An update on emerging drugs for asthma.
Garry M. Walsh PhD
School of Medicine, University of Aberdeen, Scotland, U.K.
Corresponding Author:
Dr Garry M. Walsh
Section of Immunology & Infection
Division of Applied Medicine
School of Medicine & Dentistry
Institute of Medical Sciences
University of Aberdeen
Foresterhill, Aberdeen AB25 2ZD, U.K.
Tel +44 (0)1224-437354
Fax +44 (0)1224-437348
e mail g.m.walsh@abdn.ac.uk
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Abstract
Introduction
Biopharmaceutical approaches have identified new biologic-based therapies that
target key cells and mediators that drive inflammatory responses in the asthmatic
lung. This review based on English-language original articles in Pub Med or
MedLine published in the last 5 years will update the current status, therapeutic
potential and potential problems of recent drug developments in asthma therapy.
It is recognised that airway inflammation is key to asthma pathogenesis.
Biopharmaceutical approaches have identified new therapies that target key cells
and mediators that drive the inflammatory responses in the asthmatic lung. Such an
approach resulted in the development of biologics including IL-4, IL-5 and IL-13.
However, clinical trials with these biologics in patients with asthma were for the
most part disappointing even though they proved to be highly effective in animal
models of asthma.
Expert opinion
It is becoming apparent that significant clinical effects with anti-cytokine-based
therapies are more likely in carefully selected patient populations that take asthma
phenotypes into account. It might also be more clinically effective if more than one
cytokine and/or chemokine were to be targeted rather than a single mediator.
.
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1.0 Background
Asthma is a major cause of ill-health that has markedly increased in prevalence in the UK
and the rest of the developed world in recent decades [1]. In addition to reversible airway
obstruction and airway hyperresponsiveness (AHR), asthma pathology results in
fundamental structural changes to the airway including goblet cell hyperplasia, airway
smooth muscle hypertrophy and subepithelial fibrosis [2]. Inhaled glucocorticoids (GCs)
are first-line therapy for asthma because of their potent anti-inflammatory properties that
primarily result in reduced numbers of airway inflammatory cells and their associated
mediators [3]. Clinically, GCs reduce AHR, disease exacerbations and hospitalizations
while improving lung function and quality of life and in their inhaled form are considered
the most effective medications for asthma. However, they are symptomatic medications
usually requiring lifetime therapy for the patient and asthma symptoms usually return on
GC withdrawal. Moreover, variations in the clinical response of asthmatics to inhaled
GC therapy are common while a significant subgroup of asthmatic patients responds
poorly or not at all to high-dose inhaled or systemic GC treatment [4] These
considerations, together with concerns over the adverse effects of GCs, which include
adrenal suppression, reduced growth and reduced bone mineral density; indicate a clear
need for more effective asthma therapy [5]. We have considerable knowledge regarding
the cells, mediators and other factors controlling the pathogenic changes in asthma [6].
This information has informed the identification of molecules that target aspects of the
complex inflammatory cascade in asthma. This article will update the current status of
these compounds.
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2. Anti-cytokine therapy
Interleukin-5
Eosinophils play an important protective role in the immune response to parasitic
infections and, detrimentally, in inflammatory conditions affecting the upper and lower
airways, skin and gastrointestinal tract. Eosinophils are not normally present in healthy
lungs but their accumulation is a well defined feature of the inflammatory processes in
the lungs of patients with allergic asthma where release of their arsenal of proinflammatory mediators makes a major contribution to asthma pathogenesis. It has long
been known that interleukin (IL)-5 is crucial to the development and release of
eosinophils from the bone marrow, their enhanced adhesion to endothelial cells lining the
post-capillary venules and their persistence, activation and secretion in the tissues. IL-5
was therefore selected as a potential target to prevent or blunt eosinophil-mediated
inflammation in patients with asthma, leading to the development of humanized anti-IL-5
mAb, such as mepolizumab, reslizumab and benralizumab [7]. Early clinical trials with
mepolizumab in patients with mild to severe asthma reported significant reductions in
blood and sputum eosinophil numbers but clinical outcomes were disappointing, most
likely because subjects were recruited on the basis of clinical and physiological
characteristics rather than the presence of eosinophilic airway inflammation [8]. Asthma
management strategies aimed at the control of eosinophilic airway inflammation in
addition to clinical manifestations of the condition are associated with a reduction in the
frequency of exacerbations [9]. Importantly therefore, two studies demonstrated that
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mepolizumab treatment of asthmatics not only reduced eosinophil numbers in the blood
and sputum but also resulted in a significant reduction in asthma exacerbations. Both
studies were randomized, double-blind, placebo-controlled, parallel-group studies that
investigated the effects of monthly infusions of 750 mg mepolizumab or placebo. The
first study [10] used patients with a sputum eosinophilia whose asthma symptoms were
refractory to high-dose corticosteroids and who had greater than two exacerbations
requiring oral corticosteroids during the previous 12 months. The primary end point was
the number of severe exacerbations per patient; secondary outcomes included asthma
symptoms, health-related quality of life (HRQoL) measured with the Asthma Quality of
Life Questionnaire (AQLQ), lung function, AHR and blood and sputum, eosinophil
count. Compared with placebo (32 patients), mepolizumab treatment (29 patients)
resulted in a significant reduction in blood sputum eosinophil numbers, with fewer severe
exacerbations per patient as compared to placebo together with a significant improvement
in quality of life. No significant improvements were reported for the other outcome
measures and mepolizumab appeared to be well tolerated. The second study [11] used
fewer patients (9 active, 11 placebo). These subjects exhibited persistent sputum
eosinophilia despite requiring oral prednisone for control of asthma symptoms together
with a history of exacerbations. In the mepolizumab treated group, one patient had an
exacerbation compared with twelve exacerbations in the placebo group. Of those subjects
in the placebo group, 9/10 of those analyzed exhibited sputum eosinophilia at the time of
exacerbation while in the treatment group mepolizumab significantly reduced sputum and
blood eosinophil counts to normal values. Mepolizumab treatment gave a significant and
sustained reduction in the oral prednisone dose, a modest improvement in lung function,
5
significant improvement in scores on the Juniper Asthma Control Questionnaire and
quality of life indices with no significant side effects reported. These studies in highly
selected asthma patient populations demonstrate that mepolizumab attenuates aspects of
eosinophil-induced airway inflammation refractive to GC therapy and may therefore
potentially interfere with eosinophil-induced airway remodelling in addition to reducing
asthma exacerbations. Mepolizumab may also prove useful in other settings such as GC
resistant asthma or asthma in smokers with a sputum eosinophilia. However, as
mepolizumab had no effect on AHR it is unlikely to be an effective mono therapy for
asthma and it is only likely to be effective in tightly defined patient populations who
exhibit eosinophil-induced airway inflammation. In addition, a recent open-label trial of
seven patients [12] and a case report of one patient [13] suggested that mepolizumab may
also be effective in the treatment of the eosinophilic disease Churg-Strauss syndrome, in
which IL-5 plays a pivotal role.
Ception Therapeutics Inc (presumed to be under license from Schering-Plough Corp and
UCB Celltech) are developing the humanized anti-IL-5 mAb reslizumab. One recent
randomized, placebo-controlled trial evaluated intravenous infusions of reslizumab (3.0
mg/kg) or placebo at weeks 0, 4, 8 and 12 in 106 patients with poorly controlled asthma
who were taking high-dose inhaled GCs and exhibited a sputum eosinophilia greater than
3%. When all patients were included for analysis, there was a non-significant trend
toward improvement in asthma control associated with a significant improvement in lung
function as assessed by the Asthma Control Questionnaire score together with a
significant decrease in sputum eosinophilia. In those patients with concomitant nasal
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polyposis, reslizumab treatment was associated with a significant improvement in asthma
symptom control at baseline compared with week 15. There was a non-significant
reduction in asthma exacerbations in the reslizumab group while the adverse-event
profile for reslizumab and placebo were similar [14]. Other data from limited pilot trials
suggested that reslizumab was a potentially efficacious and well-tolerated treatment for
eosinophilic esophagitis, hypereosinophilic syndrome and eosinophilic nasal polyposis
[15].
Benralizumab is a novel humanised afucosylated IgG1 mAb indicated for the potential
treatment of asthma and COPD that binds to a distinct epitope within the extracellular
domain of recombinant human IL-5R. At the time of publication, benralizumab was
undergoing phase II clinical trials in both the specified indications (ClinicalTrials.gov
identifiers: NCT01238861 and NCT01227278). Afucosylation is associated with
enhanced antibody-dependent cell cytotoxicity and benralizumab was found to induce
apoptosis in eosinophils and basophils [16]. Other anti-IL-5 mAb act by neutralising the
effects of IL-5 whereas benralizumab targets the effector cells, mainly eosinophils and
basophils, many of whose functions are driven by IL-5. Tissue eosinophils resident in
bronchial biopsies of patients with mild atopic asthma exhibited intense immune
positivity for benralizumab in contrast to resident mast cells, which were negative [16].
These findings indicate that benralizumab binds human lung tissue-resident eosinophils
expressing IL-5Ralpha and could delete these cells, thereby acting as a potential asthma
therapeutic. Indeed a phase-1 study in subjects with mild asthma demonstrated that
intravenous benralizumab (0.3-3.0 mg/kg) rapidly induced near total depletion of
7
peripheral blood eosinophils while exhibiting an adequate safety profile and doseproportional pharmacokinetics [17].
IL-4 and IL-13
Eosinophil involvement as a major pro-inflammatory effector cell in asthma is wellestablished [18] with T-helper-2 (TH-2) cells that express IL-4, IL-5 and IL-13
representing essential and central co-ordinators of asthmatic inflammation [19]. Both IL4 and IL-13 are important in eosinophil accumulation and are key factors in IgE synthesis
by B cells [20]. There is also evidence that in asthma IL-13 may act directly on airway
smooth muscle cell contractility [21,22, 23]; this together with direct effects by IL-13 on
epithelial cells and mucus production [24] may contribute to AHR and airway narrowing.
The genes encoding IL-4 and IL-13 are located on the cytokine cluster on chromosome
5q31; both cytokines share some structural similarities. Each exerts their actions through
the IL-4R/IL-13R1 receptor complex which then activates the transcription factor
STAT-6 [25]. They therefore have multiple overlapping functions although IL-4 has
independent effects via the IL-4R receptor.
Receptors for IL-13 are expressed by a multitude of cell types important in the
pathogenesis of asthma including eosinophils, mast cells together with structural airway
epithelial cells, fibroblasts and smooth muscle cells. In asthma, the most important
cellular sources of IL-13 are T cells, mast cells and eosinophils. Increased levels of IL-13
have been reported in the sputum and bronchial biopsies from patients with asthma which
correlated with increased eosinophil numbers [26, 27]. Importantly, mast cells expressing
IL-13 are present within the airway smooth muscle in asthmatic subjects suggesting a
8
pivotal role for IL-13 in interactions between these cell types [28]. IL-13 may also have
direct effects on airway smooth muscle function by enhancing the contraction effect of
acetylcholine [29]. It is now widely appreciated that the asthmatic airway epithelium is
intrinsically abnormal and critically contributes to the airway inflammatory response
[30]. An important aspect of IL-13 therefore is the effect it has on the functions of airway
epithelial cells including induction of a hyper-secretory state [31] and reduced barrier
function through down-regulation of proteins associated with maintaining epithelial tight
junctions [32]. IL-13 is a potent promoter of epithelial cell TGF production; that in turn
activates myofibroblasts and is also involved in ECM deposition leading to sub-epithelial
membrane thickening; both thought to contribute to airway remodelling [33, 34]. IL-13
therefore appears to represent a potentially effective target for asthma therapy [35].
The anti-IL-13 mAb lebrikizumab (Genentech/Chugai Pharmaceutical) has recently been
demonstrated to significantly improve lung function in patients with inadequately
controlled asthma, but only in a subgroup defined on the basis of high serum levels of
periostin [36]. The latter is a cellular matrix protein that is released by airway epithelial
cells stimulated with IL-13. Periostin exhibits effects on epithelial cells and fibroblasts
that may contribute to airway remodelling in asthma [37, 38].
A recombinant human IL-4 variant, pitrakinra (Aerovant), was developed that
competitively inhibits the IL-4Rreceptor complex to interfere with the actions of both
IL-4 and IL-13 and initial clinical trials indicated that such an approach may prove
beneficial in patients with atopic asthma [reviewed in 39]. A more recent double-blind,
9
randomized, placebo-controlled trial of inhaled pitrakinra in 534 patients with
uncontrolled, moderate-to-severe asthma reported significant effects on exacerbations
rates and symptom scores in patients with an elevated blood eosinophilia [40]. However,
another recent 12-week clinical trial with an mAb directed at the IL-4rα (AMG-317,
Amgen) reported significant reductions in blood IgE levels and eosinophils but found no
significant change in measured asthma outcomes [41]. Dual inhibition of IL-4 and IL-13
can affect the course of the late asthmatic response after experimental allergen challenge
but further large scale clinical trials on patients with day to day asthma are required to
fully validate such an approach.
Tumour necrosis factor-α
Tumour necrosis factor (TNF)-α is an important cytokine in innate immune responses
that has been implicated in several chronic inflammatory diseases including rheumatoid
arthritis and Crohn’s disease with anti-TNFα therapy proving useful in these conditions.
It is produced principally by macrophages while other pro-inflammatory cells including
monocytes, dendritic cells, B lymphocytes, T cells, neutrophils, mast cells and
eosinophils, together with the structural cells fibroblasts, epithelial cells and smooth
muscle cells represent significant sources. TNF- has pro-inflammatory effects on
eosinophils, neutrophils, T cells, epithelial cells and endothelial cells and may play a key
role in amplifying airway inflammation through activation of transcription factors such as
NF-B and AP-1. TNF- is expressed in biopsies and lavage fluid from asthmatic
airways, particularly in patients with severe asthma compared with those with wellcontrolled disease. TNF- is thought to contribute to AHR, airway remodelling and GC
10
resistance in asthma and therefore represents a potential target for therapy [7].
Humanized murine anti-TNF mAb (infliximab) and soluble TNF receptor linked to
human IgG1 (etanercept) have been developed and preliminary clinical studies in asthma
did show significant improvements in lung function, airway hypereactivity and
exacerbation rate, particularly in patients with severe asthma refractory to GC treatment
[42]. However, a more recent clinical trial with the anti-TNF biologic golimumab in
patients with severe uncontrolled persistent asthma reported negative clinical findings.
Importantly, this study was terminated early due to unacceptable adverse events including
frequent serious infections, eight malignancies and one death in the active-treatment
group compared with the placebo group [43]. Overall it appears that TNF- inhibitors
are effective in a sub-group of patients with asthma and that identification of the
correct patient population may improve clinical outcomes [44]. However, the
unfavorable risk/benefit ratio exhibited by golimumab does cast doubt on the future
of anti-TNF therapy in severe asthma.
3.0 Conclusion
The development of novel asthma anti-inflammatory therapy based on targeting cytokines has
proven to be for the most part disappointing; in particular results from animal-based studies
have been very misleading. The majority of biologics have proven inadequate in the clinical
setting in asthma even though they were highly effective in animal models of asthma. This
issue has been emphasized recently by Holgate who points out that at the time of publication
of his review articles, out of around 3,000 peer-reviewed publications implicating IL-13 as a
central mediator in asthma, only four relate to direct evidence in human asthma [45]. Two of
11
the latter studies demonstrated that elevated levels of IL-13 were present in the sputum of
around half of asthmatic patients tested with no significant association with disease severity
[26, 27]. It is not surprising therefore that anti-IL-13 therapy proved to be disappointing in
asthma therapy given that only half of the patients recruited to a given clinical trial have any
likelihood of responding to this biologic. Indeed the development of discriminatory
biomarkers and genetic profiling may identify patients with particular sub-phenotypes of
asthma. This point is illustrated by the recent studies that suggest that both mepolizumab and
lebrikizumab therapy have beneficial effects in carefully selected patient populations.
Expert Opinion
Inhaled glucocorticoids remain the gold standard treatment for asthma because they
suppress multiple inflammatory mechanisms in parallel. It might be more clinically
effective, therefore, if novel biologics were to be targeted at more than one cytokine
and/or chemokine, an approach whose potential is illustrated by pitrakinra. Another
major issue is that of the potential or actual side effects of novel compounds that are
designed to interfere with important aspects of both the innate and acquired immune
systems as exemplified by the unacceptable adverse effects associated with the
golimumab treatment in patients with severe uncontrolled asthma. What is becoming
more widely accepted is that future clinical trials of novel biologic therapy for asthma
should include very careful patient selection to ensure a significant clinical outcome. One
other important consideration is that the placebo group in trials of biologics in asthma
often exhibit a marked improvement in symptoms which may reduce the likelihood of
significant findings being observed for the test compound. This phenomenon is most
12
likely due to the close monitoring of trial subjects that ensures greater compliance in
adhering to their normal anti-inflammatory therapy. The ultimate goal would be to
develop asthma treatments that are truly disease modifying rather than the symptomatic
treatments currently available and we do seem to be starting to make some progress
towards this goal.
13
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20
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