      | 1306        |
| baseline           |          |          |           |             |
+--------------------+----------+----------+-----------+-------------+
| Shift to low       | 92 (3.0) | 54 (2.8) | 67 (3.4)  | 33 (2.5)    |
+--------------------+----------+----------+-----------+-------------+
| Shift to notably   | 4 (0.1)  | 0        | 2 (0.1)   | 0           |
| low                |          |          |           |             |
+--------------------+----------+----------+-----------+-------------+
| Low at baseline    | 77       | 38       | 41        | 22          |
+--------------------+----------+----------+-----------+-------------+
| Shift to even      | 19       | 10       | 8 (19.5)  | 6 (27.3)    |
| lower              | (24.7)   | (26.3)   |           |             |
+--------------------+----------+----------+-----------+-------------+
| Low at baseline,   | 74       | 38       | 39        | 22          |
| but not notably    |          |          |           |             |
| low                |          |          |           |             |
+--------------------+----------+----------+-----------+-------------+
| Shift to notably   | 1 (1.4)  | 1 (2.6)  | 0         | 1 (4.5)     |
| low                |          |          |           |             |
+--------------------+----------+----------+-----------+-------------+

\*adolescent/adult female subjects (ages ≥ 12 yrs in Studies 008, 009,
011C, 012, IA04 and Q2143g)

Notably low leukocyte count is \< 2,400/cmm.

**Table 91. Change from baseline in platelet counts by time point**

and terminal serum Omalizumab concentration, adult/adolescents

  ---------------- --------------- ---------- ----------- ---------- -------------
  **Time point     **Terminal                                        **Control**
  (week) &         Omalizumab                                        
  change\***       Concentration                                     
                   Quartile,**                                       

                   1 (low)         2          3           4 (high)   

  1 - 5                                                              

  n                434             373        335         214        262

  mean, median     \- 3.2, - 4.0   2.7, 1.0   \- 5.8, -   \- 0.6, -  \- 3.3, - 0.5
                                              4.0         3.0        

  range            \- 208, 182     \- 93, 130 \- 145, 141 \- 149,    \- 173, 94
                                                          189        

  6 - 13                                                             

  n                157             115        110         75         283

  mean, median     \- 3.9, - 5.0   \- 8.8, -  \- 12.2, -  \- 3.1, -  \- 7.2, - 3.0
                                   7.0        10.5        5.0        

  range            \- 128, 226     -128, 91   \- 104, 81  \- 122,    \- 221, 265
                                                          175        

  14 - 17                                                            

  n                122             148        163         169        536

  mean, median     \- 2.4, 3.0     1.2, 3.0   7.1, 7.0    2.6, - 1.0 2.8, 1.0

  range            \- 216, 69      \- 104, 95 \- 95, 91   \- 102,    \- 158, 164
                                                          255        

  18 - 25                                                            

  n                135             119        126         117        328

  mean, median     2.4, 3.0        \- 5.9, -  \- 3.6, 0.5 7.6, 6.0   3.1, 3.5
                                   5.0                               

  range            \- 168, 140     \- 136,    \- 128, 104 \- 127,    \- 199, 186
                                   103                    185        

  26 - 29                                                            

  n                78              113        110         118        375

  mean, median     5.9, 9.5        1.2, - 2.0 3.7, 7.0    7.9, 5.5   6.6, 5.0

  range            \- 146, 196     \- 111,    \- 130, 84  \- 118,    \- 141, 151
                                   105                    243        

  \> 30                                                              

  n                152             190        187         250        701

  mean, median     12.4, 12.0      12.3, 14.0 11.8, 12.0  14.4, 14.0 17.1, 15.0

  range            \- 136, 125     \- 130,    \- 134, 171 \- 154,    \- 108, 170
                                   109                    258        
  ---------------- --------------- ---------- ----------- ---------- -------------

\*change from baseline is shown in units of x 10^9^/L

Table 92. Shift frequency of liver test results in controlled studies

  -------------- -------------- -------------- -------------- --------------
  **Liver test** **All                         **AA           
                 controlled                    controlled     
                 studies, n                    studies,\*     
                 (%)**                         n(%)**         

                 Omalizumab     Control        Omalizumab     Control

  ALT/SGPT       n = 1732       1214           n = 785        686

  Low            37 (2.1)       28 (2.3)       22 (2.8)       22 (3.2)

  High           167 (9.6)      123 (10.1)     111 (14.1)     101 (14.7)

  Albumin        n = 1930       n = 1358       n = 893        n = 776

  Low            19 (1.0)       13 (1.0)       18 (2.0)       11 (1.4)

  High           30 (1.6)       13 (1.0)       13 (1.5)       9 (1.2)

  Alkaline       n = 1779       1217           n = 798        n = 674
  p\'tase                                                     

  Low            64 (3.6)       49 (4.0)       39 (4.9)       31 (4.6)

  High           48 (2.7)       47 (3.9)       29 (3.6)       27 (4.0)

  AST/SGOT       n = 1794       1243           n = 827        n = 708

  Low            62 (3.5)       46 (3.7)       29 (3.5)       23 (3.3)

  High           146 (8.1)      113 (9.1)      91 (11.0)      92 (13.0)

  Bilirubin      n = 1920       1338           n = 903        n = 774

  Low            1 (0.1)        3 (0.2)        0              0

  High           52 (2.7)       43 (3.2)       26 (2.9)       31 (4.0)

  Total protein  n = 1883       n = 1307       n = 882        n = 756

  Low            36 (1.9)       29 (2.2)       31 (3.5)       27 (3.6)

  High           98 (5.2)       50 (3.8)       41 (4.7)       33 (4.4)
  -------------- -------------- -------------- -------------- --------------

\*adolescent/adult female subjects (ages ≥ 12 yrs in Studies 008, 009,
011C, 012, IA04 and Q2143g)

Table 93. Shift analyses of serum creatinine, n (%)

+---------------------+-----------+----------+-----------+------------+
| **Category**        | **All     |          | **AA      |            |
|                     | c         |          | c         |            |
|                     | ontrolled |          | ontrolled |            |
|                     | studies** |          | st        |            |
|                     |           |          | udies\*** |            |
+---------------------+-----------+----------+-----------+------------+
|                     | Om        | Control, | Om        | Control,   |
|                     | alizumab, |          | alizumab, |            |
|                     |           | n = 1351 |           | n = 772    |
|                     | n = 1930  |          | n = 890   |            |
+---------------------+-----------+----------+-----------+------------+
| Normal or low at    | 1424      | 952      | 598       | 502        |
| baseline            |           |          |           |            |
+---------------------+-----------+----------+-----------+------------+
| Shift to high       | 292       | 174      | 127       | 98 (19.5)  |
|                     | (20.5)    | (18.3)   | (21.2)    |            |
+---------------------+-----------+----------+-----------+------------+
| Shift to notably    | 0         | 0        | 0         | 0          |
| high                |           |          |           |            |
+---------------------+-----------+----------+-----------+------------+
| High at baseline    | 506       | 399      | 292       | 270        |
+---------------------+-----------+----------+-----------+------------+
| Shift to even       | 161       | 129      | 106       | 102 (37.8) |
| higher              | (31.8)    | (32.3)   | (36.3)    |            |
+---------------------+-----------+----------+-----------+------------+
| High at baseline,   | 504       | 398      | 290       | 269        |
| but not notably     |           |          |           |            |
| high                |           |          |           |            |
+---------------------+-----------+----------+-----------+------------+
| Shift to notably    | 2 (0.4)   | 2 (0.5)  | 2 (0.7)   | 2 (0.7)    |
| high                |           |          |           |            |
+---------------------+-----------+----------+-----------+------------+

\*adolescent/adult female subjects (ages ≥ 12 yrs in Studies 008, 009,
011C, 012, Q2143g and IA04)

A \"notably high\" serum creatinine is defined as \> 1.6 mg/dL.

**Table 94. Shift frequency of urinalysis test normal at baseline to**

abnormal post-treatment

  -------------- -------------- -------------- -------------- --------------
  **Urine test** **All                         **AA           
                 controlled                    controlled     
                 studies, n                    studies,\* n   
                 (%)**                         (%)**          

                 Omalizumab     Control        Omalizumab     Control

  Glucose        n = 1269       n = 761        n = 484        363

  Neg at bsln    1262 (99.5)    757 (99.5)     479 (99.0)     359 (98.9)

  Pos post       2 (0.2)        3 (0.4)        0              3 (0.8)

  Hemoglobin     n = 1683       n = 1197       n = 734        n = 714

  Neg at bsln    1459 (86.7)    1043 (87.1)    645 (87.9)     635 (88.9)

  Pos post       168 (11.5)     144 (13.8)     91 (14.1)      82 (12.9)

  Protein        n = 1885       n = 1286       n = 936        n = 803

  Neg at bsln    1860 (98.7)    1262 (98.1)    922 (98.5)     792 (98.6)

  Pos post       49 (2.6)       38 (3.0)       23 (2.5)       20 (2.5)

  RBC            n = 1162       n = 848        n = 698        n = 597

  Neg at bsln    767 (66.0)     565 (66.6)     518 (74.2)     419 (70.2)

  Pos post       103 (13.4)     66 (11.7)      57 (11.0)      38 (9.1)

  WBC            n = 1271       n = 916        n = 746        n = 628

  Neg at bsln    752 (59.2)     564 (61.6)     485 (65.0)     432 (68.8)

  Pos post       146 (19.4)     93 (16.5)      68 (14.0)      60 (13.9)
  -------------- -------------- -------------- -------------- --------------

\*adolescent/adult female subjects (ages ≥ 12 yrs in Studies 008, 009,
011C, 012, Q2143g and IA04)

Neg = negative, Pos = positive; bsln = baseline, post = post-treatment

**Appendix G. Other Notable AE and SAE Narratives:**

Subject 1/5476 in the on-going Study 011E1 was a 72 y o male who
experienced the SAE of thrombocytopenia. At visit 1 of the 011 core
study, 11 weeks prior to the first study agent administration, the
subject had a platelet count of 110 x 10^9^/L. Immediately prior to
study agent administration (Omalizumab) in the core study, his platelet
count was 98 x 10^9^/L. The subject completed the core study and was off
Omalizumab for three months during a follow-up period. At the end of the
three month, off study agent period, his platelet count was 112 x
10^9^/L. The subject began Omalizumab treatment in Study 011E1 on May
10, 2000 (18 weeks after the last Omalizumab dose in the core study).
After 12 weeks of Omalizumab administration in Study 011E1, the
subject\'s platelet count was 98 x 10^9^/L. After 21 weeks of Omalizumab
administration in the extension study, his platelet count was 25 x
10^9^/L. At this time his hemoglobin was normal and a bone marrow
aspirate read as normal. Study drug was discontinued because of the
event. At one month following the last Omalizumab dose, the platelet
count was still 25 x 10^9^/L. Other tests showed a negative ANA, 1/40
rheumatoid factor. A platelet-associated IgG was elevated and
anti-cardiolipin antibodies were negative. Antibodies to platelet
glycoprotein Iib/IIIa and platelet glycoprotein IbIX were positive and
interpreted as consistent with idiopathic thrombocytopenia purpura. The
event was assessed as unrelated to Omalizumab. Subsequent platelet
counts (through four months of follow-up post discontinuation of
Omalizumab) have shown values between 46 x 10^9^/L and 70 x 10^9^/L.

Subject 52/7396 in the on-going Study 011E1 was a 72 y o female
diagnosed with polymyalgia rheumatica, an SAE prompting discontinuation
from the study. The subject developed fever and subsequent myalgia
approximately eight months into the extension study. The ESR was noted
to be 120 and the subject was suspected of having polymyalgia
rheumatica. The subject was treated with steroids and the SAE was
assessed as unrelated to Omalizumab.

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