How safe are the biologicals in treating asthma and rhinitis?

Abstract

A number of biological agents are available or being investigated for the treatment of asthma and rhinitis. The safety profiles of these biologic agents, which may modify allergic and immunological diseases, are still being elucidated. Subcutaneous allergen immunotherapy, the oldest biologic agent in current use, has the highest of frequency of the most serious and life-threatening reaction, anaphylaxis. It is also one of the only disease modifying interventions for allergic rhinitis and asthma. Efforts to seek safer and more effective allergen immunotherapy treatment have led to investigations of alternate routes of delivery and modified immunotherapy formulations. Sublingual immunotherapy appears to be associated with a lower, but not zero, risk of anaphylaxis. No fatalities have been reported to date with sublingual immunotherapy. Immunotherapy with modified formulations containing Th1 adjuvants, DNA sequences containing a CpG motif (CpG) and 3-deacylated monophospholipid A, appears to provide the benefits of subcutaneous immunotherapy with a single course of 4 to 6 preseasonal injections. There were no serious treatment-related adverse events or anaphylaxis in the clinical trials of these two immunotherapy adjuvants. Omalizumab, a monoclonal antibody against IgE, has been associated with a small risk of anaphylaxis, affecting 0.09% to 0.2% of patients. It may also be associated with a higher risk of geohelminth infection in patients at high risk for parasitic infections but it does not appear to affect the response to treatment or severity of the infection. Clinical trials with other biologic agents that have targeted IL-4/IL-13, or IL-5, have not demonstrated any definite serious treatment-related adverse events. However, these clinical trials were generally done in small populations of asthma patients, which may be too small for uncommon side effects to be identified. There is conflicting information about the safety TNF-alpha blocking agents, which have been primarily used in the treatment of rheumatoid arthritis, with serious infections, cardiovascular disease and malignancies being the most frequent serious adverse events. An unfavorable risk-benefit profile led to early discontinuation of a TNF-blocking agent in a double-blind placebo controlled of severe asthmatics. In summary, the risk of anaphylaxis and other treatment-related serious events with of all of the biological agents in this review were relatively small. However, most of the clinical trials were done in relatively small patient populations and were of relatively short duration. Long term studies in large patient populations may help clarify the risk-benefit profile of these biologic agents in the treatment of asthma.

Full text

Page 1

BioMed Central
Page 1 of 11
(page number not for citation purposes)
Allergy, Asthma & Clinical
Immunology
Open Access
Review
How safe are the biologicals in treating asthma and rhinitis?
Linda S Cox
Address: Department of Medicine, Nova Southeastern University Osteopathic College of Medicine, Fort Lauderdale, Florida, USA
Email: Linda S Cox - Lindaswolfcox@msn.com
Abstract
A number of biological agents are available or being investigated for the treatment of asthma and
rhinitis. The safety profiles of these biologic agents, which may modify allergic and immunological
diseases, are still being elucidated. Subcutaneous allergen immunotherapy, the oldest biologic agent
in current use, has the highest of frequency of the most serious and life-threatening reaction,
anaphylaxis. It is also one of the only disease modifying interventions for allergic rhinitis and asthma.
Efforts to seek safer and more effective allergen immunotherapy treatment have led to
investigations of alternate routes of delivery and modified immunotherapy formulations. Sublingual
immunotherapy appears to be associated with a lower, but not zero, risk of anaphylaxis. No
fatalities have been reported to date with sublingual immunotherapy. Immunotherapy with
modified formulations containing Th1 adjuvants, DNA sequences containing a CpG motif (CpG)
and 3-deacylated monophospholipid A, appears to provide the benefits of subcutaneous
immunotherapy with a single course of 4 to 6 preseasonal injections. There were no serious
treatment-related adverse events or anaphylaxis in the clinical trials of these two immunotherapy
adjuvants. Omalizumab, a monoclonal antibody against IgE, has been associated with a small risk of
anaphylaxis, affecting 0.09% to 0.2% of patients. It may also be associated with a higher risk of
geohelminth infection in patients at high risk for parasitic infections but it does not appear to affect
the response to treatment or severity of the infection.
Clinical trials with other biologic agents that have targeted IL-4/IL-13, or IL-5, have not
demonstrated any definite serious treatment-related adverse events. However, these clinical trials
were generally done in small populations of asthma patients, which may be too small for uncommon
side effects to be identified. There is conflicting information about the safety TNF-alpha blocking
agents, which have been primarily used in the treatment of rheumatoid arthritis, with serious
infections, cardiovascular disease and malignancies being the most frequent serious adverse events.
An unfavorable risk-benefit profile led to early discontinuation of a TNF-blocking agent in a double-
blind placebo controlled of severe asthmatics.
In summary, the risk of anaphylaxis and other treatment-related serious events with of all of the
biological agents in this review were relatively small. However, most of the clinical trials were done
in relatively small patient populations and were of relatively short duration. Long term studies in
large patient populations may help clarify the risk-benefit profile of these biologic agents in the
treatment of asthma.
Published: 22 October 2009
Allergy, Asthma & Clinical Immunology 2009, 5:4doi:10.1186/1710-1492-5-4
Received: 1 October 2009
Accepted: 22 October 2009
This article is available from: http://www.aacijournal.com/content/5/1/4
© 2009 Cox; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Page 2

Allergy, Asthma & Clinical Immunology 2009, 5:4 http://www.aacijournal.com/content/5/1/4
Page 2 of 11
(page number not for citation purposes)
Introduction
A number of therapeutic agents are available to treat the
symptoms and inflammation associated with allergic
rhinitis and asthma. Despite the proven efficacy of these
medications, there continues to be some patients whose
asthma [1] or rhinitis [2] is not well controlled. In addi-
tion, medications currently available for allergic rhinitis
and asthma treatment appear to be are only effective while
taken and do not appear to provide a sustained benefit
after discontinuation [3]. Limitations of current medica-
tions and a greater understanding of the pathogenesis of
allergic disease, has lead to the development of number of
a novel therapeutic approaches as well as renewed interest
in an old therapeutic approach, specific allergen immuno-
therapy. Novel therapeutic approaches that have been
used in the treatment of allergic rhinitis and asthma
include: omalizumab, alternate immunotherapy routes
such as sublingual, modified allergen immunotherapy
vaccines, anti-interleukin 5 (mepolizumab), interleukin-4
variant (pitrakinra) and tumor necrosis factor (TNF-α)
blocking agents. The intent of this paper is to review the
safety of these novel therapeutic approaches (see table 1
for summary of biological agents reviewed). Although the
focus of the review is safety, there will be some discussion
of the efficacy of these biological agents.
Definition and incidence of anaphylaxis
One of the difficulties in evaluating the safety of biologics
is that some of the suspected adverse events may be
related to the disease itself. For example, an increased risk
of malignancy has been reported with TNF-alpha block-
ers, which are used primarily in the treatment of rheuma-
toid arthritis (RA). A systematic review and meta-analysis
of 9 clinical trials that included 3493 RA patients treated
with the anti-TNF-alpha antibodies, inflxumab or adali-
mumab, found a dose-related increase in malignancies
Table 1: Summary of biological agents used in the treatment of asthma and allergic rhinitis
Biological agent Disease studiedTarget Mechanisms SafetyEfficacy
SCIT AR & asthma Specific
aeroallergens or
venom
Several immune changes
including↑IL-10 & TGF-β.
isotype switch to IgG
Surveys suggest; fatality
rate of 1 in 2.5 million
injections34-36 & near fatal
reaction rate of 5.4 per 1
million injections37
Most common AEs oral-
mucosal symptoms
AE less common than SCIT
but cases of anaphylaxis
have been reported
SRs reported in 1.6% of the
1736 patients in
postmarking surveillence
survey50
No serious treatment-
related effects46
Appears to depend on
dose
SLITAR & asthmaSpecific
aeroallergens
Probably similar to SCIT
A consistent relationship
with dose and efficacy
has not been
established39
MPL ARTRL4Shift toward Th1
response
Clinical efficacy seen in
first treat season after 4
injection treatment
course
Clinical efficacy seen in
1st & 2nd treatment
season after one 4
injection course46
Efficacy in medication
reduction &
exacerbation in asthma,
clinical improvement in
AR
No significant
improvement in
asthma55
Increased PD20
inmethacholine challenge
& asthma AE & beta-
agonist use
Increased markers of
TNF-alpha activity &
improved clinical
outcomes in refractory
asthma 59
CpG ARTRL9Shift toward Th1
response
Omalizumab Asthma & ARIgEPrevents binding of IgE to
mast cells and basophils,
downregulatuion of IgE
receptor on these cells
Anaphylaxis in 0.09 to 0.2%
of patients19,20
MepolizumabAsthmaIL-5 Blocks binding of IL-5 to
α receptor on
eosinophils
Competes with IL-4 and
IL-13 for binding to the
receptor
One episode of
hypotension after infusion
in EE study57
Non-neutralizing IgG anti-
pintrakinra antibodies in
~30% of pts
Pintrakinra58
AsthmaIL-4Rα receptor
EtanerceptAsthmaTNF-alphasoluble TNF-alpha
receptor
No significant treatment-
related AE is asthma 59 but
increased risk of serious &
opportunistic infection in
rheumatologic disease
SCIT = subcutaneous immunotherapu, SLIT = sublingual immunotherapy, AR = allergic rhinitis, MPL = -deacylated monophospholipid A, CpG =
immunostimulatory oligonucleotide sequence of DNA containing a CpG motif, TNF-alpha = tumor necrosis factor alpha, AE = adverse event, SAE
= serious adverse event, EE = eosinophilic esophagitis, PD20 = Provocative Dose, which produces a decrease in FEV1 by 20% from the initial value
or baseline value

Page 3

Allergy, Asthma & Clinical Immunology 2009, 5:4http://www.aacijournal.com/content/5/1/4
Page 3 of 11
(page number not for citation purposes)
compared with the control groups with a pooled odds
ratio of 3.3 (95% confidence interval [CI], 1.2-9.1) [4].
This increased rate of malignancy was not seen in another
study that compared the incidence of malignancy and car-
diovascular disease in two large RA observational data-
bases: BIOBADSER, a registry for safety of biologics,
which included 4459 RA patients on TNF-alpha blocking
agents in 100 centers who were followed from 2001 to
2006 and EMECAR, an external RA cohort (n = 789) estab-
lished to define the characteristics of the disease and to
assess comorbidity [5]. In the EMECAR registry, during
the period of 1999 to 2005, a TNF-alpha blocking agent
was given to 1.4%, 10.6% and 16.8% of the patients in
2000, 2003 and 2005, respectively. A higher incidence of
malignancies was found in the EMECAR database
patients, which included a minority receiving TNF-alpha
blocking agents, compared with the BIOBADSER registry,
in which all received a TNF-alpha blocking agents there
was a higher incidence of malignancy in EMECAR vs.
BIOBADSER (Relative Risk (RR) 2.9) and a lower BIOBA-
DASER by EMECAR cancer-related mortality ratio, 0.36
(0.10-1.30).
Likewise, atopy and asthma have been identified as risk
factors for anaphylaxis, the most severe and potentially
life-threatening reaction associated with the biologics dis-
cussed in this review [6]. The incidence of anaphylaxis
appears to be greater in the asthmatic population and this
may be dependent on the severity of asthma. A review of
a large patient database in the United Kingdom was per-
formed to determine the incidence of anaphylaxis in the
asthmatic and general population [7]. Specific Read codes
were used to identify potential cases of anaphylaxis. All
patients (10-79 years), who had at least one year of enroll-
ment with a general practitioner and one health contact in
the previous year during the period of 1996-2005 were
included. Two cohorts were identified: asthmatic patients
(791,225 person-yrs of follow-up) and the general popu-
lation (884,745 person-years of follow-up). Within the
asthmatic cohort, a subset of severe asthmatics, were iden-
tified based on meeting any of the following 4 criteria: '
1. ≥ 1 asthma hospitalization
2. ≥ 12 canisters of inhaled beta--agonists a year
3. ≥ 3 prescriptions of oral corticosteroids a year,
4. ≥ 3 classes of asthma medication a year
There were a total of 224 cases of anaphylaxis: 170 in the
asthma population and 54 in the general population. The
anaphylaxis incidence rate (cases/100,000 person-years)
was highest in the severe asthmatic group: 43.1 in severe
asthma patients, 15.4 in non-severe asthma patients and
6.1 in the general population. Compared to the general
population, the age-gender adjusted RR for anaphylaxis
was greater in both the severe asthmatic patients (RR 7.2,
95% confidence interval (CI), 5.0--10.3) and non-severe
asthmatic patients (RR 2.5, 95% CI, 1.8--3.5). The authors
concluded that there may be an increased risk of anaphy-
laxis in asthmatic patients that may be dependent on the
severity of asthma.
Another variable and difficulty in interpreting the safety of
biologics in research and postmarketing surveillance is
that there is no universal agreement on the definition of
anaphylaxis or the criteria for its diagnosis. In an attempt
to resolve this problem, the National Institute of Allergy
and Infectious Disease and Food Allergy and Anaphylaxis
Network convened a meeting, which included representa-
tives from multiple organizations and 3 continents, with
the intent of developing a universally accepted definition
of anaphylaxis and establishing clinical criteria that would
accurately identify cases of anaphylaxis [8]. The working
group developed three sets of criteria for the diagnosis of
anaphylaxis (table 2). These criteria are used in some of
the studies reviewed in this paper. However, in many
studies and reviews, particularly ones involving allergen
immunotherapy, the criteria for diagnosing anaphylaxis is
not clear. Recognizing that adverse reactions to biological
agents may be distinctly different from side-effects from
chemicals and drugs, a classification system for adverse
reactions to these agents has been proposed (table 3) [9].
This classification distinguishes five different categories:
Type α reactions due to high cytokine levels, type β reac-
tions due to a hypersensitivity reaction against the biolog-
ical agent, type γ reactions due to immune or cytokine
imbalance syndromes, type δ reactions due to cross-reac-
tivity between the biological agent's target and cells that
express similar or identical antigens and type ε reactions,
which do not directly affect the immune system.
Omalizumab
One of the most studied biologics for the treatment of
asthma and rhinitis is omalizumab. Omalizumab is a
95% humanized monoclonal antibody (mAb) that binds
to the Fc portion of the circulating immunoglobulin E
(IgE) molecule preventing it from attaching to the high
affinity IgE receptor, FcεR1. Omalizumab produces signif-
icant and rapid reductions in free serum IgE (up to 99%)
[10]. One study demonstrated a 96% reduction in mean
serum IgE level three days after omalizumab administra-
tion [11]. With continued treatment there is subsequent
downregulation of the FcεR1 expression on several cell
types that occurs over the next 4 to 6 months [12,13].
Omalizumab has been shown to be effective in the treat-
ment of allergic asthma and seasonal and perennial rhin-
itis [14-17]. It is currently approved by the United States

Page 4

Allergy, Asthma & Clinical Immunology 2009, 5:4http://www.aacijournal.com/content/5/1/4
Page 4 of 11
(page number not for citation purposes)
(US) Food and Drug Administration (FDA) for the treat-
ment of moderate-to-severe persistent allergic asthma in
adults and children 12 years and older. Omalizumab is
also suggested as a treatment consideration for allergic
asthmatics who are not well controlled with the combina-
tion of a medium-dose inhaled corticosteroid and a long-
acting beta-agonist in the recently published expert panel
guidelines on diagnosis and management of asthma [18].
These guidelines note that omalizumab is the only adju-
vant therapy to demonstrate added efficacy to the com-
bined regimen of a high-dose inhaled corticosteroid and a
long-acting beta agonist [19].
The most common adverse reaction from omalizumab is
injection- site pain and bruising but the package insert
contains warnings regarding malignancies, geohelmith
infections and a "black box" warning about anaphylaxis.
A "black box warning is the highest level of 5 possible
warning categories found in pharmaceutical package
inserts [20]. It is recommended, in the informed consent
process, that patients be specifically informed that a med-
ication has a "black box" warning and the reason for the
"black box" warning be provided [20]. The "black box"
warning on anaphylaxis (type β effect) was recently added
Table 2: Clinical criteria for diagnosing anaphylaxis8
Anaphylaxis is highly likely when any one of the following 3
criteria are fulfilled:
1. Acute onset of an illness (minutes to several hours) with involvement
of the skin, mucosal tissue, or both
(e.g., generalized hives, pruritus or flushing, swollen lips-tongue-uvula)
a. Respiratory compromise
(e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia)
b. Reduced BP or associated symptoms of end-organ dysfunction
(e.g., hypotonia [collapse], syncope, incontinence)
a. Involvement of the skin-mucosal tissue
(e.g., generalized hives, itch-flush, swollen lips-tongue-uvula)
b. Respiratory compromise
(e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia)
c. Reduced BP or associated symptoms
(e.g., hypotonia [collapse], syncope, incontinence)
d. Persistent gastrointestinal symptoms
(e.g., crampy abdominal pain, vomiting)
a. Infants and children: low systolic BP (age specific) or greater than 30%
decrease in systolic BP*
b. Adults: systolic BP of less than 90 mm Hg or greater than 30%
decrease from that person's baseline
AND AT LEAST ONE OF THE FOLLOWING
2. Two or more of the following that occur rapidly after
exposure to a likely allergen for that patient (minutes to
several hours):
3. Reduced BP after exposure to known allergen for that
patient (minutes to several hours):
PEF = Peak expiratory flow; BP = blood pressure.
*Low systolic blood pressure for children is defined as less than 70 mm Hg from 1 month to 1 year, less than (70 mm Hg 1 [2 times age]) from 1 to
10 years, and less than 90 mm Hg from 11 to 17 years.
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Jr., Bock SA, Branum A, et al. Second symposium on the definition and management of
anaphylaxis: summary report--Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J
Allergy Clin Immunol, 2006:391-7.
Table 3: Proposed classification of adverse side effects of biological agents9
Classification Mechanism (s)Clinical features
Type α
High cytokine & cytokine release syndrome Symptoms will depend on the cytokine or cytokine being targeted e.g., high levels of
INF-α may cause 'flu-like symptoms and anti- CD3 (muromunab) may induce
cytokine release syndrome, which may include the following symptoms: flushing,
arthralgias, capillary leak syndrome with pulmonary edema, encephalopathy, and
severe gastrointestinal symptoms
Immediate (IgE)
Delayed (IgG or T cell)
Autoimmunity
Allergic/atopic disorders
Impaired function (immunodeficiency)
Will depend on the function of the cross-reacting antigen; e.g., Acneiform eruptions
are commonly seen with cetuximab, an anti- epidermal growth factor receptor
(EGFR) mAb possibly due to cross-reactivity between skin ERFR.
Varies with the function of the biological agent; Interferon-α frequently associated
with neuropsychiatric adverse effects
Type β
Hypersensitivity
Type γ
Immune or cytokine imbalance syndrome
Type δ
Cross-reactivity
Type ε
Non-immunologic side-effects

Page 5

Allergy, Asthma & Clinical Immunology 2009, 5:4http://www.aacijournal.com/content/5/1/4
Page 5 of 11
(page number not for citation purposes)
to Xolair® (omalizumab) package insert at the direction of
the FDA in response to the spontaneous postmarketing
adverse event-reports. A review of spontaneous postmar-
keting adverse events submitted to the FDA and Genen-
tech/Novartis suggested that at least 0.2% of patients who
received Xolair® (omalizumab) experienced anaphylaxis
between June 2003 and December 2006 [21]. The review
also noted that many of the cases were delayed in onset
and characterized by a protracted progression. An Omali-
zumab Joint Task Force of the American Academy of
Allergy, Asthma and Immunology and the American Col-
lege of Allergy, Asthma and Immunology (OJTF) also
reviewed the postmarketing surveillance data from the
same time period [22]. Using the definition of anaphy-
laxis proposed at a 2005 multidisciplinary symposia [8],
the OJTF concluded that 35 patients had 41 episodes of
anaphylaxis associated with omalizumab administration.
During this time period 39,510 patients received omalizu-
mab, thus the anaphylaxis-reporting rate was 0.09% of
patients. Of those 36 events, for which the time of reac-
tion was known, 22 (61%) reactions occurred in the first
2 hours after one of the first 3 doses and within 30 min-
utes in 5 (14%) of the events that occurred after the fourth
or later doses.
The OJTF report recommends an observation period of 2
hours for the first 3 injections and 30 minutes for subse-
quent injections because 75% of the anaphylactic reac-
tions occurred within these time periods. The OJTF report
also provided recommendations on patient education
regarding anaphylaxis.
Omalizumab and malignancies
In the initial Xolair® (omalizumab) clinical trials, a higher
incidence of malignancies was observed in the group that
received Xolair® (omalizumab): 20/4127 (0.5%) Xolair®
(omalizumab)-treated patients compared with 5/2236
(0.2%) patients in the control group [23]. The observed
malignancies in the Xolair® (omalizumab)--treated
patients were heterogeneous in tumor type and organ.
There were no new cases of lymphoproliferative disease
and no cases were considered drug-related by a panel of
blinded independent oncologists. The majority of cases
(60%) were diagnosed within 6 months of treatment [24].
Overall, the clinical data did not suggest a causal relation-
ship between Xolair® (omalizumab) and malignancy.
However, the Xolair® (omalizumab) package insert does
note that "the impact of longer exposure to Xolair or use
in patients at higher risk for malignancy (e.g., elderly, cur-
rent smokers) is not known" [24]. A multicenter, prospec-
tive, observational cohort study titled Evaluating the
Clinical Effectiveness and Long-Term Safety in Patients
with Moderate to Severe Asthma (EXCELS) that includes
approximately 5000 Xolair® (omalizumab) -treated and
2500 with moderate to severe asthma not receiving
Xolair® (omalizumab), designed to evaluate the long term
safety of Xolair® (omalizumab) is currently in progress
[25].
Cardiovascular and Cerebrovascular disease
On July 16, 2009, the FDA issued a statement indicating
that review of the EXCELS study's interim safety data
showed an excess of cardiovascular and cerebrovascular
events in the patients on Xolair® (omalizumab) compared
with the asthma control group [26]. The interim data sub-
mitted by the manufacturer, Genentech, suggests a dispro-
portionate increase in
arrhythmias, cardiomyopathy and cardiac failure, pulmo-
nary hypertension, cerebrovascular disorders, and
embolic, thrombotic and thrombophlebitic events in
patients treated with on Xolair® (omalizumab) compared
with the group that did not receive this medication.
ischemic heart disease,
Being an observational study, many factors need to be
evaluated before determining the relationship between
Xolair® (omalizumab) and these adverse events. Consider-
ing that Xolair® (omalizumab) is indicated for moderate-
to-severe asthma and the prescribing/administration
process can involve a fair amount of physician and staff
time, as well as, patient time and expense, it is likely there
were considerable differences between the Xolair® (omali-
zumab)-treated group and the asthma control group in
terms of asthma severity and co-morbidities. These differ-
ences may include oral corticosteroid use, underlying car-
diovascular disease or hypertension and may account for
the differences in adverse events. The FDA did not recom-
mend any changes to the prescribing information (i.e.,
package insert) on Xolair® (omalizumab) but did recom-
mend that patients and physicians be aware that the new
information from the EXCELS study may suggest a risk of
crdiovascular and cerebrovascular events.
Omalizumab and geohelminth infection
Considering that IgE may have a protective role in the
immunity against parasitic infections, there are concerns
that anti-IgE antibodies might impair this protective effect
and increase susceptibility to parasite infection (type γ
effect). The Xolair® (omalizumab) package insert recom-
mends that patients at high risk for geohelminth infec-
tions be monitored for such infections while on treatment
citing a 1-year study of patients at high-risk for geo-
helminth infections, in which the odds ratio for infection
in the Xolair® (omalizumab)-treated group was1.96 with a
95% CI (0.88-4.36) compared with the placebo control.
Similar results were seen in a 1-year double-blind, pla-
cebo-controlled (DBPC) trial of 137 subjects (12-30
years) at high risk of geohelminth infection, who were
randomized to receive 52 weeks of treatment with Xolair®
(omalizumab) or placebo [27]. After adjusting for base-
line infection status, gender, age and study visit, there was