Current Opinion in Pulmonary Medicine

MCP 2401

Precision medicine in Asthma: Linking phenotypes to targeted treatments

Kian Fan CHUNG MD DSc FRCP

National Heart & Lung Institute, Imperial College, London & Respiratory Biomedical Research Unit; Royal Brompton & Harefield NHS Trust and Imperial College London, United Kingdom.

Running title: Precision medicine for asthma

Correspondence:

Professor K F Chung,

National Heart & Lung Institute,

Imperial College London,

Dovehouse St,

London SW3 6LY, UK

Phone +44 207594 7959

f.chung@imperial.ac.uk

[1]

Abstract 196

Purpose of review:

Asthma is a heterogeneous disease consisting of different phenotypes that are driven by

different mechanistic pathways. The purpose of this review is to emphasise the important

role of precision medicine in asthma management.

Recent findings:

Despite asthma heterogeneity, the approach to management has been on the basis of

disease severity, with the most severe patients reserved for the maximum treatments with

corticosteroids and bronchodilators. At the severe end, the recent availability of biologic

therapies in the form of anti-IgE (omalizumab) and anti-IL5 therapies (mepolizumab and

reslizumab) has driven the adaptation of precision medicine. These therapies are reserved

for severe asthma with defined either allergic or eosinophilic background, respectively.

Summary:

Unbiased definition of phenotypes or endotypes (which are phenotypes defined by

mechanisms) is an important step towards the use of precision medicine in asthma. While

T2-high asthma has been defined with targets becoming available for treating allergic or

eosinophilic asthma, the definition of non-T2 phenotypes remains a priority. Precision

medicine is also dependent on the definition of biomarkers that can help differentiate

between these phenotypes and pinpoint patients suitable for specific-targeted therapies.

Thus, precision medicine links phenotypes (endotypes) to targeted treatments for better

outcomes.

Key words: Precision medicine, asthma, phenotyping, biomarkers.

[2]

Introduction

Asthma is diagnosed by the presence of intermittent symptoms of wheeze,

cough and chest tightness that usually resolves spontaneously or with asthma

treatments, and under such an umbrella term, would exist different phenotypes of

asthma. In fact, the Global Initiative for Asthma (GINA) has now recognised asthma

as being a heterogeneous disease with different presentations, outcomes and

underlying mechanisms. Clinicians have defined several phenotypes based on the

presentation and age of onset of symptoms, the severity of the disease, and the

presence of other conditions such as allergy and eosinophilia. When these

phenotypes have been linked to long-term outcomes or to response to therapy with

corticosteroids, these have been used by clinicians to predict the course of asthma.

Despite the recognition of these phenotypes of asthma, the approach to the

management of asthma continues to be based on the severity of the condition, with

drugs added on the basis of asthma control.

Inhaled corticosteroid (ICS) therapy remains the cornerstone of treatment of

asthma because asthma is recognised as an eosinophilic inflammatory condition;

however, those who respond to ICS therapy with an improvement in lung function

such as the forced expiratory volume measured in one second (FEV1) are associated

with eosinophilia, and these usually represent up 50% of asthmatics (1, 2). Use of

blood eosinophil count as a biomarker to define responders to ICS is not used.

Treatment of patients with asthma based on their sputum eosinophil counts rather

than on symptoms results in better control of asthma with less exacerbations using

less corticosteroid therapy (3). There may be many reasons why this approach of

using sputum eosinophil counts to improve the therapy of asthma has not been

adopted. Most importantly, obtaining sputum samples from patients with asthma is

[3]

not always successful and the analysis of the samples takes time and effort. Thus,

the practice of precision (or personalised) medicine in asthma is lagging behind.

However, the introduction of specific biologic therapies such as anti-IgE and anti-IL5

antibody treatments at the Step 5 of the GINA guidelines has opened up the new era

of precision medicine in asthma. These therapies are only used in the severe allergic

asthma and in the severe eosinophilic phenotypes of asthma, respectively.

Although the practice of medicine has always been based on a personalised

approach since the dawn of medicine, with the concept of treating each patient as

being unique, this delivery has remained very limited mainly as a concept rather than

hard practice because of limitations in our understanding of what constitutes asthma.

Currently, we recognise a category of asthma as being ‘severe asthma’, defined as

by poor therapeutic responses of these patients to currently-approved asthma

medications, particularly inhaled and oral CS therapies, and approaches to

phenotyping have been proposed in the international severe asthma guidelines (4).

The clinical diversity of this group has been recognised and this group of patients

has been the subject of unbiased clustering approaches.

Phenotypes of asthma have not been well described and there has been a

lack of biomarkers developed for identifying different types of asthma. Consequently,

the treatment of asthma has remained a ‘one size fits all’. Treatments should not

only be based on the basis of severity, but on the basis of the driving mechanisms.

The introduction of new biologic therapies at Step 5 has heralded a new era of

precision medicine for asthma. This review will discuss how precision medicine will

alter the approach to the management of asthma.

What is Precision Medicine?

[4]

Precision medicine can be defined as an approach to treat and prevent

disease by taking into consideration the individual variability in genes, environment,

and lifestyle for each subject and by taking this approach, there is increased

likelihood of treating ‘the right patient with the right drug at the right time’, with

preventive measures and therapies tailored for each individual (5). Analysis of the

genes and proteins are more likely to point towards causative pathways, that would

lead to definition of endotypes which are phenotypes defined according to

mechanisms. This is more likely to lead to treatments that target the cause of these

diseases. Precision medicine is the tailoring of medical management to the individual

characteristics not only genetic or genomic but also environmental and psychosocial

characteristics, and preferences of each patient. Other terms that are used often

synonymously with precision medicine are tailored medicine, stratified medicine or

targeted medicine that will ultimately lead to targeted therapeutics. The concept of

the “P4 medicine” that is predictive, preventive, personalized, and participatory also

falls within a similar definition (https://www.systemsbiology.org/research/p4-

medicine/).

In order to be able to practise precision medicine with particular reference to

asthma, one should understand the different endotypes of asthma and the

biomarkers that will be used to help the doctor in determining the right treatment. In

addition, because asthma is a disease that changes with time, information on a daily

basis about the patient’s condition and environment that could influence the course

of the disease is needed. Such daily information may be used to predict any future

exacerbations of asthma and the influence of potential environmental factors.

Phenotyping to endotyping

[5]

Description of clinical phenotypes based on clinical variables and

inflammatory markers has been made possible by the use of unbiased methods of

clustering. The most recent report from the U-BIOPRED cohort described a well-

controlled moderate-to-severe asthma phenotype and 3 other severe phenotypes: (i)

late-onset asthma with past or current smoking and chronic airflow obstruction,

predominantly eosinophilic inflammation (ii) non-smoking severe asthma with chronic

airflow obstruction and high use of oral corticosteroid therapy and (iii) obese female

patients with frequent exacerbations but with normal lung function (6) (Fig 1). In the

American Severe Asthma Research Project (SARP) cohort, phenotypes of early

onset atopic asthma with mild to moderate severity, of obese late onset non-atopic

asthma female patients with frequent exacerbations, and of those with severe airflow

obstruction with use of oral corticosteroid therapy were identified (7). In the Leicester

cohorts, the use of sputum eosinophilia as a marker of eosinophilic asthma (8), has

resulted in the description of 2 cohorts: a cluster of non-eosinophilic inflammation

(early-onset, symptom-predominant group in female obese patients), and a cluster of

eosinophilic inflammation with late-onset disease, associated with rhinosinusitis,

aspirin sensitivity, and recurrent exacerbations. This latter eosinophilic phenotype

was also described in the SARP cohort with late onset asthma and nasal polyps with

exacerbations despite high systemic corticosteroid use; the other eosinophilic cohort

had early onset allergic asthma with low lung function (9). This clustering based on

clinical, physiological and inflammatory parameters while yielding distinct

phenotypes have not in general led to the elaboration of phenotypic biomarkers.

Definition of a severe eosinophilic asthma phenotype/endotype

[6]

Molecular phenotyping has allowed us to define the severe eosinophilic

asthma phenotype as an endotype, ie a phenotype defined by underlying

mechanisms. The clinical phenotype characterized by concomitant high blood and

sputum eosinophilia has been associated with very poor asthma control and

propensity to asthma exacerbation (9). The unbiased cluster analyses have

uncovered a phenotype of patients with late-onset, eosinophilic inflammation-

predominant asthma (6-8), and adult-onset asthma patients with a high blood

eosinophil count with frequent exacerbations and a poor prognosis (10). Persistent

airflow limitation and distal inflammation with air trapping are common in these

patients, as is upper airway pathology such as chronic rhinosinusitis with nasal

polyposis (11). Molecular support for this endotype was provided by determining the

expression of 3 genes upregulated by exposing airway epithelial cells to the T2

cytokine, IL-13, in airway epithelial cells of patients with asthma. A Th2-high

molecular phenotype was characterised by more blood and BAL eosinophils,

increased levels of serum IgE, increased expression of mucin MUC5AC, increased

expression of IL5 and IL13 in biopsies, increased bronchial hyperresponsiveness,

and respond to inhaled corticosteroids by an increase in FEV1 when compared to

those with Th2-low expression (12). Finally, the recent sputum analysis of U-

BIOPRED has defined the molecular shape of this endotype associated with high T2

pathway and also with mast cell activation pathway (13). New targeted treatments

such as anti-IL5 and anti-IL5ra antibody that caused a reduction in the exacerbation

rate support the concept that this is a severe eosinophilic asthma endotype (14, 15).

The major criteria for this endotype have been defined as (1) having severe asthma,

(2) with high load eosinophilic disease, (3) having frequent exacerbations, and (4)

the need for oral corticosteroid therapy to maintain control (16).

[7]

Unbiased molecular phenotyping

The Th2-high phenotype is only found in 37% of patients with severe asthma

when analysing genes in the airway epithelium (17). Therefore, the majority of

patients with severe asthma can be considered to be low-T2. In order to elucidate

these non-T2 endotypes, an unbiased approach to obtaining molecular phenotypes

of asthma was undertaken in U-BIOPRED. A hierarchical clustering of differentially-

expressed genes between eosinophilic and non-eosinophilic inflammatory profiles

from an analysis of sputum omics data revealed 3 molecular phenotypes (13). One

cluster was characterised by the immune receptors IL33R, CCR3 and TSLPR with

the highest enrichment of gene signatures for interleukin-13/T-helper cell type 2

(Th2) and innate lymphoid cell type 2 associated with the highest sputum

eosinophilia: this grouped patients with severe asthma with oral corticosteroid

dependency, frequent exacerbations and severe airflow obstruction. The second

cluster was characterised by interferon-, tumour necrosis factor-α- and

inflammasome-associated genes with the highest sputum neutrophilia, serum C-

reactive protein levels and prevalence of eczema. The third phenotype was

characterised by genes of metabolic pathways, ubiquitination and mitochondrial

function with paucigranulocytic inflammation and little airflow obstruction (13). The

second phenotype is in agreement with the report that in neutrophilic asthma, an

elevated gene expression of NLRP3, caspase-1 and IL-1β was seen in sputum

macrophages (18). Thus, this unbiased approach has provided an overall idea of the

various pathways associated with these 3 phenotypes of asthma, with the possibility

that each of these phenotypes is underlined by several interacting pathways.

[8]

Therefore, within this categorisation, it has been possible to define an

eosinophilic inflammation phenotype, a neutrophilic phenotype and a

paucigranulocytic phenotype according to sputum cell measurements. Furthermore,

each inflammatory phenotype was observed with several pathways that could

contribute to the definition of the phenotype. However, because there has been no

validation of these pathways yet, it is not possible to describe these as endotypes

yet. One could consider the cluster associated with the highest expression of T2 and

ILC2 pathway signature and sputum eosinophilia to be a severe eosinophilic asthma

endotype. On the other hand, the neutrophilic cluster associated with inflammasome

activation cannot be considered an endotype yet, because the role of the

inflammasome in this cluster is yet to be defined. Nevertheless, this remains a

potential therapeutic target for this cluster. Similarly, this similar argument can be

made for the third cluster that may be driven by mitochondrial oxidative stress

pathways.

Development of targeted therapies

Recent progress in the therapy of severe asthma has been marked by the

introduction of biologic treatments as add-on treatment to Step 5 of the GINA

guidelines. Such biologic treatments have now been important in defining the target

population, not only because these treatments are relatively expensive compared to

existing ones but also because such specific targeting need to be used only in those

who have the target abnormality. However, cost-effectiveness analyses will be

needed to determine the true costs of these treatments. These biologic treatments

being very specific in their actions in targeting single cytokines have opened up the

field of precision medicine, placing the emphasis on the application of precision

[9]

medicine in severe asthma since the correct patient need to be singled out for these

specifically-targeted treatments. The greatest emphasis has been on the targeted

treatments for the T2 pathway, while treatments targeted at non-T2 pathways have

been less successful (19).

Targeting the T2 pathway

Activation of Th2 and ILC2 cells can occur through the release of innate

cytokines, such as thymic stromal lymphopoietin (TSLP), interleukin IL-25, and

interleukin 33 from the epithelium, that can be induced by external stimuli such as

lipopolysaccharide, pollutants, and viruses (20). These activated Th2 or ILC2 cells

release interleukins 4, 5, and 13IL4, 5 and 13, which are expressed in the bronchial

submucosa of patients with asthma. The new biologic treatments available for

patients with severe asthma include anti-IgE antibody and anti-IL5 antibody.

Anti-IgE antibody prevents the binding of free IgE to IgE receptors on mast

cells and basophils by binding itself to free IgE. IgE production from B cells is under

the control of the T2 cytokines, IL-4 and IL-13. Anti-IL5 antibody is targeted towards

IL-5, produced by Th2 cells and ILC2s, and is important for the terminal

differentiation and maturation of eosinophils in the bone marrow and for the

mobilisation of eosinophils and eosinophil precursors into the circulation. Both anti-

IgE antibody and anti-IL5 antibody are targeted for use in patients with severe

asthma, the former for allergic asthmatics and the latter for eosinophilic asthma. In

severe persistent allergic asthma defined by patients with an allergic background

with raised serum IgE levels and at Step 4 or 5 of GINA guidelines, omalizumab, an

anti-IgE antibody, as an add-on therapy decreased severe asthma exacerbations by

26%, compared with placebo (21). Mepolizumab and reslizumab, anti-IL5 antibodies,

[10]

have been shown to benefit allergic and eosinophilic severe asthma respectively by

reducing asthma exacerbation frequency and also improving baseline airflow

obstruction (22, 23): the patients chosen for these studies had to show a raised level

of blood eosinophil count. Other potential therapies not yet approved targeting T-2

pathway include anti-IL5Rα antibody (benralizumab) that inhibits the effect of IL5 (24,

25), and anti-IL4Rα antibody (dupilumab) (26), that blocks the effects of IL-13 and IL-

4 together, both showing beneficial effects on exacerbations and lung function,

particularly in those with a raised blood eosinophil count.

More recently, tezepelumab (AMG 157/MEDI9929), a human monoclonal

antibody specific for the epithelial-cell-derived cytokine TSLP which regulates type 2

immunity through not only Th2 cells but also through ILC2 cells, has been associated

with lower rates of clinically significant asthma exacerbations than those who

received placebo, independent of baseline blood eosinophil counts to in patients with

uncontrolled moderate-to-severe asthma (27).

Non-T2 targets

There have been descriptions of non-T2 phenotypes previously. Thus, a

systemic IL-6 inflammation with clinical features of metabolic dysfunction associated

with more severe asthma has been described (28). In addition, apart from Th2 high,

a Th17 high group has been described with the Th2 high being mutually exclusive of

Th17 high (29). However, despite this targeting non-T2 targets has not proven to be

successful in providing effective therapies for asthma. Brodalumab, a human anti-

interleukin-17RA monoclonal antibody, had no effect on asthma control scores,

symptom-free days, and FEV1 in patients with inadequately controlled moderate-to-

severe asthma who were receiving inhaled corticosteroid therapy (30). Treatment

[11]

with a selective CXCR2 antagonist, AZD5069, that blocks the effect of CXCL8, did

not reduce the frequency of severe exacerbations in patients with uncontrolled

severe asthma (31). Finally, in adults with uncontrolled severe persistent asthma, the

anti-TNFα antibody golimumab had no overall beneficial effects (32). These have

raised the issue as to whether a neutrophilic asthma phenotype does exist (33), but it

is more likely that the reason for the failure of these therapies is that the right

patients were not chosen for these therapies with the lack of the appropriate

biomarkers.

The molecular phenotypes derived from sputum transcriptomic analysis in U-

BIOPRED defined a neutrophilic inflammatory phenotype (sputum neutrophil >73%),

with inflammasome, IFN and TNF activation pathways (13). This could be associated

with the microbial dysbiosis that is now increasingly being associated with severe

asthma (34), but further validation research is needed to definitely determine the

mechanism underlying the neutrophilic inflammation. Analysis of transcriptomics in

bronchial biopsies and brushings identified the co-expression of high Th2 and high

Th1 pathways indicating that more than one pathway may co-exist (35). A raised

concentration of the gastrotransmitter, hydrogen sulphide, in sputum has also been

associated as a potential biomarker of neutrophilic asthma associated with airflow

obstruction (36).

Biomarkers for precision medicine

In order to define the phenotypes that constitute the whole range of asthma

and to find the patients who will respond to specific therapies, it is important to define

the biomarkers that will help the clinician to select the right therapy for the right

patient. A biomarker can be defined as a characteristic that can be measured and

[12]

evaluated as an indicator of normal or pathological biological processes or the

biological response to a therapeutic intervention (37). Biomarkers mostly indicative of

T2-high asthma that are easily accessible to the patient are available for the

management of asthma; these include blood eosinophil count and serum IgE and

also serum periostin levels, levels of nitric oxide in exhaled breath (FeNO) and

sputum eosinophil count in some centres. Using sputum eosinophil counts as a

response biomarker to treatment with corticosteroid therapy results in better outcome

measures mainly in terms of a reduction in exacerbations compared to using

symptom severity (38). FeNO did not perform as well. Responsiveness to

corticosteroid therapy particularly in children can be predicted from a blood

eosinophil count (39), but validated cut-off levels in different populations still need to

be established. Increasingly, biomarkers will be used to select patients that would

be suitable for specific biological treatments. Baseline blood eosinophil count is

being used as a biomarker that predicts the clinical efficacy of anti-IL5 therapy in

patients with severe eosinophilic asthma with a history of exacerbations (15, 22, 40,

41) . Total serum IgE level has been used as a response biomarker for the use of

anti-IgE antibody, omalizumab, in the treatment of severe allergic asthma. High

levels of FeNO (>19.5 parts per billion) and blood eosinophil count (>260/μl)

significantly predicted those responding to omalizumab with a reduction in

exacerbations (42).

There is an increasing need for developing biomarkers that will guide

clinicians in the management of asthma. The following areas need further

development: (i) definition of molecular phenotypes of asthma, particularly those in

the non-T2/Th2 pathways (ii) develop more phenotypic and predictive biomarkers to

delineate these molecular phenotypes of asthma and (iii) obtain specific biomarkers

[13]

to predict therapeutic outcomes to more specific targeted therapies. An unbiased

approach is necessary to define the phenotypes of asthma.

While the use of omics data from multiple platforms including transcriptomics,

proteomics, lipidomics or metabolonomics in lung tissue compartments holds the

best chance of obtaining endotypes (43, 44), biomarkers need to be developed in

easily-accessible compartments, so-called bedside biomarkers, that can be assayed

relatively easily. Thus, assays involving exhaled breath, blood or urine would appear

more promising. Therefore, one unmet need is how to develop such bed-side

biomarkers. The other possibility is that composite biomarkers may be another

answer to this (45).

Conclusion

Because of the heterogeneity and complexity of asthma, a different approach from

current practice is needed to the management of asthma that takes into account

these varied features of the disease. The use of omics data and unbiased clustering

together with the use of clinical features, physiological and inflammatory data will

provide greater opportunity of phenotyping asthma according to the mechanisms

driving the disease thus leading to endotype definition. Biomarkers could be used to

define and categorise these endotypes. This will be a tremendous help for the

development of precision medicine for asthma that will allow for more precise

treatment aims and also provide a source of novel targets and hence new treatments

for each defined endotype. Precision medicine should be applied to the whole

spectrum of asthma, not just at the more severe end of the disease.

[14]

Key points

1. Severe asthma is a heterogeneous condition and phenotyping of patients with

severe asthma into a T2 and non-T2 category is possible.

2. Precision medicine is being introduced with the availability of biologic

therapies targeting IgE and IL-5, because these agents are targeted towards

specific phenotypes of severe asthma.

3. The future of precision medicine in asthma will depend on the unbiased

recognition of all the molecular phenotypes or endotypes of asthma, and the

definition of associated biomarkers.

Acknowledgements:

KFC is a Senior Fellow of the National Institute for Health Research, UK. He also

acknowledges support from the Medical Research Council and European Union.

Financial disclosure

KFC reports personal fees from Advisory Board membership with GSK, Boehringer

Ingelheim, Novartis, Astra-Zeneca and Teva, personal fees from payments for

lectures from Astra-Zeneca, Novartis and Merck, and grants for research to his

institution from Merck and GSK, all in relation to asthma, COPD and cough.

[15]

Legend to Fig:

Fig 1. Clinical phenotypes of moderate-severe asthma derived from U-BIOPRED cohort from a cluster analysis of 8 clinico-physiologic parameters. Reproduced from Reference 6 (with permission).

[16]

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