Vol.

97 (2003) 123^129

Omalizumab (Xolairs) improves quality of life in

adult patients with allergic asthma: a review
R. BUHL
Pulmonary Department, University Hospital, Mainz,Germany
Abstract Physicians are increasingly aware that asthma causes significant impairment of the patients physical, psychological, and social well-being.Whilst standard clinical endpoints provide significant information on airway status during
treatment, it is important to determine whether such improvements overcome the functional impairment that patients
have to deal with on a daily basis. As such, assessment of health-related quality of life (QoL) is an important aspect of
asthma management in clinical practice.Omalizumab (Xolairs) is a recombinant humanized monoclonal anti-immunoglobulin E (IgE) antibody that represents a new therapeutic approach to IgE-mediated diseases such as allergic asthma.
Clinical studies show that omalizumab improves the control of allergic asthma whilst reducing steroid consumption, and
enhanceslong-term disease controlin patients withrecurrent symptoms.Using established and validated QoL methodology, two placebo-controlled clinical studies in adults with moderate-to-severe allergic asthma have shown that patients
treated with omalizumab experience a clinically relevant improvement in all aspects of their asthma-related QoL,
changes that were significantly superior to those observed for placebo. Such improvements were apparent when omalizumab was added to existing therapy with inhaled corticosteroids, and maintained during a subsequent steroid-reduction phase.Through effective disease control, omalizumab therefore leads to significant improvements in health-related
QoL that are meaningful to patients with allergic asthma. r 2002 Elsevier Science Ltd. All rights reserved.
Available online at http://www.sciencedirect.com

Keywords allergic asthma; anti-IgE; omalizumab; quality of life.

INTRODUCTION
Asthma continues to represent a major public health
concern, aecting some 100 ^150 million people worldwide and accounting for an estimated 180 000 deaths on
an annual basis (1). Highest prevalence rates are apparent
in developed countries (2), where asthma consumes a
considerable proportion of scarce health-care resources
(3). Current international and national asthma management guidelines advocate the importance of combined
pharmacotherapy to control the underlying inammatory disease (e.g. inhaled corticosteroids) and relieve
acute symptoms (e.g. short-acting inhaled b2 -agonists)
(4 ^ 6). However, such regimens can be complicated (e.g.
use of multiple inhalers with dierent administration
schedules) and are often, therefore, associated with
poor patient compliance, which represents a major obstacle to successful disease control in the long term. A
need therefore exists for new therapeutic options for

Received 26 August 2002

Correspondence should be addressed to: Prof. Roland Buhl, Pulmonary
Department, University Hospital, Mainz,Germany.Tel: +49 6131177270;
Fax: +49 6131175545; E-mail: r.buhl@3-med.klinik.uni-mainz.de

the treatment of asthma that are eective, well tolerated and above all convenient for the patient.
Recent evidence conrms that over 90% of asthma
cases are allergic in nature (7,8).Trigger allergens include
housedust mites, pollens, animal danders and fungal
spores. Targeting of factors involved in the subsequent
allergen-specic response, such as immunoglobulin E
(IgE) (9), therefore represents a sound basis for the development of new therapeutic agents for the treatment
of asthma. Moreover, many asthma suerers have other
concomitant IgE-mediated allergic diseases such as seasonal allergic rhinitis (2), which means that a treatment
aimed at stopping the eects of IgE in the allergic cascade may bring about improvements in both conditions.
This scientic rationale has led to the development of
omalizumab (Xolairs), the rst agent to specically target human IgE.Omalizumab is a recombinant humanized
monoclonal anti-IgE antibody that stops the allergic
cascade by binding to free IgE (10). Indeed, studies show
that serum-free IgE levels fall to approximately 1% of
baseline values within 24 h of subcutaneous administration of omalizumab, an eect that is maintained with
continued administration (11^13). Consequently, IgE receptors on cells involved in the allergic response are

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RESPIRATORY MEDICINE

down-regulated, leading to a decreased responsiveness

to antigen challenge (14). This prole of reduced free IgE
levels and IgE receptor down-regulation suggests that
omalizumab is a promising new agent for the treatment
of allergic asthma and other allergic diseases. Indeed,
early initial studies in patients with mild allergic asthma
showed that omalizumab signicantly inhibited the early
and late responses to inhaled allergen (15), which provides evidence that IgE has a central role in mediating
the allergic cascade. Given that the late asthmatic response is generally regarded to reect the chronic inammatory changes characteristic of the disease (16),
the inhibitory eects of omalizumab demonstrate its potential utility in the long-term management of asthma.
Indeed, two long-term (28 -week) clinical studies have
subsequently conrmed that omalizumab is eective in
the treatment of adults with moderate-to-severe allergic
asthma (17,18).This eect was maintained during a subsequent 24 -week extension period (19). In these studies,
omalizumab was well tolerated and signicantly improved both standard clinical endpoints and overall disease control [i.e. the number of asthma exacerbations
per patient was reduced (Fig.1)], and provided patients
with the opportunity to signicantly lessen their dependence on inhaled corticosteroids. With any new treatment intervention for asthma, however, the question
always remains as to whether statistically signicant improvements in symptoms and disease control are clinically relevant from the patients perspective, notably in
terms of their health-related quality of life (QoL).For this
reason, an assessment of the eect of omalizumab on
health-related QoL formed an integral part of this compounds clinical development.
This review discusses the eects of asthma on healthrelated QoL and how it can be quantied, along with the
pooled ndings of clinical investigations of the eect of

Omalizumab

Mean no. of
exacerbations/patient

1.5

Placebo

1.0

0.5

**
**

***

***

0
Busse et al.
(17)

Solr et al.
(18)

Steroid-stable phase

Busse et al.
(17)

Solr et al.
(18)

Steroid-reduction phase

FIG. 1. Mean number of asthma exacerbations per patient during treatment with omalizumab in adult and adolescent patients
with moderate-to-severe asthma, when added to existing inhaled corticosteroid therapy (steroid-stable phase; 16 weeks)
and when inhaled corticosteroids were reduced (steroid-reduction phase; 12 weeks); **Po0.01, ***Po0.001vs. placebo (using
the generalized Cochran^Mantel^Haenszel test).

omalizumab on health-related QoL in adults and adolescents with allergic asthma.

THE EFFECTOF ASTHMAON

HEALTH-RELATED QOL
A primary objective of medical practice is to improve the
patients health-related QoL, i.e. the aspects of an individuals overall QoL that is principally determined by his/
her health status and which is sensitive to therapeutic intervention. Health-related QoL can therefore be simply
and adequately dened as the functional aspects of an illness and its consequent therapy upon a patient, as perceived by the patient (20), a denition that places
emphasis on health and associated impairments that patients consider important. Use of such a focused denition is important, as the expression quality of life is
somewhat nebulous and often means dierent things to
dierent individuals.
It is well established that asthma exerts a profound effect on QoL, particularly from an emotional aspect and
in terms of the ability to perform activities (21). Indeed, it
is often the extent of such functional impairment, and
the inability to perform day-to-day activities as well or
as enjoyably as the suerer would like, that leads to the
primary medical consultation rather than actual symptoms of shortness of breath, wheezing and cough per se.
For example, patients typically experience diculty with
sports and exercise, while day-to-day tasks such as going
upstairs and shopping may be troublesome due to shortness of breath. Environmental stimuli, such as exposure
to allergens (e.g. dust, pets), cigarette smoke, cold air
and atmospheric pollution, may also cause diculties
with daily activity. Such limitations are a cause of signicant frustration to patients. Other emotional aspects include concerns about having asthma, particularly the
need to use medications in the long-term and fear of
not having medication available should a life-threatening
episode occur (22). Until recently, however, clinical trials
in patients with asthma have tended to focus on conventional clinical indices of the illness alone (e.g. spirometry,
symptoms, airways hyperresponsiveness).This can partly
be explained by the tremendous medical advances that
have occurred over the last three decades in the diagnosis of the disease and evaluation of treatment intervention. Such advances have caused a shift away from
reliance on traditional medical history taking, which
usually included an assessment of symptoms as well as
how the patients daily life was aected and the associated impact on his/her feelings. Moreover, evaluation
of the subjective experiences of the patient has often
been overlooked on the basis that such experiences
are merely qualitative and often vague. Studies designed
around an evaluation of clinical outcomes alone have,
therefore, often assumed that changes in these endpoints

OMALIZUMAB AND QUALITYOF LIFE

would lead to concomitant changes in the patients daily

life, thereby conferring a QoL improvement. However,
there is an increasing body of evidence to show that conventional clinical measures of asthma, whilst providing
valuable information about the status of the aected organ system, rarely capture in full the functional impairments that are important to patients in their everyday
lives (23). Conversely, some patients may experience an
improvement in health status during therapeutic intervention but this improvement may not be captured by
clinical measures (24). To obtain a complete picture of
the patients health status during asthma therapy, therefore, both conventional clinical indices and the patients
health-related QoL, should be concomitantly measured
(25). Indeed, advances in QoL research, with the development of rigorous scientic questionnaires, now mean
that changes in subjective functional status can be reliably and accurately determined during asthma therapy.
In conjunction with routine clinical measures of airways
function, such questionnaires help to provide a more
complete assessment of overall health status in the patient with asthma, and are discussed in more detail in
the following section.

MEASURING HEALTH-RELATED QOL

IN PATIENTS WITH ASTHMA
A range of questionnaires, both generic and disease-specic, are available to determine health-related QoL in patients with asthma (24). Generic instruments include the
Sickness Impact Prole (26), the Nottingham Health
Prole (27), and the Medical Outcomes Survey ShortForm 36 questionnaire (28). These questionnaires are
designed for use in all health states, and therefore allow
burden of illness to be compared for dierent medical
conditions. To do so, however, requires that such questionnaires are broad in their comprehensiveness; consequently, they have little scope to detect small, but
subjectively important, changes in health-related QoL
for patients with specic conditions such as asthma (29).
The limitations of generic instruments have led to the
development of disease-specic QoL questionnaires that
aim to determine the level of impairment patients with a
specic disease experience during their daily life. Such
questionnaires have been developed and validated for patients with asthma, and can be used in both clinical trials
and clinical practice to assess the impact of the condition, and subsequent treatment, on a patients QoL.
Examples of asthma-specic QoL instruments are numerous and include, amongst others, the Asthma Quality of Life Questionnaire (AQLQ) (22), the St Georges
Respiratory Questionnaire (30), the Living with Asthma
Questionnaire (31), and the Respiratory Illness Quality of
Life Questionnaire (32). Of these instruments, the
AQLQ has been extensively utilized in clinical trials. This

125

questionnaire comprises 32 questions (frequently referred to as items), which were chosen by asking adult
patients with asthma to identify the aspects of their disease that were most troublesome to daily life.Questions
are grouped into four categories (domains):
K

Activity limitations: Amount of limitation of individual

activities that are important to the patient and are
aected by asthma (11 items).
Emotions: Frequency of being afraid of not having
medications, concerns about having asthma and using
medication, and frustration (ve items).
Symptoms: Frequency and discomfort associated
with shortness of breath, chest tightness, cough,
diculty breathing out, ghting for air, heavy
breathing, and diculty getting a good nights sleep
(12 items).
Exposure to environmental stimuli: Frequency of
exposure to and avoidance of environmental stimuli
such as dust, cigarette smoke and air pollution (four
items).

Each question is answered by the patient on a 7-point

scale, from 1 (extremely impaired) to 7 (no impairment).
Results are generally expressed in terms of a mean score
for each domain, along with an overall score. An increase
in domain or overall QoL score of 0.5 or greater indicates
a clinically signicant improvement in QoL, with dierences from baseline greater than 1.5 reecting a large
improvement (33). This approach allows physicians to
make a meaningful interpretation of QoL ndings, i.e.
to translate these thresholds into scenarios that illustrate what a clinically signicant change with treatment
may mean to an individual patient (34). Independent validation studies show that AQLQ has good reliability and
responsiveness with excellent cross-sectional and longitudinal validity (35), properties that make this questionnaire ideal for use in clinical trials (36). Moreover, AQLQ
has been adapted for use in a large number of languages
and can be completed by patients in 5^10 min, making
this an ideal method for assessment of the health-related
QoL of the asthma patient in routine clinical practice.

EFFECTOF OMALIZUMAB ON
HEALTH-RELATED QOL
As previously discussed, omalizumab is a recombinant
humanized monoclonal anti-IgE antibody that has demonstrated signicant clinical benets in adults with
moderate-to-severe allergic asthma in two phase III studies (17,18).These studies utilized an identical double-blind,
placebo-controlled design, in which 1071 adolescents and
adults aged12^75 years with moderate-to-severe allergic
asthma (baseline forced expiratory volume in1sec 40%
and 80% of predicted), who were symptomatic on
inhaled corticosteroids, were enrolled. All patients had

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RESPIRATORY MEDICINE

experienced asthma symptoms for at least 1 year, with

serum IgE levels of 30 ^700 IU/ml, and demonstrated positive skin-prick testing to at least one common allergen
(e.g. housedust mite, dog, cat or cockroach). Following a
run-in/baseline period, patients were randomized to receive either omalizumab or matching placebo for 16
weeks, in addition to existing treatment with inhaled
corticosteroids (steroid-stable phase). During the following 12 weeks, controlled attempts were made to gradually reduce or withdraw corticosteroid therapy
(steroid-reduction phase). Health-related QoL, in addition to routine clinical endpoints, was assessed throughout each 28 -week study using the AQLQ. In both studies,
omalizumab was administered as a subcutaneous injection once or twice each month (at least 0.016 mg/kg/IgE
[IU/ml] every 4 weeks). Most patients, however, were
conveniently dosed at monthly intervals.
The homogeneity of the design of the two studies
permitted pooling of their QoL ndings. Overall, patients treated with omalizumab experienced a clinically
relevant improvement in their asthma-related QoL, as
shown by improvements in mean score of 0.5 in all four
domains (as well as the overall score) of the AQLQ
(Fig. 2). It is interesting to note that there were large responses in some patients on placebo, consistent with
previous observations (37^ 41), although a signicant placebo response is not unique to patients with asthma

(42^ 45). Such responses, especially in the clinical trial

setting, are often attributed to psychological mechanisms such as an awareness of being closely observed and
active compliance with the presumed wishes of researchers, along with improved compliance with existing medication. Nevertheless, these placebo responses were still
signicantly lower than the improvements in QoL
achieved with omalizumab (Fig. 2), and improvements
for the latter group were consistent with other ecacy
evaluations. Overall, the level of improvement in QoL
with omalizumab during the steroid-stable phase was
higher than that observed with either leukotriene-modifying agents (41) or low-dose inhaled corticosteroids
alone (46), and comparable to that observed for salmeterol when added to the regimen of a similar population
of patients symptomatic on inhaled corticosteroids alone
(37,39).
A particularly notable nding of these studies was that
the improvement in QoL with omalizumab was maintained when controlled attempts were made to gradually
taper the dose of inhaled corticosteroid; in fact, the positive eect of omalizumab therapy on QoL relative to
placebo appeared to increase as patients progressed
through this stage of the study (see Fig. 2).The magnitude
of this improvement is particularly apparent if we examine the proportion of patients experiencing a large improvement in QoL, i.e. those patients for whom domain

End of steroid-stable phase

Omalizumab
Mean change from baseline

1.5

(a)

1.0

Placebo

***

***

***
***
Clinically
significant
improvement

0.5

0
Activities

1.0

Emotions

Symptoms

Environmental
exposure

Overall
score

End of steroid-reduction phase

1.5
Mean change from baseline

***

***

***

***

***
***
Clinically
significant
improvement

0.5

0
Activities

(b)

Emotions

Symptoms

Environmental
exposure

Overall
score

Domain

FIG. 2. Pooled analysis of least-squares meanimprovementsin asthma-related QoLduring treatment with omalizumabintwo phase
III studies of adult and adolescent patients with moderate-to-severe asthma; ***Pr0.001vs. placebo (using analysis ofcovariance methods).

OMALIZUMAB AND QUALITYOF LIFE

127

End of steroid-stable phase

Omalizumab
Placebo

40

**
31
Patients (%)

30

*
28

*
27

*
24

23

21

20

20

***
25

17

16

10

(a)

0
Activities

Emotions

Symptoms

Environmental
exposure

Overall
score

End of steroid-reduction phase

40
***
31

***
32

**
31

***
32

***
31

Patients (%)

30
21

23
20

20

22
18

10

0
Activities

Emotions

(b)

Symptoms

Environmental
exposure

Overall
score

Domain

FIG. 3. Pooled analysis of percentage of patients achievingalargeimprovementin asthma-related QoL (increasein domain or overall
score of1.5 or more relative to baseline (33)) during treatment with omalizumab intwo phase III studies of adult and adolescent patients
with moderate-to-severe asthma; *Po0.05, **Pr0.01, ***Pr0.001 vs. placebo (using the generalized Cochran^Mantel^Haenszel
test).

and/or overall QoL score increased from baseline by 1.5

points or more (33). Indeed, compared with placebo, the
proportion of patients achieving this level of QoL improvement on omalizumab was signicantly higher
across all aspects of asthma-related QoL (Fig. 3). Thus,
in terms of overall score, 31% of omalizumab-treated patients achieved a large improvement in QoL, almost twofold higher than that observed for placebo (18%).This improvement is notable when we consider that it was
achieved despite a signicant concomitant reduction in
reliance on inhaled corticosteroids. Such ndings therefore provide compelling evidence that omalizumab targets a cause of the underlying allergic disease.
Overall, the QoL benets conferred by omalizumab
therapy are conrmed by patient and investigator
opinions of treatment eectiveness, which were recorded at the end of the 28 -week treatment period in
both phase III studies. Indeed, over 60% of patients and
investigators rated treatment with omalizumab as either
excellent or good, compared with less than 40% for placebo therapy. Consequently, the proportion of patients
and investigators rating omalizumab therapy as poor

(or worse relative to pre-treatment) was low (only

14%), whereas 33% of patients and investigators recorded such an evaluation for placebo therapy. Overall,
omalizumab was signicantly superior to placebo in
terms of patient and investigator opinions of treatment
eectiveness (both Po0.001).

CONCLUSIONS
It is well established that asthma can have an adverse effect on the physical, emotional, and social aspects of an
individuals QoL. Paradoxically, clinical trials in patients
with asthma have tended to focus on standard evaluations of airway status alone, with little regard as to
whether such changes are clinically meaningful from the
patients perspective. Indeed, improvements in healthrelated QoL have often been assumed on the basis of statistically signicant changes in clinical endpoints. However, such correlation is typically weak to moderate,
which emphasizes the importance of a concomitant evaluation of health-related QoL during clinical assessment.

128

With the development of rigorous, disease-specic questionnaires, such as the AQLQ, changes in subjective functional status can now be reliably and accurately
determined, thereby provide a more complete assessment of overall health status during asthma therapy.
Omalizumab is a new preventative therapy that targets
an important cause of allergic asthma, the IgE-mediated
allergic response. In clinical studies, this agent provided
eective disease control in adults with moderate-to-severe allergic asthma, a prole that was paralleled by signicant improvements in all aspects of asthma-related
QoL. Such improvements were clinically meaningful to
patients, and were evident not only when omalizumab
was added to existing therapy with inhaled corticosteroids but also during a subsequent steroid-reduction
phase. Moreover, with convenient subcutaneous administration once or twice each month, treatment with
omalizumab may overcome the potential for poor compliance that has proved a major limitation of traditional
anti-asthma agents. On the basis of such ndings, omalizumab therefore represents a novel and highly promising
addition to available pharmacotherapies for the treatment of asthma.

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