Journal Pre-proof

An Update on Monoclonal Antibody Therapy to Treat

Moderate-to-Severe Asthma: Benefits, Choices, and Limitations

Matthew R. Elliott MD , Charles E. Grogan MD ,

Gailen D. Marshall MDPhD

PII: S0002-9343(23)00327-3
DOI: https://doi.org/10.1016/j.amjmed.2023.05.001
Reference: AJM 17167

To appear in: The American Journal of Medicine

Received date: 9 March 2023

Accepted date: 15 May 2023

Please cite this article as: Matthew R. Elliott MD , Charles E. Grogan MD ,

Gailen D. Marshall MDPhD , An Update on Monoclonal Antibody Therapy to Treat Moderate-to-
Severe Asthma: Benefits, Choices, and Limitations, The American Journal of Medicine (2023), doi:
https://doi.org/10.1016/j.amjmed.2023.05.001

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition
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© 2023 Published by Elsevier Inc.

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 1

Review

An Update on Monoclonal Antibody Therapy to Treat Moderate-to-Severe Asthma: Benefits, Choices,

and Limitations

Matthew R. Elliott, MD1, Charles E. Grogan, MD1, Gailen D. Marshall, MD, PhD

1
Co-first authors

All authors have had access to the data and a role in writing this manuscript

University of Mississippi Medical Center

2500 North State Street
Jackson, MS 39216-4505
601-815-5527

Funding: None Descargado para Baltazar Ottonello (baltazar.ottonello@hospitalitaliano.org.ar) en I

2023. Para uso personal exclusivamente. No se permiten otros usos sin autoriz

Access: all authors had access to the data and a role in writing the manuscript.

Declarations of Interest: None

Corresponding Author:

Gailen D. Marshall, Jr., MD PhD2

Division of Allergy, Asthma and Clinical Immunology
The University of Mississippi Medical Center
2500 North State Street
Jackson, MS 39216-4505
601-815-5527
gmarshall@umc.edu

Key Words: asthma, monoclonal antibody, biologics, treatment

Clinical Significance

 Asthma is a heterogeneous airway disease of variable severity with the fundamental

pathophysiology of inflammation and (usually) reversible bronchospasm
 2

 Therapy for more severe disease has focused on controlling inflammation typically by using
inhaled and/or systemic corticosteroids

 Development of monoclonal antibodies (“biologics”) offers new therapeutic options to control

disease and minimize need for long term corticosteroid therapy

 Reliable matching of specific biologic to individual patients is not yet fully established.

Abstract

Moderate or severe asthma is a complex disease process clinically manifesting as at least partially

reversible airway obstruction due to airway hyperresponsiveness. Asthma therapy was based primarily

on symptom control until recent studies of its mechanisms have led to a host of new targeted, safe, and
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effective therapies. These biologic therapies directly attack culprit inflammatory mediators at the

molecular level. In this article we review currently available biologic agents for the treatment of

moderate-to-severe asthma. We provide information deemed necessary to optimally consult with an

asthma specialist to choose, assist in financial arrangements for, and coordinate the use of these new,

promising, FDA approved biologic agents. We will also briefly review the molecular pathways targeted

with each class of biologic to provide a more in-depth understanding of why these targeted therapies

are effective. These biologics are the first of many to come that modify newly discovered components of

the immune system with which many physicians are unfamiliar.

 3

Introduction

Moderate-to-severe asthma (defined as asthma that requires treatment with high dose inhaled

corticosteroids plus a second controller to prevent it from becoming uncontrolled)1 is a complex disease

process clinically manifesting as at least partially reversible airway obstruction due to airway

hyperresponsiveness as well as mucous plugging of the airways. This results in bronchoconstriction and

underlying chronic airway obstruction from inflammation mediated by numerous cytokines and immune

cells (Figure 1). Although the pathophysiology of asthma has been appreciated for decades, the

therapeutic approach has been the use of increasingly selective bronchodilators (such as albuterol) and

anti-inflammatory agents that are mostly corticosteroid-based, given either systemically or by

inhalation. Likewise, severity of asthma has been categorized based upon the severity and frequency of

symptoms as well as the medication necessary to control symptoms2. Descargado para Baltazar Ottonello (baltazar.ottonello@hospitalitaliano.org.ar) en I
2023. Para uso personal exclusivamente. No se permiten otros usos sin autoriz

Previous treatment regimens based on symptom control have been replaced by a more focused

approach. Virtually all asthma has an inflammatory basis central to its pathophysiology (Figure 1). With

the availability of new biologic therapies, an understanding of how and where biologic therapies act to

inhibit airway inflammation has changed the treatment approach to one less focused on measurements

of symptom control.

Original clinical trials with biologics and asthma were based on the severity of symptoms with no

connection to biologic markers of inflammation in a particular patient. Thus, these studies failed to show

consistent clinical effects. Today, identification of relevant inflammatory mechanisms allow clinicians

the ability to provide targeted, personalized biologic therapies in patients with moderate-to-severe

asthma who are not adequately controlled with inhaled corticosteroids (ICS) and long-acting beta-

agonists (LABA) alone.

 4

In this article, we provide information deemed necessary to optimally consult with an asthma specialist

to choose, assist in financial arrangements for, and coordinate the use of these new, promising FDA

approved biologic agents for moderate-to-severe asthma.

Anti-IgE

Omalizumab (Xolair©) is a recombinant humanized monoclonal antibody designed to bind

immunoglobulin E (IgE) in order to prevent its binding to mast cells via the high affinity Fc receptor for

IgE (FcRI). IgE’s role in asthma and other allergic diseases such as allergic rhinitis, atopic dermatitis, and

food allergy has been well characerized.3 Allergens that interact with specific mast cell bound IgE

molecules bind and cross link these IgE molecules, leading to mast cell degranulation.4 Up to 50% of
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5,6
adults and as many as 90% of children with asthma have identifiable allergic triggers.

Omalizumab was the first biologic approved for use in asthma and is currently approved for patients

aged 6 and older with moderate-to-severe asthma inadequately controlled with ICS.7,8 Several studies

have evaluated the efficacy and safety of omalizumab use in patients with asthma, with the initial phase

3 trials being published in 2001. One study evaluated the use of omalizumab in adolescents and adults

aged 12 to 75 with severe asthma. Significantly fewer subjects in the omalizumab group (14.6%)

experienced asthma exacerbations compared to the placebo group (23.3%). In addition, the omalizumab

group had a significantly greater reduction in ICS dose and rescue inhaler use compared to placebo. 9

Another similar study evaluated the steroid reducing effects of omalizumab in adolescents and adults

aged 12 to 76 with moderate-to-severe asthma and had comparable results, showing greater reduction

of ICS doses in the treatment group compared to placebo along with significantly fewer exacerbations.10

The initial phase 3 study in children also demonstrated efficacy.11 A Cochrane Review of omalizumab use

in moderate-to-severe asthma reported in 2014 included 25 clinical trials. It found that exacerbation
 5

rates were reduced from 26% with placebo compared to 16% with omalizumab over 16 to 60 weeks.

The risk of hospitalization was reduced from 3% with placebo to 0.5% with omalizumab over 28 to 60

weeks. Those with omalizumab treatment were also significantly more likely to reduce or withdraw their

ICS dose than those with placebo, but there was no significant difference in regards to oral

corticosteroid withdrawal. Reduced rescue medication usage was also observed with omalizumab when

compared to placebo.12 In clinical practice omalizumab may not be the first choice for adult patients

given the need for demonstrated aeroallergen sensitivity and a total IgE level between 30 IU/mL and

700 IU/mL in patients aged 12 and older.

Anti-IL-5

Eosinophil activation in the airway walls contributes to bronchoconstriction, increased airway mucus
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long-term airway remodeling.

Thus, eosinophils have long been considered a potential therapeutic target in asthma management.

While there are many surface receptors that are responsible for eosinophil survival, chemotaxis, and

proliferation, interleukin-5 receptor subunit-α (IL-5Rα) is perhaps the best studied. Studies suggest that

interleukin-5 (IL-5) plays a pivotal role in promoting the expansion of the eosinophil lineage as well as

promoting activation, recruitment, and survival13. Eosinophil progenitors in the lungs give rise to mature

eosinophils via processes dependent on IL-514.

At the time of writing, there are currently no head-to-head trials comparing effectiveness of the

different IL-5 biologics. Selection of an IL-5 biologic for the treatment of moderate-to-severe

eosinophilic asthma is usually based upon the practical benefits and limitations of the medications

discussed above (frequency of dosing, route of administration, etc).

Mepolizumab (Nucala©) was the first of the currently used anti-IL-5 biologics to be approved for use as

add-on maintenance therapy for patients with moderate-to-severe asthma. It is a humanized IgG1
 6

monoclonal antibody currently approved for moderate-to-severe asthma in patients ages 6 and up who

have a peripheral eosinophil count ≥150 cells/µL. Across multiple phase 3 trials (SIRIUS15, MUSCA16, and

MENSA17), mepolizumab was found to mediate improvement in patient exacerbation rates, oral

corticosteroid use, lung function, and patient symptom scores compared to placebo. Mepolizumab is the

only anti-IL-5 biologic currently approved for the treatment of eosinophilic granulomatosis with

polyangiitis (EGPA).

In the SIRIUS study, reduction in daily oral glucocorticoid dose was measured in patients with moderate-

to-severe asthma dependent on daily systemic corticosteroid use. Compared to placebo, more patients

in the treatment group had 90-100% reduction of maintenance corticosteroid use (23% vs 11%). In the

MUSCA study, patients with moderate-to-severe asthma treated with mepolizumab were found to have

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clinically significant improvements in symptom scores (defined by
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Questionnaire) as well as FEV1.

The MENSA study examined patients with moderate-to-severe asthma complicated by recurrent

exacerbations were given mepolizumab as add-on maintenance treatment. Compared to placebo,

patients treated with mepolizumab had a reduction in exacerbations by approximately half. Patients

given mepolizumab also had an over 100ml increase in the pre-bronchodilator FEV1.

Benralizumab (Fasenra©) is also a humanized monoclonal antibody that is given subcutaneously. One

characteristic that separates benralizumab from other IL-5-specific monoclonal antibodies is the

targeting of the alpha subunit of the IL-5 receptor rather than the entire cytokine. Due to this unique

mechanism, luminal depletion of eosinophils due to antibody dependent cellular cytotoxicity can

occur18. It is unclear whether this mechanism provides different clinical benefit as compared against

other anti-IL-5 biologics. In 2017, benralizumab was approved by the FDA as an add-on maintenance

treatment for moderate-to-severe asthma in patients 12 years and older who have a peripheral
 7

eosinophil count ≥150 cells/µL. Approval was based on the results of the WINDWARD program, which

consisted of 6 phase 3 studies designed to assess the efficacy and safety of benralizumab compared to

placebo in the treatment of moderate-to-severe asthma19. Three studies in particular were cited during

the approval process; the ZONDA, SIROCCO, and CALIMA studies.

The CALIMA and SIROCCO studies examined the addition of benralizumab as add on therapy in patients

with moderate-to-severe persistent asthma. The trials were 56 and 48 weeks long, respectively, and

resulted in significant reductions in exacerbation (36% and 51% reduction, respectively) compared to

placebo. Both trials also demonstrated improvement in FEV1 as well as patient symptoms scores20,21. The

ZONDA trial examined patients with moderate-to-severe asthma reliant on chronic oral glucocorticoid

therapy. Those given benralizumab had a significantly reduced need for oral glucocorticoids, and

approximately half of those given benralizumab were able to Descargado

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completely. While lower rates of asthma exacerbation and exacerbation-related hospital visits were also

decreased, FEV1 did not significantly improve compared to placebo.

Reslizumab (Cinqair©) is another monoclonal antibody directed against IL-5, currently approved for use

in patients ≥18 years with a peripheral eosinophil count ≥400 cells/µL. Across multiple phase three

trials22,23, reslizumab was found to improve FEV1, asthma control, and quality of life in patients with

elevated blood eosinophil levels with a safety profile comparable to mepolizumab. Reslizumab is also

unique among IL-5 biologics in that it has weight-based dosing.

TARGETING IL-4 and IL-13

Dupilumab (Dupixent©) is a fully human monoclonal antibody that is directed against the IL-4Rα

subunit of the IL-4 and IL-13 receptors, effectively blocking the immune effects of IL-4 and IL-13. These

cytokines have been found to be strongly associated with type 2 inflammation and asthma

pathogenesis. While these cytokines can be produced by a variety of cells, they are primarily produced
 8

by CD4+ T-helper 2 cells. Despite sharing a receptor subunit, both have overlapping as well as distinct

functions. While both cytokines can induce B cells to isotype switch to IgE production, IL-4 serves to

promote Th2 cell differentiation and corresponding cytokine production. IL-13 promotes increased

mucus production, airway hyperreactivity and subepithelial fibrosis, which are common pathologic

findings in asthma. Production of both IL-4 and IL-13 has been found to be increased in asthma.24

Dupilumab was initially approved for use in adolescents and adults with asthma in October 2018 and

also has approval for use in other diseases, including atopic dermatitis, chronic rhinosinusitis with nasal

polyposis and eosinophilic esophagitis. Currently it is approved as add-on maintenance treatment for

patients aged 6 years and older with moderate-to-severe asthma with either the eosinophilic phenotype

or dependence on oral corticosteroids.25 There have been multiple studies evaluating the safety and

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efficacy of dupilumab use in asthma. The early phase 2a trial evaluated theParause
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patients aged 18-65 with moderate-to-severe asthma with elevated eosinophil levels who were

uncontrolled on medium-to-high dose ICS-LABA therapy. The treatment group had an exacerbation rate

of 6% compared to a 44% in the placebo group, showing an 87% reduction in exacerbation rates with

dupilumab when compared to placebo. Improvements in lung function and asthma control were also

seen.26 The phase 2b dose ranging trial evaluated the use of dupilumab in a similar patient population

regardless of peripheral eosinophil count and resulted in reduced exacerbation rates, improved lung

function and asthma control regardless of baseline peripheral eosinophil count.27

The larger phase 3 QUEST trial looked at the efficacy and safety of dupilumab in patients age 12 years

and older with uncontrolled moderate-to-severe asthma. It demonstrated a 47.7% lower rate of asthma

exacerbations compared to placebo in addition to significantly improving FEV1 and asthma control.

Patients with higher baseline eosinophils (≥300 cells/µl) showed greater improvement with 65.8%

reduction in rate of asthma exacerbations compared to placebo.28 The VENTURE phase 3 study

evaluated use of dupilumab in patients age 12 and older who were dependent on oral corticosteroids
 9

for their asthma. A statistically significant number of patients in the treatment group were able to either

reduce the dose of the oral corticosteroid or discontinue it completely: the dupilumab group had a

70.1% reduction in their glucocorticoid dose compared to 41.9% reduction in the placebo group. In

addition, the treatment group demonstrated a decreased rate of asthma exacerbations and improved

FEV1 compared to placebo despite reductions in oral corticosteroids.29 Finally, the TRAVERSE trial was an

open label extension study with patients aged 12-84 with moderate-to-severe asthma or corticosteroid

dependent asthma who participated in previous dupilumab studies. This study found that the efficacy

and safety was sustained when treatment with dupilumab was extended to 148 weeks.30 In summary,

these studies showed that dupilumab compared to placebo reduces the rate of exacerbations, improves

FEV1, improves asthma control and decreases the use of oral corticosteroids in oral corticosteroid-

dependent asthma. Descargado para Baltazar Ottonello (baltazar.ottonello@hospitalitaliano.org.ar) en I

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TARGETING A NEW CLASS OF PROIMFLAMMATORY MOLECULES - ALARMINS: Anti-TLSP

Tezepelumab (Tezspire©) is a human monoclonal antibody directed against thymic stromal

lymphopoietin (TSLP), a cytokine that is implicated in the development of atopic disease and, along with

IL-25 and IL-33, often classified as an alarmin. Alarmins are a family of cytokines produced by dead or

damaged cells to promote an inflammatory response. Thymic stromal lymphopoietin is primarily

produced by epithelial and stromal cells in the lungs, skin and gastrointestinal tract. It is produced in

response to a variety of triggers, including viruses, helminth infections, allergens, ligands for toll-like

receptors, pro-inflammatory cytokines and physical injury. Thymic stromal lymphopoietin has been

shown to promote type 2 inflammation through the activation of dendritic cells which then leads to the

differentiation of CD4+ T cells into T-helper 2 cells that produce IL-4, IL-5 and IL-13. It can also promote

the differentiation of T follicular helper cells which then induce IgG and IgE secretion by B cells. Thymic

stromal lymphopoietin has been found to be elevated in the airways of patients with moderate-to-
 10

severe asthma along with other type 2 cytokines. These levels have been found to correlate with asthma

severity.31

Tezepelumab received FDA approval in December 2021 as add-on maintenance therapy in adult and

adolescent patients 12 years and older with severe asthma that is uncontrolled on current therapy. 32

The PATHWAY trial was a phase 2, randomized, double-blind, placebo-controlled study that included

patients ages 18-75 with uncontrolled asthma despite the use of medium to high dose ICS in

combination with a LABA. This trial compared three different doses of tezepelumab to placebo and it

was found to decrease exacerbation rates by 62%, 71% and 66% in the low, medium and high dose

groups, respectively, when compared with placebo. These results were found to be independent of

eosinophil counts. Prebronchodilator FEV1 was also increased by 120ml in each treatment group

compared to placebo.33 The phase 3 NAVIGATOR trial showed similarDescargado

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including reduced asthma exacerbations, improved lung function, improved asthma control and

improved health related quality of life in the tezepelumab group when compared to placebo.34 The

SOURCE trial investigated the corticosteroid sparing effect of tezepelumab in patients with oral

corticosteroid-dependent asthma. The dose reduction of oral corticosteroids was not significantly

different in the tezepelumab vs placebo groups, though patients with a peripheral eosinophil count of at

least 150 cells/µl had a greater probability to decrease the oral steroid dose.35

SUMMARY

The first consideration in the use of these new asthma therapies is “How do I choose the best agent for

my patients?”. All of the biologics discussed are presently FDA approved only for those patients whose

asthma is not responsive to conventional asthma treatment including high dose inhaled

corticosteroids/beta-agonists. There is not yet a clearly defined algorithm to determine which biologic to

select for specific individual patients as there are limited incentives for pharmaceutical companies to
 11

perform head to head comparisons. More often, the choice is made on the basis of patient and

physician joint decision making on route, frequency of administration, cost, and availability. There are

currently no studies that support the use of dual/multiple biologic therapy for patients with poor

response to initial biologic therapy.

As of this writing, the biologics discussed above are considered add-on maintenance treatment as

controllers. As biologic therapy and our understanding of the inflammatory pathways in asthma

continues to improve, the identification of biologics with the ability to control asthma without other

therapies is a possibility.

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The authors have no declarations of interest to disclose.

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Agent Omalizumab Mepolizumab Benralizumab Reslizumab Dupilumab Tezepelumab

Trade name Xolair Nucala Fasenra Cinqair Dupixent Tezspire
Target IgE IL-5 IL-5Rα IL-5 IL-4Rα TSLP
Indication Moderate-to- Moderate-to- Moderate-to- Moderate-to- Moderate-to- Severe asthma
severe asthma severe asthma severe asthma severe asthma severe asthma inadequately
inadequately inadequately inadequately inadequately characterized by controlled on ICS.
controlled on ICS. controlled on ICS controlled on ICS controlled on ICS eosinophilic
Must who have a who have a who have a phenotype or
demonstrate peripheral peripheral peripheral with oral
aeroallergen eosinophil count eosinophil count eosinophil count corticosteroid
sensitivity and ≥150 cells/µL. ≥150 cells/µL. ≥400 cells/µL. dependent
total IgE between asthma.
30-1300 IU/mL.
Route SQ SQ SQ IV SQ SQ
Ages approved ≥6 years old ≥ 6 years old ≥ 12 years old ≥ 18 years old ≥ 6 years old ≥ 12 years old
for asthma
Adult Dose 75-375mg every 100 mg 30 mg every 4 3 mg/kg once 600 mg loading 210 mg every
2-4 weeks. administered weeks for the every 4 week. dose followed by four weeks.
Dosing based on once every 4 first 3 doses, 300 mg given
age, total IgE, weeks. followed by once every 2 weeks.
and weight. every 8 weeks
thereafter.
Adverse Injection site Injection site Injection site Injection site Injection site Pharyngitis,
reactions reactions. Less reactions. reactions. reactions. reactions. arthralgia, back
common: Hypersensitivity Most common Hypersensitivity Oropharyngeal pain.
arthralgia, pain, reactions rare. adverse event reactions rare. pain, peripheral
dizziness, Herpes zoster reported is eosinophilia.
pruritus, infections have nasopharyngitis.
dermatitis. occurred in Hypersensitivity
 15

Boxed warning: patients reactions rare.

Anaphylaxis in receiving
0.1-0.2% of Mepolizumab.
patients.
Table 1: Biologic agents indicated for asthma. IgE: Immunoglobulin E; IL-5: Interleukin 5; IL-5Rα: Interleukin 5 receptor alpha; IL-
4Rα: Interleukin 4 receptor alpha; TSLP: thymic stromal lymphopoietin; ICS: inhaled corticosteroid; SQ: subcutaneous; IV:
intravenous.

Medication Trade Name Estimated Yearly Cost

Omalizumab Xolair $39,000
Mepolizumab Nucala $37,300
Benralizumab Fasenra $30,900
Reslizumab Cinqair $31,600
Dupilumab Dupixent $38,100
Table 2: Cost of inhaler therapy and biologic agents. Estimated yearly cost from 2018 excludes loading doses as well as
administration costs69.

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Figure 1

Figure 1

Both innate and adaptive immune responses are generated against allergens, irritants, or viruses that
penetrate the epithelial barrier. These antigens are taken up by immature dendritic cells, which interact
with naive CD4+ T cells (Th0 cells). This causes differentiation into Th2 cells, which produce interleukin
(IL)-4, 5, and 13. These interleukins are also produced by type 2 innate lymphoid cells (ILC2), which are in
 16

turn activated and upregulated by IL-25, IL-33, and thymic stromal lymphopoietin (TLSP). These
cytokines are involved in a variety of functions: B-cell class switching, IgE production, inflammatory cell
trafficking, and eosinophil activation. Changes in the airway include bronchial enlargement, basement
membrane thickening, and smooth muscle contractility.

Adaptive: antigen-specific immune response; CCL: chemokine ligand; CXCL: chemokine (C-X-C motif)
ligand; ECP: eosinophil cationic protein; FeNO: fraction of exhaled nitric oxide; iDC: interstitial dendritic
cell; innate: non-antigen -specific immune responses, TARC: thymus and activation-regulated
chemokine.

Reproduced with permission of the ERS 2023. European Respiratory Journal 58 (2) 2003393; DOI:
10.1183/13993003.03393-2020 Published 5 August 2021

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