REVIEW

Severe Asthma and Biological Therapy: When, Which,and for Whom

Paola Rogliani . Luigino Calzetta . Maria Gabriella Matera .

Rossella Laitano . Beatrice Ludovica Ritondo . Nicola A. Hanania .

Mario Cazzola

Received: October 24, 2019 / Published online: December 26, 2019� The Author(s) 2019

ABSTRACT

Asthma is a heterogeneous chronic inflamma-tory disease of the airways that affects approxi-mately 300 million people worldwide. About5–10% of all asthmatics suffer from severe oruncontrolled asthma, associated with increasedmortality and hospitalization, reduced qualityof life, and increased health care costs. In recentyears, new treatments have become available,and different asthma phenotypes characterizedby specific biomarkers have been identified.

Biological drugs are currently indicated forpatients with severe asthma that is not con-trolled with recommended treatments. They aremostly directed against inflammatory mole-cules of the type 2 inflammatory pathway andare effective at reducing exacerbations, main-taining control over asthma symptoms, andreducing systemic steroid use, which is associ-ated with well-known adverse events. Althoughbiological drugs for severe asthma have had amajor impact on the management of the dis-ease, there is still a need for head-to-headcomparison studies of biologics and to identifynew biomarkers for asthma diagnosis, progno-sis, and response to treatment. Identifyingnovel biomarkers could facilitate the develop-ment of therapeutic strategies that are preciselytailored to each patient’s requirements.

Keywords: Biomarkers; Biological drugs; Mono-clonal antibodies; Phenotypes; Severe asthma

Enhanced Digital Features To view enhanced digitalfeatures for this article go to https://doi.org/10.6084/m9.figshare.11359379.

P. Rogliani � L. Calzetta (&) � R. Laitano �B. L. Ritondo � M. CazzolaRespiratory Unit, Department of ExperimentalMedicine, University of Rome ‘‘Tor Vergata’’, Rome,Italye-mail: luigino.calzetta@uniroma2.it

M. G. MateraDepartment of Experimental Medicine, Universityof Campania Luigi Vanvitelli, Naples, Italy

N. A. HananiaSection of Pulmonary, Critical Care and SleepMedicine, Baylor College of Medicine, Houston, TX,USA

Pulm Ther (2020) 6:47–66

https://doi.org/10.1007/s41030-019-00109-1

Key Summary Points

Asthma is a heterogeneous chronicinflammatory airway disease that affectsapproximately 300 million peopleworldwide, with about 5–10% of allasthmatics suffering from severe oruncontrolled asthma.

This narrative review analyzes the impactof biological agents that are currentlyapproved and under investigation in orderto aid the selection by clinicians of theappropriate biological drug for themanagement of each severe asthmaphenotype.

There is medical need for head-to-headcomparison studies of biologics as well asto identify biomarkers for asthmadiagnosis, prognosis, and response totreatment.

It is important to identify prognostic andtherapeutic biomarkers that characterizespecific phenotypes of severe asthma, asthis should allow therapeutic strategiesthat are specifically tailored to individualpatients to be devised.

Identifying novel biomarkers couldfacilitate the development of therapeuticstrategies that are precisely tailored toeach patient’s requirements.

INTRODUCTION

Asthma is a heterogeneous chronic inflamma-tory disease of the airways characterized bychronic airway inflammation, bronchocon-striction, airway hyperresponsiveness, andmucus hypersecretion. Typical symptoms arewheezing, shortness of breath, chest tightness,and cough with variable expiratory flow limi-tation [1]. Asthma affects approximately 300million people worldwide, and about 5–10% ofall asthmatics suffer from severe or

uncontrolled asthma, which is associated withincreased mortality and hospitalization,reduced quality of life (QoL), and increasedhealth care costs. According to the AmericanThoracic Society/European Respiratory Society(ATS/ERS) Task Force, asthma is defined as sev-ere when it ‘‘requires treatment with high doseinhaled corticosteroids (ICSs) plus a secondcontroller (and/or systemic corticosteroids) toprevent it from becoming uncontrolled orwhich remains uncontrolled despite this ther-apy’’ [1].

Primary endpoints of asthma managementare symptom control, fewer exacerbations,improved lung function, and minimization ofthe long-term adverse events (AEs) of therapies[1]. However, the widely used steps of careapproach to asthma treatment is often ineffec-tive due to the heterogeneity of asthma and theextreme variability in the response of asthma toavailable medications [2]. Furthermore, manypatients continue to have poor symptom con-trol and to suffer from recurrent exacerbationsdespite strictly adhering to therapy [3].Improvements in our knowledge of theetiopathological mechanisms of different phe-notypes and endotypes of severe asthma haveled to the availability of innovative therapies inthe last few years. For example, biological drugsfor severe asthma, most of which are directedagainst molecules involved in the type 2inflammatory pathway, modify the naturalhistory of the disease.

The aim of this narrative review is to discussthe effects of biological drugs that are currentlyapproved or under investigation in order to aidclinicians who are attempting to select theappropriate biological agent for managing Thelper 2 (Th2)-high/severe asthma phenotypes.This article is based on reviews of currentguidelines and literature and does not involveany studies with human participants oranimals.

SEVERE ASTHMA PHENOTYPESAND BIOLOGICAL THERAPY

Asthma is a chronic airway disease that is highlyheterogeneous in terms of its pathogenesis,

48 Pulm Ther (2020) 6:47–66

clinical manifestations, severity of symptoms,and outcomes. Recently, the integration ofgenetics, biology, and clinical features and animproved understanding of asthma pathogene-sis have led to the identification of differentasthma phenotypes characterized by specificbiomarkers. Two major groups of asthma phe-notypes that can be distinguished based on theinflammatory pathway involved, namely Th2-high and Th2-low phenotypes, have been rec-ognized. Th2-high-related inflammation is themain characteristic of Th2-high phenotypes,together with early-onset allergic asthma andlate-onset eosinophilic asthma. Neutrophilicasthma and obesity-related asthma are consid-ered Th2-low phenotypes [4].

In allergic asthma, the allergens presented tonaive CD4? T cells by dendritic cells (DCs)induce differentiation into Th2 cells. In nonal-lergic eosinophilic asthma, respiratory epithe-lium-derived cytokines and chemokines such asthymic stromal lymphopoietin (TSLP), inter-leukin (IL)-25, and IL-33 (also called alarmins)are released in response to various harmfultriggers (air pollutants, microbes, or glycolipids)[5]. Alarmins bind to the receptors on type-2innate lymphoid cells (ILC2s). Both of thesetypes of activated cells (Th2 cells and ILC2s)produce cytokines such as IL-4, IL-5, and IL-13,which are the principal effectors of type 2inflammation [6, 7]. IL-5 is the most specifictrigger for eosinophils, as it drives eosinophilmaturation in bone marrow, recruitment, andactivation [8]. IL-4 and IL-13, which share acommon receptor subchain (IL-4Ra), induceallergen-specific immunoglobulin (Ig) E syn-thesis. IgE, through its interaction with thespecific receptor FceRI (expressed in differentimmune cells), promotes the release of media-tors that are responsible for functional andstructural modifications of the bronchial wall.Also, IL-13 activates epithelial inducible nitricoxide (NO) synthase, leading to increased air-way NO production, periostin expression inlung epithelial cells and fibroblasts, mucusproduction by goblet cells, and airway smoothmuscle contractility [9].

Approximately 40–50% of all patients withasthma present the early-onset allergic pheno-type. These patients develop the disease during

childhood and are characterized by atopy, pol-ysensitization to allergens, high total IgE, highfractional exhaled NO (FeNO) levels, increasedsputum and blood eosinophils, and increasedairway periostin. High levels of IgE, FeNO, eosi-nophils, and airway periostin are consideredbiomarkers of Th2-high-related inflammation.Some of these biomarkers, such as eosinophilsand FeNO, are also associated with the late-onseteosinophilic asthma phenotype [4, 10]. Inter-estingly, eosinophils and FeNO are consideredvalid non invasive biomarkers of type 2 asthma,as they yield acceptable detection accuracy.However, their levels can be influenced byinfections, by exposure to allergens and steroids,and by age, height, sex, and smoking habit[11]. In any case, since sputum eosinophil countof C 3% is well correlated with type 2 asthma,it continues to generate considerable clinicalresearch interest [12]. Approximately 25% of allpatients with severe asthma present the late-onset eosinophilic phenotype [13], which isoften characterized by a nonsignificant responseto treatment with corticosteroids (CSs). Thisevidence indicates that the Th2 process is sepa-rate from the underlying early-onset allergicphenotype, and that blood/sputum eosinophiliacan be used as a biomarker to select patients whoshould be responsive to anti-eosinophilic ther-apies, including anti-IL-5 [14]. Moreover, adulteosinophilic asthma is sometimes associatedwith chronic sinusitis and nasal polyps inpatients without a clear history of atopy.

Th2-low phenotypes are characterized by aprevalent Th1- and Th17-driven immunity,neutrophilic inflammation, infection, andoxidative stress. These phenotypes are alsoassociated with obesity and systemic inflam-mation, including increased levels of differentcytokines such as tumor necrosis factor alpha(TNF-a), IL-6, and leptin [15]. Biological therapyof Th2-low asthma phenotypes will not be dis-cussed in the present narrative review.

Increased knowledge of molecular pathwaysand the characterization of severe asthma phe-notypes may help to drive the use of novelbiological therapies that have been approved orare under investigation. Biological therapy hasbeen demonstrated to be effective at reducingasthma exacerbations, maintaining control over

Pulm Ther (2020) 6:47–66 49

Table1

Pivotalstudiesof

biologicalagentsandinvestigated

outcom

es

Biological

drug

Target

Stud

yidentifier

Mainou

tcom

es

Asthm

aexacerbation

sLun

gfunction

OCS-sparingeffect

Omalizum

abIgE

NCT00314575

[20]

25%

reduction

NA

NA

EXTRAstudy,

NCT00314574

[21]

Greater

reductionin

protocol-defined

exacerbationsin

high

vs.low

subgroupsforall

biom

arkers:FeNO

53%

vs.1

6%;eosinophils

32%

vs.9

%;periostin30%

vs.3

%

NA

NA

ICATAST

UDY,

NCT00377572

[23]

18.5%

reductionin

annu

alized

exacerbation

rate

NA

NA

XPO

RTstudy,

NCT00314574,

[29]

67%withno

exacerbationsin

omalizum

abarm

vs.

48%

inplaceboarm

NA

NA

Mepolizum

abIL-5

DREAM

study,

NCT01000506

[14]

48%

reductionin

the75

mgmepolizum

abarm;

39%

reductionin

the250mgmepolizum

abarm;52%

reductionin

the750mg

mepolizum

abarm

NA

NA

MENSA

study,

NCT01691521

[39]

47%

reductionin

exacerbation

rate

intheIV

mepolizum

abarm,5

3%reductionin

exacerbation

rate

intheSC

mepolizum

abarm

comparedto

placebo

Meanincrease

from

baselin

ein

FEV1:100mlin

theIV

mepolizum

abarm

comparedto

placebo;

meanincreasefrom

baselin

ein

FEV1:98

mlin

theSC

mepolizum

abarm

comparedto

placebo

NA

SIRIU

Sstudy,

NCT01691508

[40]

32%

reductionin

annu

alized

exacerbation

rate

NA

50%

reductionin

glucocorticoid

dose

inthe

mepolizum

abarm

vs.0

%reductionin

glucocorticoid

dose

intheplaceboarm

COSM

OSstudy,

NCT01842607

[41]

Ann

ualized

rate

of0.93

on-treatment

exacerbations

NA

OCSdose

reductionachieved

withmepolizum

abin

theSIRIU

Sstudywas

maintained;

patients

treatedwithplaceboin

theSIRIU

Sstudy

achieved

areductionin

OCSdose

from

12.3mg/dayto

5.0mg/dayafter1year

oftreatm

entwithmepolizum

ab

COLU

MBAstudy,

NCT01691859

[42]

61%reductionin

annu

alized

rateof

on-treatment

exacerbations(0.68events)comparedto

the

off-treatm

entperiod

betweenDREAM

and

COLUMBAstudies

NA

NA

COSM

EX

study,

NCT02135692

[43]

Ann

ualized

rate

of0.93

on-treatment

exacerbations;annu

alized

rate

of0.13

exacerbationsrequiringhospitalizationor

emergencyvisit;annu

alized

rate

of0.07

exacerbationsrequiringhospitalization

NA

NA

50 Pulm Ther (2020) 6:47–66

Table1

continued

Biological

drug

Target

Stud

yidentifier

Mainou

tcom

es

Asthm

aexacerbation

sLun

gfunction

OCS-sparingeffect

Reslizum

abIL-5

NCT01508936

[46]

NA

FEV1in

subgroup

witheosinophils\

400cells/ll:

33mlgreatercomparedto

placebo.

FEV1in

patientswitheosinophils

C400/ll:270ml

greatercomparedto

placebo

NA

NCT01287039,

NCT01285323

[47]

Study1:

34%

reductionin

frequencyof

clinical

asthmaexacerbation

events;study2:

31%

reductionin

frequencyof

clinicalasthma

exacerbation

events

Improvem

entin

FEV1in

reslizumab

arms

comparedto

placeboin

both

trials

NA

Benralizum

abIL-5R

SIROCCO

study,

NCT01928771

[53]

Reduction

inannu

alasthmaexacerbation

rate(up

to51%)over

48weeks

inQ4W

andQ8W

regimenscomparedto

placebo

Pre-bronchodilatorFE

V1(upto

159ml)

improvem

entin

Q4W

andQ8W

regimens

comparedto

placebo

NA

CALIM

Astudy,

NCT01914757

[54]

Low

erannu

alexacerbation

ratesin

theQ4W

orQ8W

regimenscomparedto

placebo

Pre-bronchodilatorFE

V1im

provem

entin

the

Q4W

andQ8W

regimens

NA

ZONDAstudy,

NCT02075255

[55]

55%

reductionin

annu

alexacerbation

rate

comparedto

placebo

NA

75%meanreductionin

oralglucocorticoiddosein

both

benralizum

abdosage

regimensvs.2

5%reductionin

placeboarm

BORAstudy,

NCT02258542

[56]

Patientswitheosinophils

C300cells/ll:

annu

alized

rate

ofon-treatmentexacerbations

was

0.50

inQ4W

vs.0

.49in

Q8W

regimens,

annu

alized

rate

ofexacerbationsrequiringan

emergencyvisitwas

0.03

inQ4W

vs.0

.05in

Q8W

regimens,annu

alized

rate

ofexacerbationsrequiring

hospitalizationwas0.04

inboth

Q4W

andQ8W

regimens.Patients

witheosinophils\

300cells/ll:annu

alized

rate

ofon-treatmentexacerbationswas

0.76

inQ4W

vs.0

.64in

Q8W

regimens,annu

alized

rate

ofexacerbationsrequiringan

emergency

visitwas

0.03

inQ4W

vs.0

.04in

Q8W

regimens,annu

alized

rate

ofexacerbations

requiringhospitalizationwas

0.06

inQ4W

vs.

0.05

inQ8W

regimens

Changein

pre-bronchodilatorFE

V1from

baselin

ein

patientswith\

300eosinophils/ll:-

17ml

inQ4W

vs.-

1mlinQ8W

regimens;change

inpre-bronchodilatorFE

V1from

baselin

ein

patientswithC

300eosinophils/ll:38

mlin

Q4W

vs.4

0ml

NA

Pulm Ther (2020) 6:47–66 51

Table1

continued

Biological

drug

Target

Stud

yidentifier

Mainou

tcom

es

Asthm

aexacerbation

sLun

gfunction

OCS-sparingeffect

Dupilumab

IL- 4R

aNCT01854047

33.2–7

0.5%

reductionin

annu

alized

exacerbation

rate

100–

160mlim

provem

entin

FEV1comparedto

placebo

NA

LIBERTY

AST

HMA

QUEST

,NCT02414854

[60]

Adjustedannu

alized

exacerbation

rate:0.46

in200mgdupilumab

(Q2W

)arm

vs.0

.87in

matched

placeboarm;47.7%

rate

reductionin

dupilumab

arm

comparedto

placebo

(P\

0.001).A

djustedannu

alized

exacerbation

rate:0.52

in300mgdupilumab

(Q2W

)arm

vs.0

.97in

matched

placeboarm;46.0%

rate

reductionin

dupilumab

arm

comparedto

placebo(P

\0.001)

Changein

pre-bronchodilatorFE

V1from

baselin

e(week12):320mlin

the200mgdupilumab

arm

vs.1

80mlin

matched

placeboarm

(difference:140

ml,P\

0.001);changein

pre-

bronchofilatorFE

V1from

baselin

e(week12):

340mlin

the300mgdupilumab

arm

vs.

210mlin

matched

placeboarm

(difference

130ml,P\

0.001)

NA

LIBERTY

AST

HMA

VENTURE,

NCT02528214

[61]

59%

reductionin

rate

ofsevere

exacerbation

comparedto

placebo

220mlFE

V1im

provem

entcomparedto

placebo

Changein

glucocorticoid

dose:-

70.1%

indupilumab

arm

vs.-

41.9%

inplaceboarm

(P\

0.001);dose

reductionof

atleast50%:

80%

vs.5

0%;dose

reductionto

lessthan

5mg/day:69%

vs.3

3%;complete

discontinu

ationof

oralglucocorticoid

use:48%

vs.2

5%

Tezepelum

abTSL

PNCT02054130

[65]

61%

reductionin

exacerbation

rate

in70

mg

tezepelumab

arm,7

1%reductionin

exacerbation

rate

in210mgtezepelumab

arm,

and66%

reductionin

exacerbation

rate

in280mgtezepelumab

arm

comparedto

placebo

Improvem

entin

pre-bronchodilatorFE

V1in

all

tezepelumab

armscomparedto

placebo

NA

FeNOfractionalexhalednitricoxide,FE

V1forced

expiratory

volumein

1s,IgEim

mun

oglobulin

E,IL-5

interleukin5,IL-5Rinterleukin-5receptor,IL-4Rainterleukin-4receptor

alpha,IV

intravenous

administration,

NA

notavailable,

OCSoral

corticosteroid,Q2W

once

every2weeks,Q4W

once

every4weeks,Q8W

once

every8weeks,SC

subcutaneous

administration,

TSL

Pthym

icstromal

lymphopoietin

52 Pulm Ther (2020) 6:47–66

asthma symptoms, and reducing the need forsteroid bursts while preventing the well-knownadverse events associated with steroid use. Piv-otal studies of the utilization of biologicalagents in patients with severe asthma arereported in Table 1, along with results con-cerning the main outcomes investigated.

MONOCLONAL ANTIBODIESIN SEVERE ASTHMA

Omalizumab

Omalizumab was the first biological drug to beapproved by the US Food and Drug Adminis-tration (FDA) and European Medicines Agency(EMA) for the treatment of severe asthma[16, 17]. It is a recombinant humanized mono-clonal antibody (mAb) that selectively bindscirculating IgE, thus decreasing IgE levels inblood [18]. According to the recommendationsof the Global Initiative for Asthma (GINA) andthe EMA and FDA, omalizumab is indicated inadults and children C 6 years old with IgE-me-diated moderate-to-severe persistent allergicasthma that remains uncontrolled despite GINAstep 4 treatment, high levels of blood IgE, and atleast a sensitization to a perennial allergen [1].Omalizumab is administered subcutaneouslyevery 2–4 weeks according to the baseline totalIgE level and body weight. Although the Euro-pean label for omalizumab clarifies that thedrug is suitable for long-term use, patientsshould be re-evaluated after 16 weeks of treat-ment to assess the efficacy of the drug beforecontinuing with omalizumab therapy [19].

In a phase 3 randomized controlled trial(RCT) performed by Hanania et al.(NCT00314575), omalizumab reduced the rateof asthma exacerbation by 25% compared withplacebo, improved the mean Asthma QoLQuestionnaire score (AQLQS), reduced the dailyas-needed rescue medication administered, anddecreased the mean Asthma Symptom Score[20]. The EXTRA study (NCT00314574), a posthoc analysis of Hanania’s RCT [20], groupedpatients according to Th2 biomarker levels(high/low FeNO, blood eosinophils, and serumperiostin levels) and demonstrated that the

reduction in exacerbation rate was greater inthe groups with high biomarker levels [21]. Thissuggests that patients with high levels of Th2biomarkers may receive a greater benefit fromomalizumab therapy [21]. Other data showedthat patients with at least 300 eosinophils/llobtained a better response from omalizumabtreatment, with an up to 60% decrease inasthma exacerbations compared to patientswith less than 300 eosinophils/ll [22].

In the Inner-City Anti-IgE Therapy forAsthma (ICATA) phase 4 RCT (NCT00377572),omalizumab improved asthma control, reducedthe use of as-needed rescue medication, andabolished seasonal exacerbation peaks in inner-city children, adolescents, and young adults(6–20 years old) with persistent allergic asthmacompared with placebo [23].

It is well known that viral respiratory infec-tions are a major cause of asthma exacerbations.Indeed, it has been demonstrated that inducedairway hyperresponsiveness could be the resultof bronchoconstriction caused by neu-raminidase via the inhibition of prejunctionalmuscarinic receptors (M2 subtypes) [24]. Thus, itseems that the ability of omalizumab to reducecirculating IgE and the expression of the high-affinity IgE receptor FceRI in DCs may attenuatethe allergic response while strengthening theantiviral immune response, ultimately pre-venting exacerbations [25]. Further studies,including a meta-analysis, showed that treat-ment with omalizumab reduces the number ofemergency department visits and the need forsystemic steroid bursts [26–28].

The Xolair Persistency of Response AfterLong-Term Therapy (XPORT) long-term phase 4RCT (NCT01125748) demonstrated that long-term therapy with omalizumab results in apersistent improvement in symptom controland a reduced risk of exacerbations. This studyalso showed that discontinuation of omal-izumab is associated with increased circulatingIgE levels and basophil expression of FceRI [29].However, an open prospective study demon-strated that the effects of 6 years of omalizumabmay persist for at least 4 years after the discon-tinuation of therapy in 60% of patients [30].

In the phase 4 Real-life Effectiveness of Omal-izumabTherapy (REALITY) study (NCT01776177),

Pulm Ther (2020) 6:47–66 53

a single-center, retrospective, observational, long-term, real-life investigation demonstrated thatoverall visit adherence upon treatment with oma-lizumab was 78%, although the adherence ratedecreased by 20% every year [31]. The response totherapy rate was assessed via the StandardizedMeasure to Assess Response to Therapy (SMART)tool, according to which the response rateincreased over time, with the highest levelachieved after 5 years of treatment (85%) [31].Omalizumab was well tolerated, with no seriousAEs reported [31].

The phase 4 Real-life Prospective Observa-tional Study to Evaluate Predictors of ClinicalEffectiveness in Response to Omalizumab(PROSPERO; NCT01922037) proved that treat-ment with omalizumab reduces exacerbationand hospitalization rates and improves asthmasymptom control irrespective of blood eosino-phils and FeNO status at baseline. Indeed, theseresults contrast with those reported by Hananiaet al. (NCT00314575), indicating that bloodeosinophil count remains a controversial bio-marker of omalizumab efficacy [32].

In the PROSPERO study, the frequency ofserious AEs (SAEs) was 11.2% in both adoles-cents and adults. The most common serious AEswere asthma (3.2%), pneumonia (1.4%),chronic obstructive pulmonary disease (0.5%),anaphylactic events (0.5%), and pulmonaryembolism and status asthmaticus (0.4%). Allanaphylactic events were of moderate severityand related to omalizumab, and all occurred inthe adult population. Seven fatal adverse eventsoccurred, none of which was related to omal-izumab [32].

Mepolizumab

Mepolizumab is a mAb that is directed againstIL-5 and has been approved as an add-ontreatment for patients C 6 years old (EMA) orC 12 years old (FDA) with severe eosinophilicasthma that remains uncontrolled despite GINAstep 4 therapy [14, 33–35]. Mepolizumab isindicated in patients who have a blood eosino-phil count of C 150 cells/ll at the moment offirst administration or C 300 cells/ll in the pastyear and have had C 2 asthma exacerbations

requiring steroid bursts in the previous year[34, 35]. In agreement with guidelines from theNational Institute for Health and ClinicalExcellence (NICE) in the UK, mepolizumab isindicated in patients with a blood eosinophilcount of C 300 cells/ll or more in the previous12 months and C 4 asthma exacerbationsrequiring systemic steroids or continuous oralcorticosteroids (OCSs) equivalent to (at least)prednisolone 5 mg/day over the previous6 months [36]. Mepolizumab is administeredsubcutaneously at a fixed dose of 100 mg every4 weeks.

Recommendations from internationalguidelines regarding the duration of treatmentto assess the efficacy of mepolizumap are notconsistent. For instance, the GINA documentindicates that a 4-month trial should be ade-quate to assess the effectiveness of mepolizu-mab in patients with severe asthma [37],whereas the NICE guidelines suggest thatmepolizumab should be stopped after12 months of treatment if the asthma is notadequately controlled, or the treatment can becontinued while assessing responsiveness to thedrug each year [38].

In the DREAM (Dose Ranging Efficacy andSafety with Mepolizumab) phase 2 RCT(NCT01000506), mepolizumab significantlyreduced the exacerbation rate and time to firstexacerbation compared to placebo in patientswith severe eosinophilic asthma with C 300blood eosinophils/ll or sputum eosinophilsC 3% (P B 0.001 for all tested doses: 75, 250,and 750 mg). Enhanced mepolizumab efficacywas detected in patients with an increasedblood eosinophil count at baseline and a rela-tively high number of prior exacerbations [14].

In the MENSA (Mepolizumab as AdjunctiveTherapy in Patients with Severe Asthma) phase3 RCT (NCT01691521), mepolizumab that wasadministered either intravenously (75 mg) orsubcutaneously (100 mg) significantly reduced(by & 50%) the asthma exacerbation rate inpatients with severe eosinophilic asthma com-pared to placebo. Mepolizumab also improvedthe forced expiratory volume in 1 s (FEV1)(P\0.05 vs. placebo), the QoL assessed via theSt. George’s Respiratory Questionnaire (SGRQ),and asthma control assessed via the 5-item

54 Pulm Ther (2020) 6:47–66

Asthma Control Questionnaire (ACQ-5) (bothP\ 0.001 vs. placebo) [39].

In the SIRIUS (Steroid Reduction withMepolizumab Study) phase 3 RCT (NCT01691508), which included patients with severeasthma requiring daily maintenance OCS ther-apy, mepolizumab reduced the dose of OCSsrequired by 50% while maintaining asthmacontrol and reducing the exacerbation rate by32% compared to placebo (P\0.05) [40].

According to long-term efficacy and safetydata on mepolizumab from the COSMOS study(NCT01842607), an extension study of theMENSA and SIRIUS RCTs, patients who werepreviously treated with mepolizumab main-tained a reduced exacerbation rate whereasthose who were in the placebo arms in theprevious studies showed improvement at thesame endpoints after mepolizumab administra-tion [41]. Mepolizumab presented a positivelong-term safety profile. No increase in the AErate was observed over the study period or whencompared with previous placebo-controlled tri-als. The most common AEs were respiratorytract infection (67%), headache (29%), worsen-ing of the asthma (27%), bronchitis (21%), andinjection-site reactions (12%). Systemic allergic/hypersensitive reactions were recorded in 2% ofpatients, and \1% of patients experienced anonallergic systemic reaction. No reports ofmepolizumab-related anaphylaxis were repor-ted. On-treatment opportunistic infections (7%)were also reported, none of which were parasiticinfections. Malignancies were reported in 2% ofpatients [41].

The COLUMBA study (NCT01691859), anopen-label, long-term extension study inpatients who participated in the DREAM study,confirmed the long-term efficacy of mepolizu-mab at reducing the exacerbation rate, ACQ-5and blood eosinophil counts, and the safetyprofile of this mAb [42].

The COSMOS Extension (COSMEX) study(NCT02135692) found that the long-termadministration of mepolizumab was well toler-ated and provided persistent clinical benefits inpatients suffering from life-threatening or verysevere eosinophilic asthma [43]. The annualizedexacerbation rate was low (0.93 event/year), andpatients who had previously participated in the

MENSA [39] and COSMOS [41] studies reportedsustained reductions in the exacerbation rateand daily OCS use upon long-term treatmentwith mepolizumab [43]. Conversely, patientswho interrupted therapy with mepolizumab for[3 months between the COSMOS and theCOSMEX studies reported an improvement inACQ score and lung function as well as areduction in eosinophil count when treatmentwith mepolizumab was restarted [43]. Twenty-five percent of the total population analyzedreported serious AEs, and 0.9% of those AEswere considered to be related to the treatment[43].

Reslizumab

Reslizumab is a mAb directed against IL-5, so ithas the same mechanism of action as mepoli-zumab. It has been approved by the EMA andFDA as an add-on treatment for adult patients(C 18 years old) with severe eosinophilicasthma that remains uncontrolled despitetherapy with high-dose ICSs plus another con-troller. Reslizumab is indicated in patients withC 400 eosinophils/ll and C 3 asthma exacerba-tions in the past 12 months [36, 44, 45]. Res-lizumab is administered intravenously every4 weeks at a dose of 3 mg/kg.

Corren et al. [46], in a phase 3 RCT designedto establish the eosinophil threshold thatshould be used to select patients for reslizumabtreatment (NCT01508936), demonstrated thattreatment led to significant improvements inlung function, symptom control, rescue medi-cation use, and forced vital capacity (FVC) inpatients with C 400 eosinophils/ll. Two furtherphase 3 RCTs (NCT01287039, NCT01285323)demonstrated that reslizumab administered asan add-on therapy to ICSs with or without othercontrollers significantly reduced the asthmaexacerbation rate compared to placebo (34%and 31% respectively; both P\ 0.0001) [47].

An open-label extension study (NCT01290887) conducted by Murphy et al. [48] evalu-ated the safety and efficacy of reslizumab for upto 24 months and demonstrated that res-lizumab-experienced patients and reslizumab-naıve patients had improved lung function and

Pulm Ther (2020) 6:47–66 55

asthma control throughout the study period.The most frequently reported AEs in both res-lizumab-experienced and reslizumab-naıvepatients were asthma worsening (28% vs. 46%),nasopharyngitis (14% vs. 14%), upper respira-tory tract infection (10% vs. 9%), sinusitis (8%vs. 6%), headache (7% vs. 11%), and localadministration-related AEs (\1%). Anaphylaxisand parasitic and opportunistic infections werenot reported. Similar levels of anti-reslizumabantibody were detected in patients in bothgroups at baseline (4%) and during treatment(5%).

Benralizumab

Benralizumab is a humanized afucosylated mAbagainst IL-5 receptor a (IL-5Ra) that induceseosinophil apoptosis through the mechanism ofantibody-dependent cell-mediated cytotoxicity(ADCC) involving natural killer cells, inducingperipheral blood eosinophil depletion [49, 50].It is approved as an add-on treatment for inad-equately controlled severe eosinophilic asthmain adult patients (EMA) and subjects agedC 12 years (FDA) with C 300 blood eosinophils/ll [51, 52]. A 30 mg dose of benralizumab isadministered subcutaneously every 4 weeks forthe first 3 months and then every 8 weeks.

In two large phase 3 RCTs, SIROCCO(NCT01928771) and CALIMA (NCT01914757),which were carried out in patients with severeasthma and a high blood eosinophil count(C 300 cells/ll), 30 mg of benralizumabadministered as an add-on therapy every4 weeks or every 8 weeks were found to signifi-cantly reduce the asthma exacerbation rate (byup to 51%; P\0.0001) and to improve FEV1 (byup to 159 ml) and the blood eosinophil countcompared with the control [53, 54].

In the ZONDA phase 3 RCT (NCT02075255),OCS doses were reduced by 75% in the benral-izumab arm, compared with 25% in the placeboarm, over 28 weeks of treatment. The annualexacerbation rate was reduced by 55% com-pared to placebo, but there was no change inFEV1 [55].

In an extension study (NCT02258542), Busseet al. [56] demonstrated that benralizumab

administered for 2 years maintained its efficacyand had a safety and tolerability profile similarto that observed over 1 year in the SIROCCOand CALIMA RCTs. The most common AEs wereviral upper respiratory tract infections (14–16%;mostly bacterial pneumonia) and worseningasthma (7–10%). No cases of helminth infectionwere reported, and rates of hypersensitivity AEswere similar across the study groups. Posi-tive anti-drug antibody responses were detectedin 8–11% of patients receiving benralizumab fora second year, but a slight decrease in eosino-phil-depleting activity due to high titers of anti-drug antibodies was noted at very low troughconcentrations of benralizumab [56].

Dupilumab

Dupilumab is a humanized mAb directed againstthe a chain of the IL-4 receptor (IL-4Ra), which iscommon to both IL-4 and IL-13, so this drug isable to inhibit the signaling of both ILs. Dupi-lumab is approved by the FDA as an add-onmaintenance therapy in patients with moderate-to-severe asthma who are aged C 12 years andhave an eosinophilic phenotype or OCS-depen-dent asthma, and by the EMA as an add-onmaintenance treatment for severe asthma withtype 2 inflammation characterized by raisedblood eosinophils and/or raised FeNO in ado-lescents aged C 12 years that is inadequatelycontrolled with high-dose ICS plus anothermedicinal product for maintenance treatment.

Dupilumab is administered subcutaneouslyat an initial dose of 400 mg (two 200 mg injec-tions) followed by 200 mg every 2 weeks, or atan initial dose of 600 mg (two 300 mg injec-tions) followed by 300 mg every 2 weeks.According to the EMA, a starting dose of 600 mgis recommended only for patients with OCS-dependent asthma or moderate-to-severe atopicdermatitis (for which dupilumab is also indi-cated) [57]. The FDA approved both regimens(400/200 mg and 600/300 mg) without specificindications, except for patients with OCS-de-pendent asthma or moderate-to-severe atopicdermatitis, for whom an initial dose of 600 mgadministered subcutaneously is indicated [58].

56 Pulm Ther (2020) 6:47–66

In a phase 2 dose-ranging study (NCT01854047),Wenzel et al. [59] allocatedpatientswithsevere uncontrolled asthma to four groups withdifferent dosing and timing schemes (200 mgevery 4 weeks, 300 mg every 4 weeks, 200 mgevery 2 weeks, and 300 mg every 2 weeks). Thedupilumab groups showed improved lung func-tion and patient-reported outcomes as well asfewer severe exacerbations compared with pla-cebo. Although these results were observed in theoverall population, the subgroupwith at least 300eosinophils/ll showed the greatest reduction inthe annualized severe exacerbation rate andimprovement in FEV1 [59].

In the LIBERTY ASTHMA QUEST phase 3RCT (NCT02414854) conducted in patientsaged C 12 years old with uncontrolled asthma,dupilumab significantly reduced asthma exac-erbations by & 50% and improved FEV1. Twodupilumab dosing schemes, 200 mg and 300 mgevery 2 weeks, were tested [60]. In this study,the safety profile was favorable. The frequencyof AEs was similar across the interventiongroups (81.0%). Injection-site reaction was themost frequent AE (15.2% in the lower-dosedupilumab group vs. 5.4% in the matched pla-cebo group; 18.4% in the higher-dose dupilu-mab group vs. 10.3% in the matched placebogroup). An eosinophil count of[3000 per cubicmillimeter during the intervention period wasconsidered to indicate an AE (AE rate: 1.2% inthe dupilumab groups combined and 0.3% inthe placebo groups combined). SAEs (worseningof hypereosinophilia and chronic eosinophilicpneumonia) were suffered by two patients inthe dupilumab groups who showed increasedblood eosinophils. Conjunctivitis was alsoobserved during the study period, with nomeaningful difference in rate between the studygroups. The most frequent SAE was pneumonia(suffered by 8.2% of patients receiving dupilu-mab and 8.4% of patients receiving placebo).Persistent anti-drug antibody responses werereported, but they had no meaningful effect ondrug safety or efficacy.

In the LIBERTY ASTHMA VENTURE phase 3RCT (NCT02528214), Rabe et al. [61] demon-strated that dupilumab is effective at reducingthe need for OCSs while maintaining asthmacontrol, reducing asthma exacerbations (by

59.3%), and improving lung function. The fre-quency of AEs during the trial period was simi-lar in the two groups (62% in the dupilumabgroup and 64% in the placebo group).

In a recent post-hoc analysis of a phase 2study (NCT01854047), dupilumab produced asignificant and clinically meaningful improve-ment in asthma symptom control as assessedvia ACQ-5, AM/PM Asthma Symptoms Score,QoL, and productivity in an intention-to-treatpopulation who received the drug administeredat a dose of 200/300 mg every 2 weeks [62].Another post-hoc analysis of the same study(NCT01854047) indicated that dupilumab200 mg and 300 mg administered every 2 weekssignificantly (P\ 0.05) reduced the rate of sev-ere exacerbations and significantly (P\ 0.05)improved lung function, asthma control, andQoL compared to placebo, regardless of theexacerbation history of the patient [63].

According to a post hoc analysis of the LIB-ERTY ASTHMA QUEST study (NCT02414854),dupilumab administered at 200 mg and 300 mgsignificantly (P\0.001) reduced the rate ofsevere exacerbations in uncontrolled, moderate-to-severe asthma patients with evidence ofallergic asthma (- 36.9% and - 45.5%, respec-tively) and in patients without an allergiccomponent (- 60.0% and - 44.6%, respec-tively) [64]. In patients with or without allergicasthma, both doses significantly (P\ 0.01)improved asthma control as well as lung func-tion compared to placebo [64]. Dupilumab200 mg and 300 mg also significantly reducedtotal serum IgE compared to placebo in patientswith asthma with or without an allergic com-ponent [64].

BIOLOGICAL DRUGS UNDERDEVELOPMENT

Tezepelumab is a humanized mAb that is underdevelopment. It binds TSLP, preventing theinteraction of TSLP with its receptor, which isexpressed on different immune cells of the type2 inflammatory cascade. Corren et al. [65] con-ducted a phase 2 RCT (NCT02054130) thataimed to compare tezepelumab administered at70 mg and 210 mg every 4 weeks and

Pulm Ther (2020) 6:47–66 57

tezepelumab administered at 280 mg every2 weeks with placebo. All dosage regimensshowed statistically significant reductions in theannualized asthma exacerbation rate andimprovements in the pre-bronchodilator FEV1

compared with placebo. Reductions in theinvestigated Th2 biomarkers (eosinophils,FeNO, and IgE) in patients treated with teze-pelumab suggest that this mAb affects the IL-4,IL-5 and IL-13 pathways [65].

The drug-related SAEs observed in the RCTwere pneumonia and stroke (which occurred inthe same patient in the low-dose tezepelumabgroup) and Guillain–Barre syndrome (in themedium-dose tezepelumab group). Neitherinvestigational product-related anaphylacticreactions nor the identification of neutralizingantibodies were reported [65].

Several studies that aim to evaluate thesafety, tolerability, and efficacy profile of teze-pelumab in adult patients with severe uncon-trolled asthma are ongoing (CASCADE,NCT03688074; DIRECTION, NCT03927157;NAVIGATO, NCT03347279). A further phase 3RCT will evaluate the glucocorticoid sparingeffect of tezepelumab in adults with OCS-de-pendent asthma (SOURCE, NCT03406078).

DISCUSSION

The treatment approach for severe asthma haschanged significantly during the past decade.Effective identification of specific biomarkersfor severe asthma has become the basis forbiomarker-related personalized medicine thathas replaced the conventional strategy based onnonspecific drugs such as corticosteroids andbronchodilators—the so-called blockbusterdrugs. The characterization of molecular targetshas allowed the identification of patients withsevere asthma who would benefit from specificbiological treatments. Nevertheless, the class ofbiological agents that represent the best thera-peutic option for patients with overlappingphenotypes is still unclear. Therefore, there is aneed for further discriminatory biomarkers thatcan allow better patient selection and can beused to predict the response of the patient totargeted therapy. Furthermore, there is a lack of

direct comparisons between currently approvedbiological therapies. Thus, head-to-head RCTsand further network meta-analyses performedaccording to the Preferred Reporting Items forSystematic Reviews and Meta-Analyses Proto-cols (PRISMA-P) and registered in the Interna-tional Prospective Register of SystematicReviews (PROSPERO) are needed to help clini-cians to better identify the best biological ther-apy for each severely asthmatic patient [66].

Before starting treatment with a biologicalagent, it is necessary to correctly diagnose sev-ere asthma and exclude possible confoundingconditions that mimic asthma symptoms,namely chronic obstructive pulmonary disease(COPD), bronchiectasis, intermittent laryngealobstruction (ILO), and hypersensitivity pneu-monitis [67]. Comorbidities should also beassessed and eventually treated. The most fre-quent comorbidities associated with asthmainclude gastroesophageal reflux disease, aspira-tion, rhinosinusitis, obstructive sleep apnea,cardiovascular comorbidities, ILO, and infec-tions [68].

The characterization of etiopathogeneticpathways defining the aspects of severe asthmahas allowed the identification of specificbiomarkers for specific phenotypes. Prognosticand therapeutic information can be obtained byfocusing on these specific molecular targets.This approach may facilitate the effectivetreatment of this complex and heterogeneousdisorder. The recent approval of novel biologi-cal agents has definitely changed the naturalhistory of severe Th2-high asthma. Conversely,targeting the Th2 pathway in nonphenotypedpatients seems to be barely effective.

In the GINA recommendations, biologicaltherapy is suggested in patients with severeasthma who show typical biomarkers of type 2airway inflammation. Currently recognizedTh2-high asthma phenotypes include early- andlate-onset forms of asthma. The early-onset al-lergic asthma phenotype is characterized byatopy, polysensitization to allergens, a hightotal IgE, high FeNO levels, high sputum andblood eosinophil counts, and increased airwayperiostin. Late-onset eosinophilic asthma isoften characterized by CS treatment refractori-ness and an association with chronic sinusitis

58 Pulm Ther (2020) 6:47–66

and nasal polyps. Blood eosinophils and FeNOare considered valid noninvasive alternativebiomarkers to the detection of sputum eosino-phil counts of C 3%.

In order to identify the most effective andappropriate biological therapy to treat severeasthma, it is necessary to consider the thera-peutic indications reported by internationalagencies, namely the EMA and FDA, as well asbiomarkers (as predictors of response), althoughtheir role is often controversial. In this respect,Table 2 summarizes the indications for cur-rently approved biological therapies for severeasthma treatment in terms of patient age, dis-ease characteristics, posology, the main bene-fits, and the most common AEs, in agreementwith the relevant EMA and FDA documents.

For patients with allergic non-eosinophilicsevere asthma, high levels of blood IgE, and atleast a sensitization to a perennial allergen,omalizumab should be considered the first-choice biological treatment. Conversely, forpatients with eosinophilic nonallergic severeasthma, it is reasonable to add an anti-IL-5biological agent to the standard therapy. Anti-IL-4Ra is the treatment for severe eosinophilictype 2 asthma or patients requiring mainte-nance OCS [37].

Due to a lack of head-to-head comparisontrials, there are currently no recommendationsfor choosing among all of the currently avail-able biologics that target the IL-5 pathway.Therefore, despite being limited by differencesin study design, several network meta-analyseshave been conducted. In this respect, a match-ing-adjusted indirect comparison indicated thatbenralizumab and mepolizumab have similarefficacy profiles [69]. A network meta-analysissuggested that reslizumab could be more effec-tive than benralizumab in patients with mod-erate-to-severe eosinophilic asthma, a highblood eosinophil count, and two or moreexacerbations in the previous year [70]. Anotherindirect treatment comparison showed that,compared to reslizumab and benralizumab,mepolizumab reduced the risk of asthma exac-erbations and improved disease control regard-less of the blood eosinophil threshold [71]. Inan arm-based network meta-analysis that aimedto assess the effects of monoclonal antibodies

on the rate of asthma exacerbation, there wasno significant difference between the investi-gated agents [72]. Conversely, the results ofanother quantitative synthesis indicated that,although all current mAbs were effective atreducing the risk of exacerbation and improv-ing FEV1 compared to placebo, only dupilumabwas significantly more effective than omal-izumab at reducing the risk of exacerbation, andthere was no difference between mepolizumab,reslizumab, benralizumab, and dupilumab [73].Interestingly, dupilumab was also found to besignificantly more effective than omalizumab,mepolizumab, and benralizumab at improvingFEV1, whereas omalizumab, mepolizumab, res-lizumab, and benralizumab yielded similarimprovements in FEV1 [73].

According to the GINA recommendations, a4-month trial should be conducted to assessasthma control. In the case of failed asthma con-trol, it ispossible toattempt toswitchtoadifferenttype-2 targeted biological drug if the patient iseligible. Currently, only a few studies have beenconducted on biological drug switching inpatients with severe asthma. One of these, a24-week prospective, multicenter, open-label,single-group, self-controlled study, showed thatreslizumabsignificantly improvedasthmacontrolin patients with severe eosinophilic asthma and apoor response to omalizumab [74]. In the OSMOstudy, a multicenter, open-label, single-arm,32-week trial, patients with severe asthmauncontrolled by omalizumab showed animprovement inasthmacontrolafter switching tomepolizumab [75]. Interestingly, this result wasconfirmed by real-world evidence [76]. Prelimi-nary findings also suggest that that in patientstreated with mepolizumab who had poor asthmasymptom control, switching to benralizumab ledto improved QoL scores and reduced OCS main-tenance doses [77]. Moreover, two triple-switchcase reports indicate that patients show long-termresponsiveness to mepolizumab after failed oma-lizumabtherapyandbronchial thermoplasty [78].However, how and when to switch from onebiological drug to another and the treatment timeatwhich the patient should be judged to be eithera responder or nonresponder to therapy are yet tobe adequately established.

Pulm Ther (2020) 6:47–66 59

Table2

Approvedbiologicaltherapiesforsevere

asthmatreatm

ent:when,

which,and

forwhom,inagreem

entwithEMA

andFD

Adocuments

Omalizum

abMepolizum

abReslizum

abBenralizum

abDup

ilumab

Dateof

issueof

marketing

authorization

andreference

ofproduct

inform

ation

EMA2005

[82]

FDA2003

[83]

EMA

2015

[35]

FDA2015

[34]

EMA2016

[84]

FDA2016

[85]

EMA2018

[86]

FDA2017

[87]

EMA2019

[57]

FDA2017

[58]

Age

ofpatients

(when)

EMA:6yearsof

ageandolder

FDA:6yearsof

ageandolder

EMA:6yearsof

ageandolder

FDA:12

yearsof

ageandolder

EMA:adultpatients

FDA:adultpatients

EMA:adultpatients

FDA:12

yearsof

ageand

older

EMA:12

yearsof

ageandolder

FDA:12

yearsof

ageandolder

mAB(which)

Hum

anized

anti-IgE

Hum

anized

anti-IL-5

Hum

anized

anti-IL-5

Hum

anized

anti-IL-5R

aHum

anized

anti-IL-4Ra

Disease

characteristics

(for

whom)

EMA:add-on

treatm

entforIgE-

mediatedasthmawithpositive

skin

testor

invitroreactivity

toa

perenn

ialaeroallergen,frequent

daytim

esymptom

sor

night-time

awakenings,m

ultipledocumented

severeasthmaexacerbationsdespite

treatm

entwithhigh

dosesof

aIC

S/LABAcombination;reduced

lung

function

(FEV1\

80%

predicted)

inpatientsaged

12years

orover

FDA:moderateto

severe

persistent

asthmawithapositive

skin

testor

invitroreactivity

toaperenn

ial

aeroallergen

andsymptom

sthat

are

inadequatelycontrolledwithIC

S

EMA:add-on

treatm

entforsevere

refractory

eosinophilicasthma

FDA:add-on

treatm

entforsevere

asthmawitheosinophilicphenotype

EMA:add-on

treatm

entfor

severe

eosinophilicasthma

inadequatelycontrolleddespite

treatm

entwithhigh-doseIC

Ssplus

anothermedicinal

productformaintenance

treatm

ent

FDA:add-on

treatm

entfor

severe

eosinophilicasthma

EMA:add-on

treatm

ent

forsevere

eosinophilic

asthmainadequately

controlleddespite

treatm

entwithhigh-

dose

ICS/LABA

combination

FDA:add-on

treatm

ent

forsevere

eosinophilic

asthma

EMA:add-on

treatm

entfortype

IIsevere

asthmawithincreasedblood

eosinophils

and/or

raised

exhaled

nitricoxideinadequatelycontrolled

byhigh-doseIC

Ssplus

another

asthmamedicinalproduct

FDA:add-ontreatm

entfor

moderate-

to-severeeosinophilicasthmaor

oralcorticosteroid-dependent

asthma

Posology

75–6

00mgin

oneto

four

subcutaneous

injections

every

4weeks;themaxim

umrecommendeddoseis600mgevery

2weeks

100mgadministeredsubcutaneously

once

every4weeks

inadultsand

adolescentsaged

12yearsor

over;

40mgadministered

subcutaneouslyonce

every4weeks

inchildrenaged

between6and

11years

3mgforeach

kgof

bodyweight

viaintravenousinfusion

once

every4weeks

30mgby

subcutaneous

injectionevery4weeks

forthefirst3doses,

andthen

every8weeks

thereafter

Aninitialdose

of400mg(two

200mgsubcutaneous

injections)

followed

by200mggivenevery

otherweek;

aninitialdose

of600mg(two300mgsubcutaneous

injections)followed

by300mg

giveneveryotherweek;forpatients

requiringconcom

itantoral

corticosteroidsor

withcomorbid

moderate-to-severeatopic

derm

atitisforwhich

dupilumab

isindicated,startwithan

initiald

ose

of600mgfollowed

by300mg

giveneveryotherweek

60 Pulm Ther (2020) 6:47–66

Although a withdrawal from biologicaltherapy could be attempted after at least12 months of treatment to check whetherasthma symptom control has been achievedwith medium-dose ICS add-on therapy, there iscurrently limited evidence concerning theactual feasibility of biologic therapy cessation[29, 43].

Moreover, in patients with severe asthma thatis uncontrolled despite receiving add-on therapywith a biologic agent, the use of combinationbiological therapy could be considered. However,the efficacy and safety profile of such a combina-tion therapy inpatients eligible formultiplemAbshas not been carefully studied; relevant dataoriginate mainly from case reports [79].

Clinical trials of biological agents directedagainst IL-6, IL-17, or IL-33 in patients withTh2-low asthma phenotypes are ongoing, butcurrent knowledge suggests that these subjectsshould be treated with chronic macrolide,bronchial thermoplasty, or imatinib [80].Although important advances have been made,efforts are still needed to identify usefulbiomarkers for Th2-low severe asthma pheno-types and to define appropriate therapies forthese patients.

CONCLUSIONS

The use of biological agents has revolutionizedthe management of severe asthma. Neverthe-less, many patients with asthma remain inade-quately controlled. Thus, further effort isneeded to identify other potential moleculartargets that could be used as prognostic andtherapeutic biomarkers, as this will facilitatetherapeutic strategies that are precisely tailoredto each patient’s requirements [81].

ACKNOWLEDGEMENTS

Funding. This study was supported by insti-tutional funds (1010107CTBOE16 University ofRome ‘‘Tor Vergata’’). No funding was receivedfor the publication of this study.

Table2

continued

Omalizum

abMepolizum

abReslizum

abBenralizum

abDup

ilumab

Mainbenefits

Adults

andadolescents:

&50%

reductionin

thenu

mber

ofexacerbations;im

provem

entin

qualityof

lifeandreductionin

the

useof

ICS.

Children:

&20%

reductionin

thenu

mber

ofexacerbations.Dataarereported

vs.p

lacebo

Adults

andadolescents:

&50%

reductionin

thenu

mber

ofexacerbations;abouthalfof

the

patientsreducedthedaily

dose

oforalcorticosteroid

dose

bymore

than

50%to

adoseof

5mgor

less.

Children:

thereductionin

eosinophillevelsin

thebloodwas

comparablewiththat

detected

inadults.D

ataarereported

vs.

placebo

&30%

reductionin

thenu

mber

ofexacerbations;im

provem

ent

inlung

function

andasthma

symptom

s;decreasednu

mber

ofbloodeosinophils.D

ataare

reported

vs.p

lacebo

&50%

reductionin

the

numberof

exacerbations;

&50%

reductionin

thedaily

oral

corticosteroid

dose.

Dataarereported

vs.

placebo

&50%

reductionin

thenu

mberof

exacerbations;im

provem

entin

lung

function;&

30%

reduction

inthedaily

oralcorticosteroid

dose.D

ataarereported

vs.placebo

Mostcommon

adverseevents

Patientsaged

12yearsor

over:

headache

andinjectionsite

reactions.Childrenaged

between6

and12

years:headache

andpyrexia

Headache,injectionsite

reactions,

back

pain

Increase

inlevelsof

theenzyme

creatine

phosphokinasein

the

blood,correlated

withpossible

damageto

muscles.

Anaphylacticreactionsmay

affect

B1%

patients

Headache,pharyngitis

Infections,eye

disorders

(conjunctivitisandrelated

cond

itions)andinjectionsite

reactions

EMAEuropeanMedicines

Agency,FD

AUSFood

andDrugAdm

inistration,

ICSinhaledcorticosteroids,IL

interleukin,

LABAlong-actingb2agonist,mABmonoclonalantibody

Pulm Ther (2020) 6:47–66 61

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.

Disclosures. Paola Rogliani has participatedas a lecturer and advisor in scientific meetingsand courses under the sponsorship of Almirall,AstraZeneca, Biofutura, Boehringer Ingelheim,Chiesi Farmaceutici, GlaxoSmithKline, Menar-ini Group, Mundipharma, and Novartis. Herdepartment was funded by Almirall, BoehringerIngelheim, Chiesi Farmaceutici, Novartis, andZambon. Rossella Laitano and Beatrice LudovicaRitondo have nothing to disclose. Maria Gab-riella Matera has participated as a lecturer andadvisor in scientific meetings and courses underthe sponsorship of Almirall, AstraZeneca,Boehringer Ingelheim, Chiesi Farmaceutici,GlaxoSmithKline, and Novartis, and has been aconsultant to ABC Farmaceutici and ChiesiFarmaceutici. Her department was funded byNovartis. Nicola A. Hanania has served as aconsultant to Boehringer Ingelheim GmbH,Sunovion Pharmaceuticals Inc., Novartis AG,Mylan Inc., Pearl Therapeutics Inc., and PfizerInc.. His institution received grant support onhis behalf from GlaxoSmithKline plc, Boehrin-ger Ingelheim GmbH, Pfizer Inc., Pearl Thera-peutics Inc., and Sunovion Pharmaceuticals Inc.Mario Cazzola has participated as a facultymember and advisor in scientific meetings andcourses under the sponsorship of Almirall,AstraZeneca, Biofutura, Boehringer Ingelheim,Chiesi Farmaceutici, GlaxoSmithKline, Menar-ini Group, Lallemand, Mundipharma, Novartis,Pfizer, Recipharm, Verona Pharma, and Zam-bon, and is or has been a consultant to ABCFarmaceutici, AstraZeneca, Chiesi Farmaceutici,Recipharm, Lallemand, Novartis, Ockham Bio-tech, Verona Pharma, and Zambon. Hisdepartment was funded by Almirall, BoehringerIngelheim, Novartis, and Zambon. LuiginoCalzetta has participated as an advisor in sci-entific meetings under the sponsorship ofBoehringer Ingelheim and Novartis, receivednon-financial support from AstraZeneca, aresearch grant partially funded by Chiesi

Farmaceutici, Boehringer Ingelheim, Novartis,and Almirall, and is or has been a consultant toABC Farmaceutici, Recipharm, Zambon, VeronaPharma, and Ockham Biotech. His departmentwas funded by Almirall, Boehringer Ingelheim,Chiesi Farmaceutici, Novartis, and Zambon.

Compliance with Ethics Guidelines. Thisarticle is based on reviews of current guidelinesand literature and did not involve any studieswith human participants or animals.

Open Access. This article is distributedunder the terms of the Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any non-commercial use, distribution, and reproductionin any medium, provided you give appropriatecredit to the original author(s) and the source,provide a link to the Creative Commons license,and indicate if changes were made.

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