**Pulmonary Advisory Committee Meeting of May 15, 2003**

**Draft Topics for Discussion**

Note: These are areas for your consideration in preparing for the May 15
Advisory Committee Meeting. We will likely be asking for discussion
relating to these areas at the meeting. Multiple discussion topics are
listed. Depending upon the discussion and advice relating to the topics
addressed early in the course of the meeting, some later topics may
become less important. A decision to defer some topics may be made
during the meeting to ensure that adequate discussion is obtained on the
most important issues.

1\)

Genentech proposes the use of omalizumab in the treatment of allergic
asthma among adults and adolescents. Genentech has submitted 4
randomized, placebo-controlled, double-blind studies of subcutaneous
omalizumab use in allergic asthma; studies 008, 009, 010, and 011.
Additional studies in allergic asthma patients include a phase 2 study
relying on IV administration, and two controlled but open label trials
designed primarily for safety assessments.

We would like discussion of the study results with attention to whether
these studies provide substantial evidence of meaningful efficacy of
omalizumab in the treatment of allergic asthma.

2\)

Substantial fractions of patients screened for these studies were
ineligible for enrollment due the presence of a baseline IgE
concentration that was outside the permitted limits (either too high or
too low) or their IgE concentration was too great for their specific
body weight to fall within the range of IgE-weight permitted in the
dosing table.

A discussion of the effect of these exclusions upon clinical practice
will be useful. For example, patients whose IgE concentration value from
a first test did not fall within a permitted dosing range could
conceivably be evaluated with repeated retesting until a serum IgE
concentration was obtained that did permit dosing.

Discussion of the expected stability or variability of IgE levels in
allergic asthma may be valuable, especially as it applies to selecting
patients for omalizumab therapy. Please include in your thinking whether
the clinical study findings can be generalized to patients whose initial
serum IgE concentrations preclude use of omalizumab therapy but
repetitive testing ultimately results in the detection of an acceptable
serum concentration.

3\)

The expected stability or instability of serum IgE concentrations enters
into assessment of this treatment in a second manner, when considering
efficacy over long periods of time. The dosing of this treatment is
based upon weight and pre-treatment IgE concentration. IgE levels cannot
be re-evaluated while receiving omalizumab, or for an extended period
after dosing is discontinued because the apparent serum IgE
concentration is substantially altered by omalizumab. Efficacy has been
evaluated only through 1 year of dosing.

Discussion relating to the stability of IgE levels in allergic asthma
over long periods of time (e.g., years, relevant for the potential
duration of treatment with omalizumab) will be useful. Please consider
if planning a one-time evaluation of IgE concentration, leading to
prolonged dosing based upon this one measurement, can be relied upon to
ensure long-term efficacy of the treatment

4\)

Subjects receiving certain common asthma medications were excluded from
the majority of the studies. For example, Studies 008 and 009 excluded
patients receiving any agent from among the following: leukotriene
modifying agents, long-acting beta agonists, cromolyns,
anticholinergics, oral steroids and xanthines. Study 011 allowed
long-acting beta agonists and oral steroids, but excluded the other
agents.

The findings of these studies may describe efficacy within a relatively
narrow range of allergic asthma patients. Study 011 suggested little or
no efficacy in patients receiving oral steroids.

Please consider and prepare for discussions to identify patient
populations for which generalizations of efficacy may be reasonable.
Populations to consider include (but need not be limited to):

-   Subjects receiving only inhaled steroids

-   Subjects receiving inhaled steroids irrespective of any other
    concomitant asthma controller medications

-   Subjects receiving maintenance therapy with oral steroids

5\)

If marketed, omalizumab would be the first passive immunotherapy for
allergic asthma. Documentation of atopy (e.g., skin reactivity) is
frequently required prior to active immunotherapy. The role of
documenting aeroallergen reactivity prior to omalizumab therapy warrants
discussion. Please recall that subjects enrolled in the major omalizumab
safety and efficacy studies were required to have demonstrable skin
reactivity to certain aeroallergens as a defining criterion of allergic
asthma.

a)  Please consider whether classifying a patient as having "allergic
    asthma" commonly requires a demonstration of skin reactivity at the
    present time within the general practice of pulmonary/allergy
    medicine. Specifically, please consider whether the type of therapy
    being considered (among those presently available) enters into the
    classification process.

b)  Please consider whether the population of patients to whom the
    safety and efficacy of omalizumab can be generalized can be
    adequately described without an explicit reference to skin
    reactivity.

6\)

Malignancies were an uncommon occurrence during clinical trials.
However, the incidence of all malignancies was unequal between the
treatment groups, with 20 events in approximately 3000 patient-years
with omalizumab, and 5 events in approximately 1500 patient-years in
control groups (rates of 6.3/1000 patient-years compared to 3.3/1000
patient-years). The rate increase of approximately 3 cancers per 1000
patient-years remained when examining cancers excluding non-melanoma
skin cancer. Please give consideration to the strength of the evidence
in establishing that there is or is not a risk of malignancy associated
with this product. Please also consider the degree of emphasis that may
be warranted in an advisement to the medical community regarding this
issue.

7\)

Anaphylaxis and/or important allergic reactions have been observed with
this product. Please prepare for discussion regarding these observations
and their importance in the setting of this disorder.

8\)

A few published reports suggest IgE may have a role in mucosal immune
function, and altered mucosal immunity may lead to adverse events. No
excess in respiratory system adverse events was observed. However, an
overall increase in digestive system adverse events largely without
specific highlighted adverse event terms was observed. This increase did
include an imbalance in the rate of appendicitis. Also observed was a
small increase in the rate of female genitourinary adverse events, again
largely without an ability to attribute this to specific adverse event
types. Please discuss the importance of these events within the overall
safety profile of this product.

9\)

In addition to the above adverse events, rash was also observed with a
small percentage increase in the omalizumab treated patients. Please
prepare to discuss the significance of this finding.

10\)

Certain aspects of the submitted safety database may place limitations
on the interpretation of the results. For example, comprehensive data is
limited to one year of omalizumab exposure. Additionally, the database
contains only approximately 150 geriatric subjects treated with
omalizumab. Please discuss the importance of these limitations, if any.
Please discuss if these or other limitations or findings may necessitate
the submission of additional data from the applicant prior to being able
to form a risk-benefit assessment.

11\)

Please give consideration to the overall risk-benefit comparison for the
product and for which populations, if any, the comparison may be
favorable.